African Ancestry-specific risks of EoE in African American population
Published: November 15, 2022
Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus with genetic predisposition as a strong risk factor. The disease affects people of all races and ethnicities worldwide. However, genome-wide association studies of EoE have been conducted in European populations and, thus, may not have uncovered genetic risk variants that are specific to other ancestral populations. To discover ancestry-specific genetic risk variants in admixed populations, such as African Americans, ancestry-appropriate genotyping arrays and analytical approaches are needed. A recent study published in The Journal of Allergy and Clinical Immunology (JACI) used genotypes from the Multi-Ethnic Genotyping Array (MEGA) in both an admixture mapping and a genome-wide association study (GWAS) to identify ancestry-specific risk variants associated with EoE in African American populations.
Gautam et al studied 137 physician-diagnosed EoE cases and 1465 non-EoE controls of African American ancestries. Genotyping was performed using the MEGA array followed by genotype imputation carried out with the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) reference panel. Local and global African ancestry proportions were estimated using the RFMix v2 statistical tool. A GWAS was conducted using all variants that passed QC and with minor allele frequency at least 0.01. To further identify ancestry-specific loci associated with EoE, admixture mapping was performed using case-only and case-control designs. Fine-mapping and functional prioritization of the ancestry-specific admixture mapping loci were conducted to prioritize and identify variants with functional evidence. FUMA, a gene prioritization tool based on GWAS summary statistics, was used to identify genes associated with EoE. The results were further validated with differential gene expression analysis based on RNASeq data in esophageal cells from individuals of European ancestry.
Global African ancestry proportions were significantly lower among EoE cases compared to controls (0.751 vs. 0.786, p-value = 0.012). GWAS identified an intronic variant (rs17131726, p-value = 2.39e-27) in the Dimethylarginine Dimethylaminohydrolase 1 gene (DDAH1) at chromosome 1p22.3 that was associated with EoE in African Americans. The risk variant was a low frequency variant with African ancestry-specific risk. Other GWAS loci with marginal effects also showed an enrichment of African-ancestry specific risk of EoE. Admixture mapping identified one locus (15q11.2) with higher proportion of European ancestry and two loci (12q24.23 and 9p13.3) with higher proportions of African ancestry that were associated with EoE. Fine mapping and multi-omic functional annotations prioritized the variants rs2297879 (ARHGEF39) at 9p13.3 and rs11068264 (FBXW8) and rs7307331 (VSIG10) at 12q24.23 as potential African-ancestry risk variants. Differential expression analysis showed that esophageal expression of DDAH1 and VSIG10 was downregulated and ARHGEF39 was upregulated among EoE cases.
The previous discovery of genetic risk of EoE were primarily Euro-centric and may have missed genetic variants that contribute to EoE risk in African Americans. Using GWAS and admixture mapping approaches, this study identified multiple target variants and genes associated with EoE in the African American population. Although higher global European ancestry was associated with higher risk of EoE in African Americans, both admixture mapping and GWAS results point towards novel genetic risk loci for EoE that potentially harbor African-ancestry alleles. The potential importance of the identified loci was supported by differential expression of the candidate genes in the esophagus of EoE patients. Our study provides evidence to support the need for diversifying genetic studies of EoE and likely other allergic diseases to non-European ancestries to improve the representation of disease-risk variants that improve the translation of genetic research into clinical practice.
The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.
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