Variation in ERAP2 has opposing effects on severe respiratory infection and autoimmune disease

• Published in: American journal of human genetics 2023-04, Vol.110 (4), p.691-702
• Main Authors: Hamilton, Fergus, Mentzer, Alexander J., Parks, Tom, Baillie, J Kenneth, Smith, George Davey, Ghazal, Peter, Timpson, Nicholas J.
• Format: Article
• Language: English
• Subjects: Aminopeptidases - genetics; Aminopeptidases - metabolism; Autoimmune Diseases - genetics; balancing selection; COVID-19; ERAP2; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Haplotypes - genetics; Humans; infection; Mendelian randomization; Plague; pneumonia; Polymorphism, Single Nucleotide - genetics
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2023.02.008

ERAP2 is an aminopeptidase involved in immunological antigen presentation. Genotype data in human samples from before and after the Black Death, an epidemic due to Yersinia pestis, have marked changes in allele frequency of the single-nucleotide polymorphism (SNP) rs2549794, with the T allele suggested to be deleterious during this period, while ERAP2 is also implicated in autoimmune diseases. This study explored the association between variation at ERAP2 and (1) infection, (2) autoimmune disease, and (3) parental longevity. Genome-wide association studies (GWASs) of these outcomes were identified in contemporary cohorts (UK Biobank, FinnGen, and GenOMICC). Effect estimates were extracted for rs2549794 and rs2248374, a haplotype tagging SNP. Additionally, cis expression and protein quantitative trait loci (QTLs) for ERAP2 were used in Mendelian randomization (MR) analyses. Consistent with decreased survival in the Black Death, the T allele of rs2549794 showed evidence of association with respiratory infection (odds ratio; OR for pneumonia 1.03; 95% CI 1.01–1.05). Effect estimates were larger for more severe phenotypes (OR for critical care admission with pneumonia 1.08; 95% CI 1.02–1.14). In contrast, opposing effects were identified for Crohn disease (OR 0.86; 95% CI 0.82–0.90). This allele was shown to associate with decreased ERAP2 expression and protein levels, independent of haplotype. MR analyses suggest that ERAP2 expression may be mediating disease associations. Decreased ERAP2 expression is associated with severe respiratory infection with an opposing association with autoimmune diseases. These data support the hypothesis of balancing selection at this locus driven by autoimmune and infectious disease. The T allele at the ERAP2 SNP rs2549794 has been suggested as deleterious during the Black Death. We have found that the T allele is associated with increased risk of respiratory infection, with opposing effects for Crohn disease, supporting the hypothesis of balancing selection driven by autoimune and infectious disease.