African American ancestry contribution to asthma and atopic dermatitis

Abstract

Objective: Asthma and atopic dermatitis (AD) are complex diseases with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. Here we summarize current knowledge from asthma and AD genome-wide association studies (GWAS) and pharmacogenetic studies in African ancestry populations.

Data sources: GWAS catalog; PUBMed.

Study selections: GWAS catalog studies with trait annotations "asthma" and "atopic eczema" and African ancestry individuals in the discovery dataset; the recent CAAPA asthma GWAS; reports on pharmacogenetic studies in asthma and AD.

Results: Although GWASs have revolutionized gene discovery for multiple complex traits, African Americans continue to be severely underrepresented in sufficiently powered genetics studies. Indeed, of the 16 asthma and 21 AD loci that reached genomewide significance in Europeans, very few have replicated in African ancestry populations. Challenges in comparing results from European vs African ancestry cohorts include modest sample size, differences in risk allele frequency, effect size, correlation between genetic variants, and environmental exposure in evolutionary history. African Americans also constitute a small percentage of dermatological and respiratory-focused clinical trials. Pharmacogenetic studies have similarly been focused largely on non-Hispanic whites, despite compelling evidence that genetic variation from different ancestral backgrounds may alter therapeutic efficacy of asthma and AD drugs.

Conclusion: Large-scale genetic studies of asthma and AD in African Americans are essential to reduce research and health disparities and empower scientific discoveries.

Figure 1:. Illustration of factors that influence between population differences of variants associated with asthma related phenotypes

A). Genetic Impact – differences in allele frequency. African- or Asian-ancestry asthmatics are more likely to carry the homozygous Arg16Arg genotype of a common coding variant (Gly16Arg) in the gene encoding the beta-2 adrenergic receptor (ADRB2, which is associated with poorer lung function during regular treatment with albuterol [Ortega, V. E. J Allergy Clin Immunol (2014)]. Allele frequencies from the 1000 Genomes Project are shown. CEU=Utah residents with ancestry from northern and western Europe; YRI=Individuals from Yoruba in Ibadan, Nigeria; ASW=African Americans from the southwest United States; MEX=Mexican Americans from Los Angeles, CA; CHB=Han Chinese from Beijing, China; JPT=Japanese from Tokyo, Japan. B). Genetic effect - differences in effect size. i.) The IL1Rl1 rs10173081 asthma risk allele odds ratio is larger in European Americans and Latinos compared to African American and African-Caribbean populations [Torgerson, D.G. Nat Genet (2011)] ii.) rs335016 is associated with asthma in Latinos but have zero effect (odds ratio = 1) in African American and African-Caribbean populations [Torgerson, D.G. Nat Genet (2011)]. iii). The minor allele of SNP rs2786098 located in the CRB1 gene is protective for asthma in European ancestry children (odds ratio < 1), but increases risk for asthma in African American children (odds ratio > 1) [Sleiman, P. M. N Engl J Med (2010)] A). Differences in linkage disequilibrium. Variants reported by GWAS are not necessarily causal, but may be a “tagging” variant that is correlated with the true causal variant. The pairwise correlation between genome-wide significant SNPs in the chr17q21–12 locus from the TAGC meta-analysis [Demenais, F. Nat Genet (2018)] is shown in European (CEU) vs. African (YRI) ancestry populations from the 1000 Genomes Project. The correlation structure between asthma associated variants is markedly different in the two populations.