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• W2988807305 abstract "In this issue of the Journal, Abuabara et al1Abuabara K. You Y. Margolis D.J. Hoffmann T.J. Risch N. Jorgenson E. Genetic ancestry does not explain increased atopic dermatitis susceptibility or worse disease control among African American subjects in 2 large US cohorts.J Allergy Clin Immunol. 2020; 145: 192-198.e11Google Scholar evaluated the association of self-identified race/ethnicity, genetic measures of African ancestry, skin-pigment measures, and polygenic risk scores on atopic dermatitis (AD) outcomes in 2 independent cohorts: the Pediatric Eczema Elective Registry (PEER) and Genetic Epidemiology Research on Adult Health and Aging (GERA) cohorts. Up to 10% of the American population has AD, and African American subjects have a 1.7-fold increased risk of AD.2Shaw T.E. Currie G.P. Koudelka C.W. Simpson E.L. Eczema prevalence in the United States: data from the 2003 National Survey of Children's Health.J Invest Dermatol. 2011; 131: 67-73Google Scholar Understanding any genetic underpinnings to the disparities in AD are critical given a heritability estimate of around 84%. This study represents the largest genetic study of AD in African American subjects. Although the authors confirmed prior studies that found AD is both more prevalent and more severe in African American subjects than their white counterparts,2Shaw T.E. Currie G.P. Koudelka C.W. Simpson E.L. Eczema prevalence in the United States: data from the 2003 National Survey of Children's Health.J Invest Dermatol. 2011; 131: 67-73Google Scholar they found no association of AD outcomes with genetic measures of African ancestry and no association with polygenic risk scores. Here we discuss the lack of identified genetic association with polygenic risk scores, which have limited generalizability to non-European subjects,3Martin A.R. Kanai M. Clinical use of current polygenic risk scores may exacerbate health disparities.Nat Genet. 2019; 51: 584-591Google Scholar and then address the more specific question of lack of association with global African ancestry. Despite high heritability estimates, the role of genetic factors in AD outcomes within African American populations has been relatively understudied. A prior genome-wide association study (GWAS) of 5843 participants with African ancestry and AD identified by using the electronic record phenotyping system found that none of the variants identified met genome-wide significance despite the nominal significance of 9 of 136 loci that were previously reported in European populations.4Almoguera B. Vazquez L. Mentch F. March M.E. Connolly J.J. Peissig P.L. et al.Novel locus for atopic dermatitis in African Americans and replication in European Americans.Nat Genet. 2019; 143: 1229-1231Google Scholar The low yield of this prior GWAS and the lack of association for the current study’s polygenic risk score might be due to a number of factors, including disease misclassification, the frequency of relevant genetic risk factors in populations of African origin (rare variants), lack of representation of these populations in prior GWAS studies used to inform polygenic risk scores, and lack of representation of population-specific risk variants on the gene chips used to study these populations. There are racially specific allele frequency differences in known genetic risk factors for AD. In keeping with studies using less intensive genotyping methods, in a sequencing study evaluating filaggrin (FLG) variants in the PEER cohort, the odds of having an FLG loss-of-function variant was 2.44-fold greater in white children compared with African American children.5Margolis D.J. Mitra N. Wubbenhorst B. D'Andrea K. Kraya A.A. Hoffstad O. et al.Association of filaggrin loss-of-function variants with race in children with atopic dermatitis.JAMA Dermatol. 2019; ([Epub ahead of print])Google Scholar In this study 4 well-documented risk variants captured 92.6% of the variation in white subjects but only captured 36% of the variation in African American subjects. In another study by the same group, 9 unique rare variants were identified in African American subjects, and these variants had a similar risk effect to previously described loss-of-function alleles in white populations. Notably, because these variants are rare, it becomes statistically more difficult to identify these effects in smaller sample sizes. Additionally, other skin barrier (ie, FLG2) and immunomodulatory genes, such as thymic stromal lymphopoietin (TSLP), have been identified as potential risk factors for the persistence of AD in African American studies.6Margolis D.J. Gupta J. Apter A.J. Ganguly T. Hoffstad O. Papadopoulos M. et al.Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects.J Allergy Clin Immunol. 2014; 133: 784-789Google Scholar,7Margolis D.J. Kim B. Apter A.J. Gupta J. Hoffstad O. Papadopoulos M. et al.Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis.JAMA Dermatol. 2014; 150: 254-259Google Scholar FLG2 might increase the risk of persistent AD in African American subjects by 50%6Margolis D.J. Gupta J. Apter A.J. Ganguly T. Hoffstad O. Papadopoulos M. et al.Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects.J Allergy Clin Immunol. 2014; 133: 784-789Google Scholar but has not been associated with AD risk in European populations.8Paternoster L. Standl M. Waage J. Baurecht H. Hotze M. Strachan D.P. et al.Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.Nat Genet. 2015; 47: 1449-1456Google Scholar TSLP variants modified the effects of FLG variants in African American subjects.7Margolis D.J. Kim B. Apter A.J. Gupta J. Hoffstad O. Papadopoulos M. et al.Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis.JAMA Dermatol. 2014; 150: 254-259Google Scholar This might be particularly relevant because African American subjects have more of a TH2 endotype.9Sanyal R.D. Pavel A.B. Glickman J. Chan T.C. Zheng X. Zhang N. et al.Atopic dermatitis in African American patients is TH2/TH22-skewed with TH1/TH17 attenuation.Ann Allergy Asthma Immunol. 2019; 122: 99-110.e6Google Scholar Collectively, these findings suggest that rare variants in known genes (FLG) and other population-specific genetic risk factors need to be assessed in polygenic risk scores in African American populations. In addition, there are built-in biases in the methodology used to evaluate genetic associations in non-European populations. GWASs are more than 80% European, and the majority of non-European populations are East Asians. Thus both African American and Latino subjects, who together comprise more than 30% of the US population, are dramatically underrepresented in modern genetic studies at approximately 2% and less than 0.5%, respectively, in a recent survey.3Martin A.R. Kanai M. Clinical use of current polygenic risk scores may exacerbate health disparities.Nat Genet. 2019; 51: 584-591Google Scholar As a result, the polygenic risk scores derived from GWASs will be much more accurate for European subjects compared with populations of non-European origin. This disparity is to the point at which several genetic testing companies offer polygenic risk assessment of breast and prostate cancer to inform cancer-screening protocols only to populations of European ancestry, citing insufficient data to apply these tools in other populations. Furthermore, most of the genetic variation described in genotyping chips has been derived from populations of European origin, resulting in a built-in bias that limits identification of African-specific variation. However, it is likely that this will be less problematic with the advent of whole-genome sequencing technologies. The Axiom population-specific genotype arrays (Thermofisher Scientific, Waltham, Mass) used in this study were state of the art and should have captured genetic variation in this population. However, it is still likely that polygenic risk scores derived from GWASs are intrinsically biased against finding genetic associations in non-European populations. In addition, there might be biological differences in endotypes of disease that are population specific. A recent study of both African American and white subjects carried out immunohistochemical staining, RNA sequencing, and RT-PCR confirmation in lesional and nonlesional skin from patients with AD and control subjects. In this study pathway analysis revealed less innate immune activation and less TH1 and TH17 pathway activation in African American participants compared with European American participants. Levels of TH2 and TH22 pathway gene activation were similar between groups.9Sanyal R.D. Pavel A.B. Glickman J. Chan T.C. Zheng X. Zhang N. et al.Atopic dermatitis in African American patients is TH2/TH22-skewed with TH1/TH17 attenuation.Ann Allergy Asthma Immunol. 2019; 122: 99-110.e6Google Scholar Although that study is limited by a small sample size, agnostic molecular endotyping approaches are needed to better understand endotypes of AD and their frequencies in different populations because there can be differences in genetic association by endotype. Although the lack of significant associations with polygenic risk scores is explicable as summarized in Fig 1, the lack of an association with global estimates of African ancestry is interesting. The authors suggest that this finding might suggest that the social and environmental factors associated with African ancestry are more important in AD disparities than genetic factors. Although this might be possible, it is also plausible that local genetic ancestry or rare variants might be more relevant than global ancestry. Indeed, population-specific rare variants are underrepresented or missed on standard GWAS platforms and hence not necessarily correlated with global ancestry estimated by using these platforms. As such, it remains quite possible that some of the disparity is due to poorly identified local genetic factors. In addition to the issues related to inadequacy of polygenic risk scores and the poor representation of rare variants on GWAS platforms, there are other important limitations in the current study, including use of International Classification of Diseases, Ninth Revision, codes for the larger GERA cohort. The European Academy of Allergy and Clinical Immunology and the World Allergy Organization published a strategic article and review in which they emphasized that hypersensitivity diseases are poorly coded in the International Classification of Diseases,10Demoly P. Tanno L.K. Akdis C.A. Lau S. Calderon M.A. Santos A.F. et al.Global classification and coding of hypersensitivity diseases—an EAACI-WAO survey, strategic paper and review.Allergy. 2014; 69: 559-570Google Scholar raising the question of disease misclassification bias. Despite the limitations, the authors should be applauded because they have performed the largest genetic study of AD in populations of African ancestry, and the study’s lack of association with polygenic risk scores and global estimates of ancestry reveals the importance of genetic sequencing studies in populations of African ancestry. For future studies to further elucidate the genetic basis of disparities in patients with AD, it remains critically important to perform large studies with whole-genome sequencing data and intensive precise phenotyping in globally diverse populations who are underrepresented in research despite greater disease prevalence. Genetic ancestry does not explain increased atopic dermatitis susceptibility or worse disease control among African American subjects in 2 large US cohortsJournal of Allergy and Clinical ImmunologyVol. 145Issue 1PreviewAtopic dermatitis (AD) is more common among African American children. Whether there are racial/ethnic difference among adults with AD and the causes for those disparities are unclear. Full-Text PDF" @default.
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