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perda de fun&#231;&#227;o do gene <span class="elsevierStyleItalic">FLG</span> associadas &#224; DA tem sido observada&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Mais de&#160;60&#160;variantes do gene <span class="elsevierStyleItalic">FLG</span> que levam &#224; perda de fun&#231;&#227;o do gene <span class="elsevierStyleItalic">FLG</span> foram identificadas em associa&#231;&#227;o com DA&#59; as mais comuns entre os europeus s&#227;o c&#46;1537C<span class="elsevierStyleHsp" style=""></span>&#62;T&#58;R501X e 2282del4&#58;S761Cfs&#42;36 e&#44; entre os africanos subsaarianos&#44; c&#46;9947C<span class="elsevierStyleHsp" style=""></span>&#62;G&#58;S3316&#42;&#46; Poucos estudos foram realizados em pacientes latino&#8208;americanos com DA&#46; Nosso objetivo foi avaliar a frequ&#234;ncia de variantes do gene <span class="elsevierStyleItalic">FLG</span> &#40;no &#233;xon&#8208;3&#41; entre pacientes com DA para comparar popula&#231;&#245;es brasileiras e internacionais e explorar suas caracter&#237;sticas cl&#237;nicas&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Foi realizado estudo transversal no ambulat&#243;rio de dermatologia &#40;FMABC&#59; Santo Andr&#233;&#44; S&#227;o Paulo&#41;&#46; Oitenta pacientes com DA &#40;crit&#233;rios de Hanifin e Rajka&#41; de ambos os sexos foram inclu&#237;dos e examinados por dermatologista experiente para avaliar a gravidade da doen&#231;a &#40;SCORAD&#44; EASI&#41; e coletar amostras de sangue venoso para an&#225;lise laboratorial e da mucosa oral para an&#225;lise gen&#233;tica&#46; Os participantes&#47;respons&#225;veis assinaram termo de consentimento livre e esclarecido&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">A coleta para an&#225;lise gen&#233;tica foi realizada por <span class="elsevierStyleItalic">swab</span> da mucosa da regi&#227;o bucinadora dos pacientes e colocado num tubo de ensaio est&#233;ril &#40;Oragene Collector OG&#8208;500&#174;&#44; DNA Genotek Inc&#46;&#44; Kanata&#44; Ontario&#41;&#44; que foi submetido ao sequenciamento pelo m&#233;todo de Sanger&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">A extra&#231;&#227;o de DNA foi realizada utilizando precipita&#231;&#227;o com etanol&#44; e um reagente prepIT 2P fornecido pelo kit Oragene&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">A rea&#231;&#227;o em cadeia da polimerase &#40;PCR&#41; e a an&#225;lise de seu sequenciamento foram realizadas com foco no &#233;xon&#8208;3 para identificar as variantes gen&#233;ticas mais comuns &#8211; c&#46;1537C<span class="elsevierStyleHsp" style=""></span>&#62;T&#58;R501X &#40;rs61816761&#41; e c&#46;2282del4&#58;S761Cfs&#42;36 &#40;rs558269137&#41; utilizando <span class="elsevierStyleItalic">primers</span> validados da Thermo Fischer Scientific&#174; &#40;Applied Biosystems&#44; Foster City&#44; CA&#41;&#44; &#40;Hs00274028 forward&#58; 5&#8217;CTA ACA CTG GAT CCC TGG TTC CTA 3&#8217; e reverse 5&#8217; CTG AGA CAG CAG AGC CAC CAA GA 3&#8217; e Hs00395823&#44; forward&#58; 5&#8217; CAG ACC TAT CTA CCG ATT GCT CGT 3&#8217; e reverse&#58; 5&#8217; AAA TCA GGC ACTCGT&#160;CAC ACA CAG AA 3&#8217;&#41;&#46; Essa estrat&#233;gia possibilitou investigar outras variantes em &#225;reas vizinhas ao <span class="elsevierStyleItalic">loci</span> alvo&#44; mas n&#227;o cobriu toda a regi&#227;o de codifica&#231;&#227;o do &#233;xon&#8208;3 &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46; Os produtos de PCR foram purificados com esferas de DNA &#40;Agencourt &#8211; AMPure XP&#8208;Beckman Coulter&#44; Brea&#44; CA&#41;&#46; As amostras purificadas juntamente com&#160;10&#160;&#956;L desses <span class="elsevierStyleItalic">primers</span> foram utilizadas para a rea&#231;&#227;o de sequenciamento&#46; O ciclo de sequenciamento foi realizado com o kit Big Dye Terminator v3&#46;1 &#40;<span class="elsevierStyleItalic">Thermo Fisher Scientific</span>&#41;&#46; Os produtos de sequenciamento foram submetidos &#224; eletroforese capilar no ABI 3500 DNA <span class="elsevierStyleItalic">Analyzer</span> &#40;Applied Biosystems&#44; Foster City&#44; CA&#41;&#46; Os dados de sequenciamento foram avaliados com o <span class="elsevierStyleItalic">software</span> Seq A&#40;14&#41; &#8211; Applied Biosystems&#44; Foster City&#44; CA&#46; O PROVEAN &#40;<span class="elsevierStyleItalic">Protein Variation Effect Analyzer</span>&#41; v1&#46;1 foi usado para prever se uma varia&#231;&#227;o de sequ&#234;ncia de prote&#237;na causada por uma substitui&#231;&#227;o <span class="elsevierStyleItalic">missense</span> afetaria a fun&#231;&#227;o da prote&#237;na &#40;dispon&#237;vel em <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">A preval&#234;ncia de cada variante identificada foi comparada ao banco de dados p&#250;blico brasileiro de variantes gen&#244;micas &#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; com&#160;1&#46;171&#160;amostras da popula&#231;&#227;o da mesma regi&#227;o e um banco de dados internacional &#40;genomAD&#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; com&#160;76&#46;156&#160;indiv&#237;duos n&#227;o aparentados de diferentes etnias&#46; A signific&#226;ncia estat&#237;stica foi definida como&#160;p &#8804; 0&#44;001&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Dados demogr&#225;ficos principais&#44; gravidade cl&#237;nica&#44; eosinofilia e n&#237;veis de IgE est&#227;o na <a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#46; A maioria dos pacientes apresentava DA moderada e grave&#160;&#40;79&#37;&#41;&#44; n&#237;veis elevados de IgE&#160;&#40;98&#37;&#41; e eosinofilia&#160;&#40;68&#37;&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Os resultados da an&#225;lise gen&#233;tica da amostra de DA e a compara&#231;&#227;o com os dois controles populacionais est&#227;o na <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#46; Vinte e seis variantes gen&#233;ticas do &#233;xon&#8208;3 do gene <span class="elsevierStyleItalic">FLG</span> foram detectadas em&#160;60&#160;pacientes &#40;75&#37;&#59; 95&#37;IC&#58;&#160;65&#37;&#8211;85&#37;&#41;&#46; Homozigose e heterozigose composta n&#227;o foram identificadas&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Variantes do gene <span class="elsevierStyleItalic">FLG</span> com perda de fun&#231;&#227;o da filagrina foram observadas em oito pacientes com DA &#40;10&#37;&#59; 95&#37;&#160;IC&#160;3&#37;&#8211;17&#37;&#41;&#46; Duas variantes prevalentes no mundo &#40;c&#46;1537C<span class="elsevierStyleHsp" style=""></span>&#62;T&#58;R501X e 2282delCAGT&#58;S761Cfs&#42;36&#41; foram observadas em&#160;seis&#160;pacientes &#40;7&#44;5&#37;&#41;&#46; Outra variante patog&#234;nica &#40;c&#46;2512C<span class="elsevierStyleHsp" style=""></span>&#62;T&#58;R826X&#41; foi identificada em dois pacientes &#40;2&#44;5&#37;&#41;&#46; Essas tr&#234;s variantes patog&#234;nicas foram mais prevalentes na amostra de DA que nos controles brasileiros &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; A variante 2282delCAGT&#58;S761Cfs&#42;36 &#233; comum em europeus&#44; enquanto c&#46;2512C<span class="elsevierStyleHsp" style=""></span>&#62;T&#58;R826X &#233; comum entre afro&#8208;americanos&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Foram encontradas oito variantes sin&#244;nimas do gene <span class="elsevierStyleItalic">FLG</span>&#44; quatro delas amplamente distribu&#237;das no Brasil e no mundo&#46; Entretanto&#44; quatro delas &#40;c&#46;1665T<span class="elsevierStyleHsp" style=""></span>&#62;G&#58;rs152285733&#44; c&#46;1737A<span class="elsevierStyleHsp" style=""></span>&#62;C&#58; sin&#244;nimo&#44; c&#46;1521G<span class="elsevierStyleHsp" style=""></span>&#62;A&#58; sin&#244;nimo e c&#46;1800T<span class="elsevierStyleHsp" style=""></span>&#62;C&#58; sin&#244;nimo&#41; foram observadas como mais comuns na amostra de DA do que no mundo &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; A variante c&#46;1476T<span class="elsevierStyleHsp" style=""></span>&#62;C&#58; sin&#244;nimo&#44; rara na popula&#231;&#227;o brasileira e internacional &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; &#233; comum entre afro&#8208;americanos&#46; O sin&#244;nimo c&#46;2544T<span class="elsevierStyleHsp" style=""></span>&#62;C&#44; considerado comum entre pacientes com DA e controles regionais&#44; &#233; extremamente raro no mundo &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Catorze variantes <span class="elsevierStyleItalic">missense</span> foram detectadas&#59; duas delas &#40;c&#46;1712A<span class="elsevierStyleHsp" style=""></span>&#62;G&#58;H559R&#44; c&#46;1777A<span class="elsevierStyleHsp" style=""></span>&#62;T&#58;T581S&#41; foram mais comuns entre pacientes com DA que controles regionais e internacionais &#40;p &#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Nenhuma variante do gene <span class="elsevierStyleItalic">FLG</span> foi associada &#224; gravidade cl&#237;nica da DA&#44; eosinofilia ou IgE s&#233;rica elevada &#40;p<span class="elsevierStyleHsp" style=""></span>&#62; 0&#44;1&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Esses resultados refor&#231;am o alto polimorfismo do &#233;xon&#8208;3 do gene <span class="elsevierStyleItalic">FLG</span> e sua associa&#231;&#227;o &#233;tnica&#44; dificultando a generaliza&#231;&#227;o dos resultados gen&#244;micos em rela&#231;&#227;o aos fen&#243;tipos de DA&#44; especialmente em popula&#231;&#245;es altamente miscigenadas&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">5&#44;7&#44;8</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Segundo a literatura&#44; variantes nulas eram esperadas em&#160;14&#37;&#8211;42&#37; dos pacientes com DA&#44; e dessas&#44; 20&#160;encontradas no &#233;xon&#8208;3&#46; Al&#233;m disso&#44; varia&#231;&#245;es foram relatadas do gene <span class="elsevierStyleItalic">FLG</span> entre pacientes com DA de diferentes etnias&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">A popula&#231;&#227;o brasileira &#233; multirracial ap&#243;s&#160;500&#160;anos de miscigena&#231;&#227;o entre indiv&#237;duos da Europa Ocidental&#44; &#193;frica e Amer&#237;ndia&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a> As variantes c&#46;2512C<span class="elsevierStyleHsp" style=""></span>&#62;T&#58;R826X e 2282delCAGT&#58;S761Cfs&#42;36 nos pacientes com DA corroboram essas ancestralidades&#44; embora a variante c&#46;2544T<span class="elsevierStyleHsp" style=""></span>&#62;C&#58; sin&#244;nimo seja uma caracter&#237;stica dessa regi&#227;o&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Considerando associa&#231;&#227;o epidemiol&#243;gica com o desenvolvimento da doen&#231;a&#44; variantes do gene <span class="elsevierStyleItalic">FLG per</span><span class="elsevierStyleItalic">se</span> n&#227;o explicam completamente a varia&#231;&#227;o na gravidade da DA&#44; eosinofilia ou n&#237;veis elevados de IgE&#44; refor&#231;ando os aspectos multifatoriais da doen&#231;a&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#44;8&#44;10</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Por fim&#44; identificamos variantes nulas do gene <span class="elsevierStyleItalic">FLG</span> &#40;no &#233;xon&#8208;3&#41; &#40;c&#46;1537C<span class="elsevierStyleHsp" style=""></span>&#62;T&#58;501X&#44; c&#46;2282del4&#58;S761Cfs&#42;36 e c&#46;2512C<span class="elsevierStyleHsp" style=""></span>&#62;T&#58;R826X&#41; em&#160;10&#37; dos pacientes brasileiros com DA&#44; mesmo sem associa&#231;&#227;o com as principais caracter&#237;sticas cl&#237;nicas da DA&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Suporte financeiro</span><p id="par0100" class="elsevierStylePara elsevierViewall">Fundo de Apoio &#224; Dermatologia do Estado de S&#227;o Paulo &#8211; Sebasti&#227;o Sampaio &#40;FUNADERSP&#41;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Contribui&#231;&#227;o dos autores</span><p id="par0105" class="elsevierStylePara elsevierViewall">Cristina Marta Maria Laczynski&#58; Concep&#231;&#227;o e desenho&#44; aquisi&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Carlos D&#8217;Apparecida Santos Machado Filho&#58; Revis&#227;o cr&#237;tica do conte&#250;do intelectual&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">H&#233;lio Amante Miot&#58; Revis&#227;o cr&#237;tica do conte&#250;do intelectual&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Denise Maria Christofolini&#58; Revis&#227;o cr&#237;tica do conte&#250;do intelectual&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Itatiana Ferreira Rodart&#58; Processamento do material gen&#233;tico&#44; an&#225;lise e interpreta&#231;&#227;o dos dados e revis&#227;o do conte&#250;do intelectual&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Paulo Ricardo Coelho&#58; Revis&#227;o cr&#237;tica do conte&#250;do intelectual&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Todos os autores leram e aprovaram a vers&#227;o final do manuscrito&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Conflito de interesses</span><p id="par0140" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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          "pt" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Gene <span class="elsevierStyleItalic">FLG</span> incluindo distribui&#231;&#227;o dos &#233;xons&#44; tamanho dos &#233;xons&#44; &#237;ntrons&#44; indica&#231;&#227;o de regi&#227;o de codifica&#231;&#227;o da profilagrina&#44; posi&#231;&#227;o dos <span class="elsevierStyleItalic">primers</span> e eletroferogramas das tr&#234;s mais frequentes variantes patog&#234;nicas encontradas em nossa amostra&#46;</p>"
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>I&#8211;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
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                  \t\t\t\t">24 &#40;30&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>III&#8211;IV&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>V&#8211;VI&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">47&#44;84&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">30&#44;25&#37;&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
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Vol. 98. Núm. 2.
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Vol. 98. Núm. 2.
Páginas 236-239 (1 março 2023)
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Prevalência do polimorfismo do gene filagrina (éxon‐3) em pacientes com dermatite atópica em população brasileira multirracial
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Cristina Marta Maria Laczynskia,
Autor para correspondência
crislacz@hotmail.com

Autor para correspondência.
, Carlos D’Apparecida Santos Machado Filhoa, Hélio Amante Miotb, Denise Maria Christofolinic, Itatiana Ferreira Rodartc, Paulo Ricardo Criadoa
a Disciplina de Dermatologia, Centro Universitário FMABC, Santo André, SP, Brasil
b Departamento de Dermatologia, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, Botucatu, SP, Brasil
c Departamento de Genética, Centro Universitário FMABC, Santo André, SP, Brasil
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Dermatite atópica (DA) é doença crônica, multifatorial, cujo fenótipo clínico resulta da interação de fatores genéticos e ambientais.1 A desregulação imunológica e a integridade da barreira cutânea determinam sua gravidade, predispondo a infecções e permeabilidade a antígenos.2 É motivo comum de atendimento dermatológico, principalmente na infância (< 12 anos), representando 25,8% das consultas dermatológicas.3

O gene que codifica a filagrina (FLG) é altamente polimórfico, na região do complexo de diferenciação epidérmica (1q21.3), codificando as proteínas mais importantes envolvidas na homeostase da barreira cutânea. FLG é o principal fator genético associado à DA, e seu éxon‐3 transcreve a maior parte da proteína profilagrina. Alterações da barreira cutânea estão presentes em pacientes com DA sem alterações do gene FLG; entretanto, a presença de variantes que levam à perda de função foram associadas a fenótipos clínicos como doença persistente de início precoce, asma e sensibilização alérgica.1,4 Intensa disparidade étnica na frequência de variantes que levam à perda de função do gene FLG associadas à DA tem sido observada.5

Mais de 60 variantes do gene FLG que levam à perda de função do gene FLG foram identificadas em associação com DA; as mais comuns entre os europeus são c.1537C>T:R501X e 2282del4:S761Cfs*36 e, entre os africanos subsaarianos, c.9947C>G:S3316*. Poucos estudos foram realizados em pacientes latino‐americanos com DA. Nosso objetivo foi avaliar a frequência de variantes do gene FLG (no éxon‐3) entre pacientes com DA para comparar populações brasileiras e internacionais e explorar suas características clínicas.

Foi realizado estudo transversal no ambulatório de dermatologia (FMABC; Santo André, São Paulo). Oitenta pacientes com DA (critérios de Hanifin e Rajka) de ambos os sexos foram incluídos e examinados por dermatologista experiente para avaliar a gravidade da doença (SCORAD, EASI) e coletar amostras de sangue venoso para análise laboratorial e da mucosa oral para análise genética. Os participantes/responsáveis assinaram termo de consentimento livre e esclarecido.

A coleta para análise genética foi realizada por swab da mucosa da região bucinadora dos pacientes e colocado num tubo de ensaio estéril (Oragene Collector OG‐500®, DNA Genotek Inc., Kanata, Ontario), que foi submetido ao sequenciamento pelo método de Sanger.

A extração de DNA foi realizada utilizando precipitação com etanol, e um reagente prepIT 2P fornecido pelo kit Oragene.

A reação em cadeia da polimerase (PCR) e a análise de seu sequenciamento foram realizadas com foco no éxon‐3 para identificar as variantes genéticas mais comuns – c.1537C>T:R501X (rs61816761) e c.2282del4:S761Cfs*36 (rs558269137) utilizando primers validados da Thermo Fischer Scientific® (Applied Biosystems, Foster City, CA), (Hs00274028 forward: 5’CTA ACA CTG GAT CCC TGG TTC CTA 3’ e reverse 5’ CTG AGA CAG CAG AGC CAC CAA GA 3’ e Hs00395823, forward: 5’ CAG ACC TAT CTA CCG ATT GCT CGT 3’ e reverse: 5’ AAA TCA GGC ACTCGT CAC ACA CAG AA 3’). Essa estratégia possibilitou investigar outras variantes em áreas vizinhas ao loci alvo, mas não cobriu toda a região de codificação do éxon‐3 (fig. 1). Os produtos de PCR foram purificados com esferas de DNA (Agencourt – AMPure XP‐Beckman Coulter, Brea, CA). As amostras purificadas juntamente com 10 μL desses primers foram utilizadas para a reação de sequenciamento. O ciclo de sequenciamento foi realizado com o kit Big Dye Terminator v3.1 (Thermo Fisher Scientific). Os produtos de sequenciamento foram submetidos à eletroforese capilar no ABI 3500 DNA Analyzer (Applied Biosystems, Foster City, CA). Os dados de sequenciamento foram avaliados com o software Seq A(14) – Applied Biosystems, Foster City, CA. O PROVEAN (Protein Variation Effect Analyzer) v1.1 foi usado para prever se uma variação de sequência de proteína causada por uma substituição missense afetaria a função da proteína (disponível em https://provean.jcvi.org/index.php).

Figura 1.

Gene FLG incluindo distribuição dos éxons, tamanho dos éxons, íntrons, indicação de região de codificação da profilagrina, posição dos primers e eletroferogramas das três mais frequentes variantes patogênicas encontradas em nossa amostra.

(0.24MB).

A prevalência de cada variante identificada foi comparada ao banco de dados público brasileiro de variantes genômicas (ABraOm; hg38 – https://abraom.ib.usp.br/) com 1.171 amostras da população da mesma região e um banco de dados internacional (genomAD; v3.1.2 – https://gnomad.broadinstitute.org/) com 76.156 indivíduos não aparentados de diferentes etnias. A significância estatística foi definida como p ≤ 0,001.6

Dados demográficos principais, gravidade clínica, eosinofilia e níveis de IgE estão na tabela 1. A maioria dos pacientes apresentava DA moderada e grave (79%), níveis elevados de IgE (98%) e eosinofilia (68%).

Tabela 1.

Características principais clínicas, demográficas e laboratoriais da amostragem de DA (n=80)

Variáveis  Valores 
Sexo, n (%)
Feminino  40 (50) 
Masculino  40 (50) 
Idade (anos), média (DP)  16 (12) 
Fototipo, n (%)
I–II  24 (30) 
III–IV  51 (64) 
V–VI  5 (6) 
Etnia, n (%)
Caucasiana  54 (68) 
Asiática  1 (1) 
Africana  25 (31) 
Gravidade da DA, n (%)
Leve  17 (21) 
Moderada  45 (56) 
Grave  18 (23) 
SCORAD, média (DP)  36 (17) 
EASI, média (DP)  13.5 (10.2) 
Níveis elevados de IgEa, n (%)  79 (98) 
Eosinófilos>5%, n (%)  46 (68) 

DA, dermatite atópica; IgE, imunoglobulina sérica E; DP, desvio padrão; SCORAD, Scoring Atopic Dermatitis; EASI, Eczema Area Severity Index.

a

De acordo com os valores de referência para cada faixa etária: 0–1 ano: até 15,0 UI/mL; 1–2 anos: 1,0 a 19,0 UI/mL; 2–3 anos: até 32 UI/mL; 4–9 anos: até 101,0 UI/mL; acima de 15 anos: 1,0 a 183,0 UI/mL; mediana: 98,44.

Os resultados da análise genética da amostra de DA e a comparação com os dois controles populacionais estão na tabela 2. Vinte e seis variantes genéticas do éxon‐3 do gene FLG foram detectadas em 60 pacientes (75%; 95%IC: 65%–85%). Homozigose e heterozigose composta não foram identificadas.

Tabela 2.

Variantes do gene FLG (éxon 3) em 80 pacientes brasileiros com dermatite atópica e sua prevalência de acordo com os bancos de dados populacionais AbraOM (da mesma população brasileira) e com o gnomAD (de populações latinas, afro‐americanas, europeias e internacionais)

Variante  Zigosidade  dbSNP  Consequência proteica  DA, n (%)  AbraOM (Brasil)  gnomAD
            Latina/ miscigenada  Europeia  Afro‐americana  Internacional 
c.1396A>G  HT  rs2011331  T454A  38 (47,50)  33,09%  39,36%  16,02%  47,84%  30,25% 
c.1468C>T  HT  rs11584340  P478S  39 (48,75)  25,06%  35,76%  15,90%  13,81%  20,34% 
c.1476T>C  HT  rs561848191  Sinônimo  2 (2,50)  <0,01%  0,01%  <0,01%  0,53%  0,14% 
c.1521G>A  HT  rs75530805  Sinônimo  1 (1,25)  NA  <0,01%  <0,01%  <0,01%  <0,01% 
c.1521G>C  HT  rs75530805  Sinônimo  21 (26,25)  1,49%  0,60%  <0,01%  5,1%  1,47% 
c.1530G>C  HT  rs13376095  E498D  3 (3,75)  0,05%  0,22%  <0,01%  2,62%  0,74% 
c.1537C>T  HT  rs61816761  R501Xa  3 (3,75)  0,08%  <0,01%  <0,01%  <0,01%  <0,01% 
c.1591C>A  HT  rs12036682  H519N  1 (1,25)  0,03%  0,05%  0,06%  <0,01%  0,58% 
c.1665T>G  HT  rs152285733  Sinônimo  8 (10,00)  NA  NA  NA  NA  NA 
c.1712A>G  HT  rs546475787  H559R  6 (7,50)  <0,01%  <0,01%  <0,01%  <0,01%  <0,01% 
c.1737A>C  HT  rs71625187  Sinônimo  25 (31,25)  NA  <0,01%  <0,01%  <0,01%  <0,01% 
c.1777A>T  HT  rs145627745  T581S  31 (38,75)  0,09%  0,49%  1,37%  0,27%  0,79% 
c.1800T>C  HT  rs152285598  Sinônimo  14 (17,50)  NA  NA  NA  NA  NA 
c.2167C>T  HT  rs115087788  R711C  1 (1,25)  <0,01%  0,20%  <0,01%  0,82%  0,25% 
c.2210C>T  HT  rs3120655  T725I  13 (16,25)  8,07%  3,53%  0,17%  34,83%  9,98% 
c.2217C>A  HT  rs7512779  H727Q  2 (2,50)  1,96%  <0,01%  <0,01%  <0,01%  <0,01% 
c.2261C>A  HT  rs3120654  S742Y  13 (16,25)  8,03%  3,47%  0,13%  34,77%  10,06% 
c.2271T>C  HT  rs150144110  s745=  1 (1,25)  0,01%  <0,01%  <0,01%  0,19%  <0,01% 
c.2299G>A  HT  rs74129461  E755K  23 (28,75)  23,40%  34,96%  15,90%  7,73%  18,57% 
c.2282del4CAGT#  HT  rs558269137  S761Cfs*36#  3 (3,75)  0,06%  <0,01%  2,19%  <0,01%  1,26% 
c.2319A>C  HT  rs11204979  Sinônimo  2 (2,50)  0,82%  0,59%  <0,01%  5,41%  1,57% 
c.2377G>C  HT  rs148739675  D781H  1 (1,25)  0,21%  0,07%  <0,01%  0,66%  0,19% 
c.2396C>T  HT  rs77032592  S787F  1 (1,25)  0,56%  0,28%  <0,01%  3,26%  0,94% 
c.2512C>T  HT  rs115746363  R826Xa  2 (2,50)  0,13%  <0,01%  <0,01%  0,72%  0,21% 
c.2544T>C  HM  rs3120653  Sinônimo  37(46,25)  33,60%  <0,01%  <0,01%  0,02%  <0,01% 

dbSNP (rs), referência SNP número nas bases de dados internacionais (posição cromossômica); HT, heterozigose; HM, homozigose; DA, dermatite atópica; NA, não achada.

a

Mutação com perda de função (patogênica).

Variantes do gene FLG com perda de função da filagrina foram observadas em oito pacientes com DA (10%; 95% IC 3%–17%). Duas variantes prevalentes no mundo (c.1537C>T:R501X e 2282delCAGT:S761Cfs*36) foram observadas em seis pacientes (7,5%). Outra variante patogênica (c.2512C>T:R826X) foi identificada em dois pacientes (2,5%). Essas três variantes patogênicas foram mais prevalentes na amostra de DA que nos controles brasileiros (p<0,001). A variante 2282delCAGT:S761Cfs*36 é comum em europeus, enquanto c.2512C>T:R826X é comum entre afro‐americanos.

Foram encontradas oito variantes sinônimas do gene FLG, quatro delas amplamente distribuídas no Brasil e no mundo. Entretanto, quatro delas (c.1665T>G:rs152285733, c.1737A>C: sinônimo, c.1521G>A: sinônimo e c.1800T>C: sinônimo) foram observadas como mais comuns na amostra de DA do que no mundo (p <0,001). A variante c.1476T>C: sinônimo, rara na população brasileira e internacional (p <0,001), é comum entre afro‐americanos. O sinônimo c.2544T>C, considerado comum entre pacientes com DA e controles regionais, é extremamente raro no mundo (p <0,001).

Catorze variantes missense foram detectadas; duas delas (c.1712A>G:H559R, c.1777A>T:T581S) foram mais comuns entre pacientes com DA que controles regionais e internacionais (p <0,001).

Nenhuma variante do gene FLG foi associada à gravidade clínica da DA, eosinofilia ou IgE sérica elevada (p> 0,1).

Esses resultados reforçam o alto polimorfismo do éxon‐3 do gene FLG e sua associação étnica, dificultando a generalização dos resultados genômicos em relação aos fenótipos de DA, especialmente em populações altamente miscigenadas.5,7,8

Segundo a literatura, variantes nulas eram esperadas em 14%–42% dos pacientes com DA, e dessas, 20 encontradas no éxon‐3. Além disso, variações foram relatadas do gene FLG entre pacientes com DA de diferentes etnias.8

A população brasileira é multirracial após 500 anos de miscigenação entre indivíduos da Europa Ocidental, África e Ameríndia.9 As variantes c.2512C>T:R826X e 2282delCAGT:S761Cfs*36 nos pacientes com DA corroboram essas ancestralidades, embora a variante c.2544T>C: sinônimo seja uma característica dessa região.

Considerando associação epidemiológica com o desenvolvimento da doença, variantes do gene FLG perse não explicam completamente a variação na gravidade da DA, eosinofilia ou níveis elevados de IgE, reforçando os aspectos multifatoriais da doença.1,8,10

Por fim, identificamos variantes nulas do gene FLG (no éxon‐3) (c.1537C>T:501X, c.2282del4:S761Cfs*36 e c.2512C>T:R826X) em 10% dos pacientes brasileiros com DA, mesmo sem associação com as principais características clínicas da DA.

Suporte financeiro

Fundo de Apoio à Dermatologia do Estado de São Paulo – Sebastião Sampaio (FUNADERSP).

Contribuição dos autores

Cristina Marta Maria Laczynski: Concepção e desenho, aquisição, análise e interpretação dos dados.

Carlos D’Apparecida Santos Machado Filho: Revisão crítica do conteúdo intelectual.

Hélio Amante Miot: Revisão crítica do conteúdo intelectual.

Denise Maria Christofolini: Revisão crítica do conteúdo intelectual.

Itatiana Ferreira Rodart: Processamento do material genético, análise e interpretação dos dados e revisão do conteúdo intelectual.

Paulo Ricardo Coelho: Revisão crítica do conteúdo intelectual.

Todos os autores leram e aprovaram a versão final do manuscrito.

Conflito de interesses

Nenhum.

Agradecimentos

Aos pacientes que consentiram em participar deste estudo, ao Prof. Caio Parente Barbosa, do Departamento de Genética do Centro Universitário FMABC, a Juliana Zangirolami Raimundo, do Departamento de Bioestatística do Centro Universitário FMABC, e a Larissa K. Martinez Meirinho Magalhães, do Departamento de Dermatologia do Centro Universitário FMABC.

Referências
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Z. Mu, J. Zhang.
The Role of Genetics, the Environment, and Epigenetics in Atopic Dermatitis.
Adv Exp Med Biol., 1253 (2020), pp. 107-140
[2]
T. Czarnowicki, J.G. Krueger, E. Guttman-Yassky.
Skin barrier and immune dysregulation in atopic dermatitis: an evolving story with important clinical implications.
J Allergy Clin Immunol Pract., 2 (2014), pp. 371-379
[3]
H.A. Miot, G.O. Penna, A.M.C. Ramos, M.L.F. Penna, S.M. Schmidt, F.B. Luz, et al.
Profile of dermatological consultations in Brazil (2018).
An Bras Dermatol., 93 (2018), pp. 916-928
[4]
C. Drislane, A.D. Irvine.
The role of filaggrin in atopic dermatitis and allergic disease.
Ann Allergy Asthma Immunol., 124 (2020), pp. 36-43
[5]
A. Hertz, L. Azulay-Abulafia, A.P.D. Nascimento, C.Y. Ohara, F.C. Kuschnir, L.C. Porto.
Analysis of filaggrin 2 gene polymorphisms in patients with atopic dermatitis.
An Bras Dermatol., 95 (2020), pp. 173-179
[6]
A.C. Miola, H.A. Miot.
p‐value and effect‐size in clinical and experimental studies.
J Vasc Bras., 20 (2021), pp. e20210038
[7]
H. Baurecht, A.D. Irvine, N. Novak, T. Illig, B. Buhler, J. Ring, et al.
Toward a major risk factor for atopic eczema: meta‐analysis of filaggrin polymorphism data.
J Allergy Clin Immunol., 120 (2007), pp. 1406-1412
[8]
H. Blakeway, V. Van-de-Velde, V.B. Allen, G. Kravvas, L. Palla, M.J. Page, et al.
What is the evidence for interactions between filaggrin null mutations and environmental exposures in the aetiology of atopic dermatitis?. A systematic review.
Br J Dermatol, 183 (2020), pp. 443-451
[9]
S.D. Pena, G. Di Pietro, M. Fuchshuber-Moraes, J.P. Genro, M.H. Hutz, F.S.G. Kehdy, et al.
The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected.
[10]
M. Ota, T. Sasaki, T. Ebihara, E. Yokosawa, Y. Murakami, H. Matsunaka, et al.
Filaggrin‐gene mutation has minimal effect on the disease severity in the lesions of atopic dermatitis.
J Dermatol., 48 (2021), pp. 1688-1699

Como citar este artigo: Laczynski CMM, Machado Filho CDS, Miot HA, Christofolini DM, Rodart IF, Criado PF. Prevalence of filaggrin gene polymorphism (exon‐3) in patients with atopic dermatitis in a multiracial Brazilian population. An Bras Dermatol. 2023;98:240–3.

Trabalho realizado no Centro Universitário FMABC, Santo André, SP, Brasil.

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