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with the most common among Europeans being c&#46;1537C&#62;T&#58;R501X and 2282del4&#58;S761Cfs&#42;36 and&#44; in sub-Saharan Africans&#44; c&#46;9947C&#62;G&#58;S3316&#42;&#46; Few studies have been carried out on Latin-American patients with AD&#46; The objective of the present study was to assess the frequency of <span class="elsevierStyleItalic">FLG</span> variants &#40;in exon-3&#41; in AD patients to compare Brazilian and international populations and explore their clinical characteristics&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">A cross-sectional study was carried out at the Dermatology Outpatient Clinic &#40;FMABC&#59; Santo Andr&#233;&#44; S&#227;o Paulo&#41;&#46; Eighty patients with AD &#40;Hanifin and Rajka&#8217;s criteria&#41; of both sexes were included and examined by an experienced dermatologist to assess disease severity &#40;SCORAD&#44; EASI&#41; and to collect venous blood samples for laboratory analysis and oral mucosa for genetic analysis&#46; 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&#40;Applied Biosystems&#44; Foster City&#44; CA&#41;&#44; &#40;Hs00274028 forward&#58; 5&#39;CTA ACA CTG GAT CCC TGG TTC CTA 3&#39; and reverse 5&#39; CTG AGA CAG CAG AGC CAC CAA GA 3&#39; and Hs00395823&#44; forward&#58; 5&#39; CAG ACC TAT CTA CCG ATT GCT CGT 3&#39; and reverse&#58; 5&#39; AAA TCA GGC ACTCGT CAC ACA CAG AA 3&#39;&#41;&#46; This strategy allowed the investigation of other variants in areas neighboring the target loci&#44; but it did not cover the entire exon-3 coding region &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The PCR products were purified with DNA beads &#40;Agencourt &#8210; AMPure XP-Beckman Coulter&#44; Brea&#44; CA&#41;&#46; The purified samples&#44; together with 10<span class="elsevierStyleHsp" style=""></span>&#956;L of these primers&#44; were used for the sequencing reaction&#46; The sequencing cycle was performed with the Big Dye Terminator v3&#46;1 kit &#40;Thermo Fisher Scientific&#41;&#46; The sequencing products were submitted to capillary electrophoresis on the ABI 3500 DNA Analyzer &#40;Applied Biosystems&#44; Foster City&#44; CA&#41;&#46; The sequencing data were evaluated with Seq A &#40;14&#41; software &#40;Applied Biosystems&#44; Foster City&#44; CA&#41;&#46; PROVEAN &#40;Protein Variation Effect Analyzer&#41; v1&#46;1 was used to predict whether a protein sequence variation caused by a missense substitution would affect protein function &#40;available at <a href="https://provean.jcvi.org/index.php">https&#58;&#47;&#47;provean&#46;jcvi&#46;org&#47;index&#46;php</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">The prevalence of each identified variant was compared to the Brazilian public database of genomic variants &#40;ABraOm&#59; hg38 &#8211; <a href="https://abraom.ib.usp.br/">https&#58;&#47;&#47;abraom&#46;ib&#46;usp&#46;br&#47;</a>&#41; with 1&#44;171 samples from the population of the same region and an international database &#40;gnomAD&#59; v3&#46;1&#46;2 &#8211; <a href="https://gnomad.broadinstitute.org/">https&#58;&#47;&#47;gnomad&#46;broadinstitute&#46;org&#47;</a>&#41; with 76&#44;156 unrelated individuals of different ethnicities&#46; The statistical significance was set at p<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The main demographic data&#44; clinical severity&#44; eosinophilia&#44; and IgE levels are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Most patients had moderate and severe AD &#40;79&#37;&#41;&#44; elevated IgE levels &#40;98&#37;&#41;&#44; and eosinophilia &#40;68&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">The results of the genetic analysis of the AD sample and the comparison with the two population controls are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; Twenty-six <span class="elsevierStyleItalic">FLG</span> exon-3 genetic variants were detected in 60 patients &#40;75&#37;&#59; 95&#37; CI 65&#37;&#8210;85&#37;&#41;&#46; Homozygosity and compound heterozygosity were not identified&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">FLG</span> variants with filaggrin loss-of-function were observed in eight AD patients &#40;10&#37;&#59; 95&#37;CI 3&#37;&#8211;17&#37;&#41;&#46; Two variants prevalent in the world &#40;c&#46;1537C&#62;T&#58;R501X and 2282delCAGT&#58;S761Cfs&#42;36&#41; were observed in six &#40;7&#46;5&#37;&#41; patients&#46; Another pathogenic variant &#40;c&#46;2512C&#62;T&#58;R826X&#41; was identified in two &#40;2&#46;5&#37;&#41; patients&#46; These three pathogenic variants were more prevalent in the AD sample than in the Brazilian controls &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; The 2282delCAGT&#58;S761Cfs&#42;36 variant is common among Europeans&#44; while c&#46;2512C&#62;T&#58;R826X is common among African-Americans&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Eight synonymous variants were found in the <span class="elsevierStyleItalic">FLG</span> gene&#44; four of them widely distributed in Brazil and worldwide&#46; However&#44; four of them &#40;c&#46;1665T&#62;G&#58;rs152285733&#44; c&#46;1737A&#62;C&#58; synonymous&#44; c&#46;1521G&#62;A&#58; synonymous&#44; and c&#46;1800T&#62;C&#58; synonymous&#41; were observed to be more common in the AD sample than in the world &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; The variant c&#46;1476T&#62;C&#58; synonymous&#44; rare in the Brazilian and in the international population &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; is common among African-Americans&#46; The synonymous c&#46;2544T&#62;C&#44; considered common among AD patients and regional controls&#44; is extremely rare in the world &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Fourteen missense variants were detected&#44; with two of them &#40;c&#46;1712A&#62;G&#58;H559R&#44; c&#46;1777A&#62;T&#58;T581S&#41; being more common among AD patients than in regional and international controls &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">No <span class="elsevierStyleItalic">FLG</span> variant was associated with AD clinical severity&#44; eosinophilia&#44; or elevated serum IgE levels &#40;p<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;1&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">These results reinforce the high polymorphism of exon-3 in <span class="elsevierStyleItalic">FLG</span> and its ethnic association&#44; making it difficult to generalize genomic results in relation to AD phenotypes&#44; especially in highly mixed populations&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;7&#44;8</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">According to the literature&#44; null variants were expected in 14&#37; to 42&#37; of AD patients&#44; and&#44; of these&#44; 20 were found in exon-3&#46; In addition&#44; variations in <span class="elsevierStyleItalic">FLG</span> have been reported among AD patients of different ethnicities&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The Brazilian population has a multiracial composition&#44; after 500 years of miscegenation amongst individuals from Western Europe&#44; Africa&#44; and the Amerindian populations&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> The c&#46;2512C&#62;T&#58;R826X and 2282delCAGT&#58;S761Cfs&#42;36 variants in AD patients corroborate these ancestries&#44; meanwhile the c&#46;2544T&#62;C&#58; synonymous variant is characteristic of this region&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Considering the epidemiological association with disease development&#44; isolated variants in <span class="elsevierStyleItalic">FLG</span> gene do not fully explain the variation in AD severity&#44; eosinophilia&#44; or elevated IgE levels&#44; reinforcing the multifactorial aspects of the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;8&#44;10</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In conclusion&#44; we authors identified null variants of the <span class="elsevierStyleItalic">FLG</span> gene &#40;in exon-3&#41; &#40;c&#46;1537C&#62;T&#58;501X&#44; c&#46;2282del4&#58;S761Cfs&#42;36 and c&#46;2512C&#62;T&#58;R826X&#41; in 10&#37; of Brazilian patients with AD&#44; but without an association with the main clinical characteristics of AD&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Financial support</span><p id="par0100" class="elsevierStylePara elsevierViewall">Fundo de Apoio &#224; Dermatologia do Estado de S&#227;o Paulo &#8210; Sebasti&#227;o Sampaio &#40;FUNADERSP&#41;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Authors&#8217; contributions</span><p id="par0105" class="elsevierStylePara elsevierViewall">Cristina Marta Maria Laczynski&#58; Design and planning of the study&#44; collection&#44; analysis and interpretation of data&#59; approved the final version of the manuscript&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Carlos D&#8217;Apparecida Santos Machado Filho&#58; Critical review of the intellectual content&#59; approved the final version of the manuscript&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">H&#233;lio Amante Miot&#58; Critical review of the intellectual content&#59; approved the final version of the manuscript&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Denise Maria Christofolini&#58; Critical review of the intellectual content&#59; approved the final version of the manuscript&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Itatiana Ferreira Rodart&#58; Processing of genetic material&#44; analysis and interpretation of data and review of the intellectual content&#59; approved the final version of the manuscript&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Paulo Ricardo Coelho&#58; Critical review of the intellectual content&#59; approved the final version of the manuscript&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflicts of interest</span><p id="par0135" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Schematic picture of the <span class="elsevierStyleItalic">FLG</span> gene including the distribution of exons&#44; size of exons&#44; introns&#44; indication of profilaggrin coding region&#44; position of primers and electropherograms of the three most frequent pathogenic variants found in the present sample&#46;</p>"
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">AD&#44; Atopic dermatitis&#59; IgE&#44; Serum immunoglobulin E&#59; SD&#44; Standard deviation&#59; SCORAD&#44; Scoring Atopic Dermatitis&#59; EASI&#44; Eczema Area Severity Index&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variables</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Values&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">Sex&#44; n &#40;&#37;&#41;</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age &#40;years&#41;&#44; mean &#40;SD&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16 &#40;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="3" align="left" valign="middle">Phototype&#44; n &#40;&#37;&#41;</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">I&#8210;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 &#40;30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">III&#8210;IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51 &#40;64&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">V&#8210;VI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="3" align="left" valign="middle">Ethnicity&#44; n &#40;&#37;&#41;</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Caucasian&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">54 &#40;68&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asian&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Afro-descendant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25 &#40;31&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="3" align="left" valign="middle">AD severity&#44; n &#40;&#37;&#41;</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mild&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45 &#40;56&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Severe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18 &#40;23&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SCORAD&#44; mean &#40;SD&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36 &#40;17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EASI&#44; mean &#40;SD&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#46;5 &#40;10&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">Elevated levels of IgE<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&#44; n &#40;&#37;&#41;</td><td class="td" title="\n
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                  """
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">dbSNP &#40;rs&#41;&#44; Reference SNP number in international databases &#40;chromosomal position&#41;&#59; HT&#44; Heterozygous&#59; HM&#44; Homozygous&#59; AD&#44; Atopic dermatitis&#59; NF&#44; Not found&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t">HT&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">38 &#40;47&#46;50&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">30&#46;25&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">20&#46;34&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">HT&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Synonymous&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">NF&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  """
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            0 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Mutation with loss of function &#40;pathogenic&#41;&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">FLG gene variants &#40;exon 3&#41; in 80 Brazilian patients with atopic dermatitis and their prevalence according to AbraOM population databases &#40;from the same Brazilian population&#41; and gnomAD &#40;from Latin&#44; African-American&#44; European and international populations&#41;&#46;</p>"
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                    0 => array:2 [
                      "titulo" => "The Role of Genetics&#44; the Environment&#44; and Epigenetics in Atopic Dermatitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Z&#46; Mu"
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                    0 => array:2 [
                      "doi" => "10.1007/978-981-15-3449-2_4"
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                        "tituloSerie" => "Adv Exp Med Biol"
                        "fecha" => "2020"
                        "volumen" => "1253"
                        "paginaInicial" => "107"
                        "paginaFinal" => "140"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32445093"
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                      "titulo" => "Skin barrier and immune dysregulation in atopic dermatitis&#58; an evolving story with important clinical implications"
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                          "etal" => false
                          "autores" => array:3 [
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Letter - Research
Prevalence of filaggrin gene polymorphisms (exon-3) in patients with atopic dermatitis in a multiracial Brazilian population
Cristina Marta Maria Laczynskia,
Corresponding author
crislacz@hotmail.com

Corresponding author.
, Carlos D’Apparecida Santos Machado Filhoa, Hélio Amante Miotb, Denise Maria Christofolinic, Itatiana Ferreira Rodartc, Paulo Ricardo Criadoa
a Discipline of Dermatology, Centro Universitário Faculdade de Medicina do ABC, Santo André, SP, Brazil
b Department of Dermatology, Faculty of Medicine, Universidade Estadual Paulista, Botucatu, SP, Brazil
c Department of Genetics, Centro Universitário FMABC, Santo André, SP, Brazil
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    "titulo" => "Prevalence of filaggrin gene polymorphisms &#40;exon-3&#41; in patients with atopic dermatitis in a multiracial Brazilian population"
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Atopic dermatitis &#40;AD&#41; is a chronic&#44; multifactorial disease whose clinical phenotype results from the interaction of genetic and environmental factors&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Immune dysregulation and skin barrier integrity determine its severity&#44; predisposing to infections and antigen permeability&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> It is a common reason for dermatological consultation&#44; especially in childhood &#40;&#60;12 years&#41; representing 25&#46;8&#37; of dermatological consultations&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The gene encoding filaggrin &#40;<span class="elsevierStyleItalic">FLG</span>&#41; is highly polymorphic and is located in the region of the epidermal differentiation complex &#40;1q21&#46;3&#41;&#44; encoding the most important proteins involved in skin barrier homeostasis&#46; <span class="elsevierStyleItalic">FLG</span> is the main genetic factor associated with AD and its exon-3 transcribes most of the profilaggrin protein&#46; Skin barrier alterations are present in AD patients without filaggrin changes&#59; however&#44; the presence of <span class="elsevierStyleItalic">FLG</span> variants leading to loss of function has been associated with clinical phenotypes such as persistent early-onset disease&#44; asthma&#44; and allergic sensitization&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4</span></a> Marked ethnic disparity has been observed in the frequency of <span class="elsevierStyleItalic">FLG</span> variants leading to loss of filaggrin function in AD&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">More than 60 variants in <span class="elsevierStyleItalic">FLG</span> leading to loss of filaggrin function have been identified in association with AD&#44; with the most common among Europeans being c&#46;1537C&#62;T&#58;R501X and 2282del4&#58;S761Cfs&#42;36 and&#44; in sub-Saharan Africans&#44; c&#46;9947C&#62;G&#58;S3316&#42;&#46; Few studies have been carried out on Latin-American patients with AD&#46; The objective of the present study was to assess the frequency of <span class="elsevierStyleItalic">FLG</span> variants &#40;in exon-3&#41; in AD patients to compare Brazilian and international populations and explore their clinical characteristics&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">A cross-sectional study was carried out at the Dermatology Outpatient Clinic &#40;FMABC&#59; Santo Andr&#233;&#44; S&#227;o Paulo&#41;&#46; Eighty patients with AD &#40;Hanifin and Rajka&#8217;s criteria&#41; of both sexes were included and examined by an experienced dermatologist to assess disease severity &#40;SCORAD&#44; EASI&#41; and to collect venous blood samples for laboratory analysis and oral mucosa for genetic analysis&#46; The participants&#47;guardians signed a free and informed consent form&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The specimen collected for genetic analysis was obtained by swabbing the patients&#8217; mucosa of the inner cheek and placing it in a sterile test tube &#40;Oragene Collector OG-500&#174;&#44; DNA Genotek Inc&#46;&#44; Kanata&#44; Ontario&#41;&#46; It was submitted to sequencing using the Sanger method&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">DNA extraction was performed using ethanol precipitation and a prepIT 2P reagent provided together with the Oragene kit&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Polymerase chain reaction &#40;PCR&#41; and its sequencing analysis were performed focusing on exon-3 to identify the most common genetic variants&#8211; c&#46;1537C&#62;T&#58;R501X &#40;rs61816761&#41; and c&#46;2282del4&#58;S761Cfs&#42;36 &#40;rs558269137&#41; using validated primers from Thermo Fischer Scientific&#174; &#40;Applied Biosystems&#44; Foster City&#44; CA&#41;&#44; &#40;Hs00274028 forward&#58; 5&#39;CTA ACA CTG GAT CCC TGG TTC CTA 3&#39; and reverse 5&#39; CTG AGA CAG CAG AGC CAC CAA GA 3&#39; and Hs00395823&#44; forward&#58; 5&#39; CAG ACC TAT CTA CCG ATT GCT CGT 3&#39; and reverse&#58; 5&#39; AAA TCA GGC ACTCGT CAC ACA CAG AA 3&#39;&#41;&#46; This strategy allowed the investigation of other variants in areas neighboring the target loci&#44; but it did not cover the entire exon-3 coding region &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The PCR products were purified with DNA beads &#40;Agencourt &#8210; AMPure XP-Beckman Coulter&#44; Brea&#44; CA&#41;&#46; The purified samples&#44; together with 10<span class="elsevierStyleHsp" style=""></span>&#956;L of these primers&#44; were used for the sequencing reaction&#46; The sequencing cycle was performed with the Big Dye Terminator v3&#46;1 kit &#40;Thermo Fisher Scientific&#41;&#46; The sequencing products were submitted to capillary electrophoresis on the ABI 3500 DNA Analyzer &#40;Applied Biosystems&#44; Foster City&#44; CA&#41;&#46; The sequencing data were evaluated with Seq A &#40;14&#41; software &#40;Applied Biosystems&#44; Foster City&#44; CA&#41;&#46; PROVEAN &#40;Protein Variation Effect Analyzer&#41; v1&#46;1 was used to predict whether a protein sequence variation caused by a missense substitution would affect protein function &#40;available at <a href="https://provean.jcvi.org/index.php">https&#58;&#47;&#47;provean&#46;jcvi&#46;org&#47;index&#46;php</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">The prevalence of each identified variant was compared to the Brazilian public database of genomic variants &#40;ABraOm&#59; hg38 &#8211; <a href="https://abraom.ib.usp.br/">https&#58;&#47;&#47;abraom&#46;ib&#46;usp&#46;br&#47;</a>&#41; with 1&#44;171 samples from the population of the same region and an international database &#40;gnomAD&#59; v3&#46;1&#46;2 &#8211; <a href="https://gnomad.broadinstitute.org/">https&#58;&#47;&#47;gnomad&#46;broadinstitute&#46;org&#47;</a>&#41; with 76&#44;156 unrelated individuals of different ethnicities&#46; The statistical significance was set at p<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The main demographic data&#44; clinical severity&#44; eosinophilia&#44; and IgE levels are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Most patients had moderate and severe AD &#40;79&#37;&#41;&#44; elevated IgE levels &#40;98&#37;&#41;&#44; and eosinophilia &#40;68&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">The results of the genetic analysis of the AD sample and the comparison with the two population controls are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; Twenty-six <span class="elsevierStyleItalic">FLG</span> exon-3 genetic variants were detected in 60 patients &#40;75&#37;&#59; 95&#37; CI 65&#37;&#8210;85&#37;&#41;&#46; Homozygosity and compound heterozygosity were not identified&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">FLG</span> variants with filaggrin loss-of-function were observed in eight AD patients &#40;10&#37;&#59; 95&#37;CI 3&#37;&#8211;17&#37;&#41;&#46; Two variants prevalent in the world &#40;c&#46;1537C&#62;T&#58;R501X and 2282delCAGT&#58;S761Cfs&#42;36&#41; were observed in six &#40;7&#46;5&#37;&#41; patients&#46; Another pathogenic variant &#40;c&#46;2512C&#62;T&#58;R826X&#41; was identified in two &#40;2&#46;5&#37;&#41; patients&#46; These three pathogenic variants were more prevalent in the AD sample than in the Brazilian controls &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; The 2282delCAGT&#58;S761Cfs&#42;36 variant is common among Europeans&#44; while c&#46;2512C&#62;T&#58;R826X is common among African-Americans&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Eight synonymous variants were found in the <span class="elsevierStyleItalic">FLG</span> gene&#44; four of them widely distributed in Brazil and worldwide&#46; However&#44; four of them &#40;c&#46;1665T&#62;G&#58;rs152285733&#44; c&#46;1737A&#62;C&#58; synonymous&#44; c&#46;1521G&#62;A&#58; synonymous&#44; and c&#46;1800T&#62;C&#58; synonymous&#41; were observed to be more common in the AD sample than in the world &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; The variant c&#46;1476T&#62;C&#58; synonymous&#44; rare in the Brazilian and in the international population &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; is common among African-Americans&#46; The synonymous c&#46;2544T&#62;C&#44; considered common among AD patients and regional controls&#44; is extremely rare in the world &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Fourteen missense variants were detected&#44; with two of them &#40;c&#46;1712A&#62;G&#58;H559R&#44; c&#46;1777A&#62;T&#58;T581S&#41; being more common among AD patients than in regional and international controls &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">No <span class="elsevierStyleItalic">FLG</span> variant was associated with AD clinical severity&#44; eosinophilia&#44; or elevated serum IgE levels &#40;p<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;1&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">These results reinforce the high polymorphism of exon-3 in <span class="elsevierStyleItalic">FLG</span> and its ethnic association&#44; making it difficult to generalize genomic results in relation to AD phenotypes&#44; especially in highly mixed populations&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;7&#44;8</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">According to the literature&#44; null variants were expected in 14&#37; to 42&#37; of AD patients&#44; and&#44; of these&#44; 20 were found in exon-3&#46; In addition&#44; variations in <span class="elsevierStyleItalic">FLG</span> have been reported among AD patients of different ethnicities&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The Brazilian population has a multiracial composition&#44; after 500 years of miscegenation amongst individuals from Western Europe&#44; Africa&#44; and the Amerindian populations&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> The c&#46;2512C&#62;T&#58;R826X and 2282delCAGT&#58;S761Cfs&#42;36 variants in AD patients corroborate these ancestries&#44; meanwhile the c&#46;2544T&#62;C&#58; synonymous variant is characteristic of this region&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Considering the epidemiological association with disease development&#44; isolated variants in <span class="elsevierStyleItalic">FLG</span> gene do not fully explain the variation in AD severity&#44; eosinophilia&#44; or elevated IgE levels&#44; reinforcing the multifactorial aspects of the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;8&#44;10</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In conclusion&#44; we authors identified null variants of the <span class="elsevierStyleItalic">FLG</span> gene &#40;in exon-3&#41; &#40;c&#46;1537C&#62;T&#58;501X&#44; c&#46;2282del4&#58;S761Cfs&#42;36 and c&#46;2512C&#62;T&#58;R826X&#41; in 10&#37; of Brazilian patients with AD&#44; but without an association with the main clinical characteristics of AD&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Financial support</span><p id="par0100" class="elsevierStylePara elsevierViewall">Fundo de Apoio &#224; Dermatologia do Estado de S&#227;o Paulo &#8210; Sebasti&#227;o Sampaio &#40;FUNADERSP&#41;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Authors&#8217; contributions</span><p id="par0105" class="elsevierStylePara elsevierViewall">Cristina Marta Maria Laczynski&#58; Design and planning of the study&#44; collection&#44; analysis and interpretation of data&#59; approved the final version of the manuscript&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Carlos D&#8217;Apparecida Santos Machado Filho&#58; Critical review of the intellectual content&#59; approved the final version of the manuscript&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">H&#233;lio Amante Miot&#58; Critical review of the intellectual content&#59; approved the final version of the manuscript&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Denise Maria Christofolini&#58; Critical review of the intellectual content&#59; approved the final version of the manuscript&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Itatiana Ferreira Rodart&#58; Processing of genetic material&#44; analysis and interpretation of data and review of the intellectual content&#59; approved the final version of the manuscript&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Paulo Ricardo Coelho&#58; Critical review of the intellectual content&#59; approved the final version of the manuscript&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflicts of interest</span><p id="par0135" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variables</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Values&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">Sex&#44; n &#40;&#37;&#41;</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age &#40;years&#41;&#44; mean &#40;SD&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16 &#40;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="3" align="left" valign="middle">Phototype&#44; n &#40;&#37;&#41;</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">I&#8210;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 &#40;30&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">III&#8210;IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51 &#40;64&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">V&#8210;VI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="3" align="left" valign="middle">Ethnicity&#44; n &#40;&#37;&#41;</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Caucasian&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">54 &#40;68&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Asian&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Afro-descendant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25 &#40;31&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="3" align="left" valign="middle">AD severity&#44; n &#40;&#37;&#41;</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mild&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45 &#40;56&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Severe&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18 &#40;23&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SCORAD&#44; mean &#40;SD&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">36 &#40;17&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EASI&#44; mean &#40;SD&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#46;5 &#40;10&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elevated levels of IgE<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&#44; n &#40;&#37;&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">79 &#40;98&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Eosinophils &#62; 5&#37;&#44; n &#40;&#37;&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46 &#40;68&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">According to the reference values for each age group&#58; 0&#8210;1 year&#58; up to 15&#46;0<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#59; 1&#8210;2 years&#58; 1&#46;0 to 19&#46;0<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#59; 2&#8210;3 years&#58; up to 32<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#59; 4&#8210;9 years&#58; up to 101&#46;0<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#59; over 15 years&#58; 1&#46;0 to 183&#46;0<span class="elsevierStyleHsp" style=""></span>IU&#47;mL&#59; Median&#58; 98&#46;44&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Main clinical&#44; demographic and laboratory characteristics of the Brazilian AD sample &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>80&#41;&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0145"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">dbSNP &#40;rs&#41;&#44; Reference SNP number in international databases &#40;chromosomal position&#41;&#59; HT&#44; Heterozygous&#59; HM&#44; Homozygous&#59; AD&#44; Atopic dermatitis&#59; NF&#44; Not found&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Variant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Zygosity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">dbSNP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Protein consequence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">AD&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">AbraOM &#40;Brazil&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">gnomAD</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Latin&#47; Mixed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">European&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">African-American&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">International&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">c&#46;1396A&#62;G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">rs2011331&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T454A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38 &#40;47&#46;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&#46;09&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">39&#46;36&#37;&nbsp;\t\t\t\t\t\t\n
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Article information
ISSN: 03650596
Original language: English
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