The importance of studying genetic ancestry in eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a chronic allergic condition leading to an excess of eosinophils in the esophagus. It is characterized by difficult and painful swallowing, a narrowing of the esophagus, and food impaction. Most individuals with EoE are atopic: individuals with allergic conditions such as food allergy, atopic dermatitis, and asthma are at greater risk for EoE. Although EoE has historically been a common condition, there has been a marked increase in the incidence of EoE in recent years, which may be due to increased food allergens, aeroallergens, and/or other environmental factors, coupled with increased diagnosis resulting from increased physician awareness. A systematic review across the United States, Canada, and Europe found a prevalence of 22.7 cases per 100,000 people (95% CI = 12.4-36), with a higher prevalence in men than in women (odds ratio = 2.01 [95% CI: 1.63-2.48]).1Arias A. Pérez-Martínez I. Tenías J.M. Lucendo A.J. Systematic review with meta-analysis: the incidence and prevalence of eosinophilic oesophagitis in children and adults in population-based studies.Aliment Pharmacol Ther. 2016; 43: 3-15Crossref PubMed Scopus (169) Google Scholar Although EoE is more prevalent in White individuals than in African American individuals, it is important to note that African American individuals are more likely to be diagnosed at younger ages, more likely to present with failure to thrive, and have a different clinical presentation of disease.2Sperry S.L.W. Woosley J.T. Shaheen N.J. Dellon E.S. Influence of race and gender on the presentation of eosinophilic esophagitis.Am J Gastroenterol. 2012; 107: 215Crossref PubMed Scopus (89) Google Scholar EoE is a complex disease, and as with all allergy conditions, there is an interplay between genes and environment. Heritability studies support a major genetic component along with environmental component in twin studies,3Alexander E.S. Martin L.J. Collins M.H. Kottyan L.C. Sucharew H. He H. et al.Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis.J Allergy Clin Immunol. 2014; 134: 1084Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar and genome-wide association studies (GWASs) have found multiple loci associated with EoE.4Kottyan L.C. Davis B.P. Sherrill J.D. Liu K. Rochman M. Kaufman K. et al.Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease.Nat Genet. 2014; 46: 895Crossref PubMed Scopus (212) Google Scholar,5Chang X. March M. Mentch F. Nguyen K. Glessner J. Qu H. et al.A genome-wide association meta-analysis identifies new eosinophilic esophagitis loci.J Allergy Clin Immunol. 2022; 149: 988-998Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar GWASs and candidate gene analyses in mostly European cohorts have identified multiple genetic variants and genes that increase the risk of EoE; these include CCL26, FLG, CRLF2, DSG1, TSLP/WDR36, CAPN14, LRRC32/C11orf30, STAT6, and ANKRD27.6Kottyan L.C. Rothenberg M.E. Genetics of eosinophilic esophagitis.Mucosal Immunol. 2017; 10: 580Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Consistent with much biomedical research, there is a substantial underrepresentation of non-European populations, including African American populations, in genetic studies of EoE. Because of differing allele frequencies and linkage disequilibrium, the genetic findings from a European ancestry population may not be the same as for an African American population, and this is particularly important in allergic disease, where there are known differences by ancestry and health disparities. In addition to increasing research equity, performing genetic studies of EoE in non-European populations allows for more potential risk variants to be discovered. In the current issue of the Journal of Allergy and Clinical Immunology, Gautam et al present an in-depth analysis of the genetics of EoE in an African American population.7Gautam Y. Caldwell J. Kottyan L. Chehade M. Dellon E. Rothenberg M.E. et al.Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans.J Allergy Clin Immunol. 2023; 151: 1337-1350Abstract Full Text Full Text PDF Scopus (1) Google Scholar They do this by using both admixture mapping and GWAS with follow-up functional validation to ensure that their analyses passed both statistical and biologic validity. Gautam et al7Gautam Y. Caldwell J. Kottyan L. Chehade M. Dellon E. Rothenberg M.E. et al.Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans.J Allergy Clin Immunol. 2023; 151: 1337-1350Abstract Full Text Full Text PDF Scopus (1) Google Scholar included 138 case patients with EoE and 1465 controls, all of whom were African American. All but 26 of the case patients with EoE were from the Cincinnati Center for Eosinophilic Disorders cohort; the controls were selected from the Cincinnati Genomic Control cohort, the Consortium of Food Allergy Researchers cohort, and the Consortium of Eosinophilic Gastrointestinal Disease Researchers cohort. The case patients and controls were selected on the basis of self-reported race as Black or African American. This selection criterion based on admixture allowed Gautam et al7Gautam Y. Caldwell J. Kottyan L. Chehade M. Dellon E. Rothenberg M.E. et al.Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans.J Allergy Clin Immunol. 2023; 151: 1337-1350Abstract Full Text Full Text PDF Scopus (1) Google Scholar to leverage continental ancestries represented in the cases and controls in their study in a powerful admixture mapping analysis approach. Admixture mapping is a method used to identify genetic loci associated with a specific ancestral population in a population of mixed ancestry that includes African American individuals, given the complex patterning of ancestry from both Africa and Europe. In the case of a disease such as EoE, where continental ancestry is associated with differential prevalence of disease, a locus associated with the trait of interest is expected to have ancestry patterns divergent from that of the rest of the genome, which allows for the use of admixture mapping to identify risk variants. Because of the possibility of a higher power of admixture mapping owing to lowered multiple testing and correlations with differential disease burden across ancestries, the admixture mapping method is still commonly used in the GWAS era to identify risk loci when GWASs are underpowered. It has been used to identify risk loci for other atopic diseases in Latino and African American individuals. In their study, Gautam et al7Gautam Y. Caldwell J. Kottyan L. Chehade M. Dellon E. Rothenberg M.E. et al.Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans.J Allergy Clin Immunol. 2023; 151: 1337-1350Abstract Full Text Full Text PDF Scopus (1) Google Scholar used 2 admixture mapping approaches: one using only the case patients with EoE (comparing each locus against the genome) and the other using both the case patients and the controls (comparing case versus control ancestry). Both approaches first identify the ancestry at every locus along the entire genome, in this case African or European ancestry. The case patient–only approach then compares the local ancestry at each locus across the case patients with the average global ancestry to identify regions of the genome with significantly higher or lower than average local ancestry proportions. The second approach uses both case patients and controls and compares the local ancestry of the case patients with the local ancestry of the controls to identify regions that have higher or lower than expected ancestry in the case patients than in the controls. The great advantage of admixture mapping over other methods is the high power to identify regions of the genome associated with the disease and the ability to use both case patient–only and case-control analyses. The case patient–only admixture mapping identified 3 significant loci. These included 2 loci where higher African ancestry was associated with increased risk of EoE (9p13 and 12q24.22-23) and 1 locus where higher European ancestry was associated with increased risk of EoE (15q11). The signals for 12q24.22-23 and 9p13 were replicated in the case-control analysis. Fine-mapping and functional prioritization of the admixture mapping loci allowed Gautam et al7Gautam Y. Caldwell J. Kottyan L. Chehade M. Dellon E. Rothenberg M.E. et al.Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans.J Allergy Clin Immunol. 2023; 151: 1337-1350Abstract Full Text Full Text PDF Scopus (1) Google Scholar to refine their analyses and identify potential candidate genes underlying their association peaks. Gautam et al7Gautam Y. Caldwell J. Kottyan L. Chehade M. Dellon E. Rothenberg M.E. et al.Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans.J Allergy Clin Immunol. 2023; 151: 1337-1350Abstract Full Text Full Text PDF Scopus (1) Google Scholar next performed a genetic association analysis (GWAS). This method has a higher multiple testing burden than admixture mapping, but Gautam et al7Gautam Y. Caldwell J. Kottyan L. Chehade M. Dellon E. Rothenberg M.E. et al.Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans.J Allergy Clin Immunol. 2023; 151: 1337-1350Abstract Full Text Full Text PDF Scopus (1) Google Scholar did identify 1 locus that was promising (P < 1e–5) and several suggestive loci. The lead variant for the top GWAS hit (rs1713726) is found at moderate frequency in African populations with a minor allele frequency (MAF) of 4%; however, the minor allele frequency is close to zero in other populations, including Europeans, indicating that this variant may be African population–specific. Therefore, previous studies of EoE in participants of European ancestry would have never been adequately powered to discover this locus. The variant rs1713726 is found in an intronic region of the DDAH1 gene, expression of which has been shown to be involved in the metabolism of nitric oxide, and it has previously been associated with inflammatory effects of asthma in mice8Kinker K.G. Gibson A.M. Bass S.A. Day B.P. Deng J. Medvedovic M. et al.Overexpression of dimethylarginine dimethylaminohydrolase 1 attenuates airway inflammation in a mouse model of asthma.PLoS One. 2014; 985148Crossref Scopus (21) Google Scholar and other inflammation-based conditions such as inflammatory bowel disease.9Krzystek-Korpacka M. Fleszar M.G. Bednarz-misa I. Lewandowski L. Szczuka I. Kempinski R. et al.Transcriptional and metabolomic analysis of L-arginine/nitric oxide pathway in inflammatory bowel disease and its association with local inflammatory and angiogenic response: preliminary findings.Int J Mol Sci. 2020; 21: 1641Crossref PubMed Scopus (26) Google Scholar Gautam et al7Gautam Y. Caldwell J. Kottyan L. Chehade M. Dellon E. Rothenberg M.E. et al.Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans.J Allergy Clin Immunol. 2023; 151: 1337-1350Abstract Full Text Full Text PDF Scopus (1) Google Scholar further validated this finding by comparing the results of RNA sequencing of 10 case patients with EoE with the results of RNA sequencing of 6 controls; they found that gene expression at DDAH1 was significantly reduced in the case patients with EoE, with a 6-fold difference (false discovery rate < 0.05). In addition to DDAH1, Gautam et al7Gautam Y. Caldwell J. Kottyan L. Chehade M. Dellon E. Rothenberg M.E. et al.Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans.J Allergy Clin Immunol. 2023; 151: 1337-1350Abstract Full Text Full Text PDF Scopus (1) Google Scholar identified 2 other genes with high fold changes between case patients and controls passing multiple testing: PTGES (a 5.85-fold change) and NRXN1 (a 5.56-fold change). Through a meta-analysis GWAS, PTGES has previously been associated with an increased risk of asthma in African American individuals.10Almoguera B. Vazquez L. Mentch F. Connolly J. Pacheco J.A. Sundaresan A.S. et al.Identification of four novel loci in Asthma in European American and African American Populations.Am J Respir Crit Care Med. 2017; 195: 456-463Crossref PubMed Scopus (63) Google Scholar The researchers performed ancestry-specific GWASs, and this association was found only in the GWAS of African American individuals. Gautam et al7Gautam Y. Caldwell J. Kottyan L. Chehade M. Dellon E. Rothenberg M.E. et al.Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans.J Allergy Clin Immunol. 2023; 151: 1337-1350Abstract Full Text Full Text PDF Scopus (1) Google Scholar used the results from admixture mapping and GWAS to prioritize candidate genes by using functional pathway and network analysis. From this, they identified 7 genes in 2 loci (12q23.22-23 and 9p13) from the admixture mapping, 40 genes within 57 risk loci from the GWASs, and 15 genes from functional mapping and annotation of GWASs. In total, this integrative approach combining ancestry and genotypes identified 60 potential candidate genes for EoE. In summary, Gautam et al7Gautam Y. Caldwell J. Kottyan L. Chehade M. Dellon E. Rothenberg M.E. et al.Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans.J Allergy Clin Immunol. 2023; 151: 1337-1350Abstract Full Text Full Text PDF Scopus (1) Google Scholar performed the first admixture mapping and GWAS for EoE in an African American population. Their study is a reminder that admixture mapping is a powerful method that can help identify loci in smaller studies of underrepresented admixed populations, including major racial/ethnic groups in the Americas such as African American and Latino individuals. In keeping with their discovery in African American individuals, the loci identified in the study by Gautam et al7Gautam Y. Caldwell J. Kottyan L. Chehade M. Dellon E. Rothenberg M.E. et al.Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans.J Allergy Clin Immunol. 2023; 151: 1337-1350Abstract Full Text Full Text PDF Scopus (1) Google Scholar may never have been detected by using only European data sets. As genomic studies of non-European populations tend to have much smaller sample sizes than studies using European populations, this is an important method to identify risk variants that may be at low frequency in European populations. Gautam et al7Gautam Y. Caldwell J. Kottyan L. Chehade M. Dellon E. Rothenberg M.E. et al.Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African Americans.J Allergy Clin Immunol. 2023; 151: 1337-1350Abstract Full Text Full Text PDF Scopus (1) Google Scholar follow their admixture mapping–driven approach to identify and functionally validate 60 potential candidate genes for EoE, some of which have previously been linked to other atopic conditions. Further research on these genes may lead to new insights into EoE. Genome-wide admixture and association analysis identifies African ancestry–specific risk loci of eosinophilic esophagitis in African AmericansJournal of Allergy and Clinical ImmunologyVol. 151Issue 5PreviewEosinophilic esophagitis (EoE), a chronic allergic inflammatory disease, is linked to multiple genetic risk factors, but studies have focused on populations of European ancestry. Few studies have assessed Black or African American (AA) populations for loci involved in EoE susceptibility. Full-Text PDF