A Polynesian-specific copy number variant encompassing the MHC Class I Polypeptide-related Sequence A (MICA) gene associates with gout

Abstract Gout is of particularly high prevalence in the Māori and Pacific (Polynesian) populations of Aotearoa New Zealand (NZ). Here, we investigated the contribution of common population-specific CNV to gout in the Aotearoa NZ Polynesian population. Microarray-generated genome-wide genotype data from Aotearoa NZ Polynesian individuals with (n = 1196) and without (n = 1249) gout were analyzed. Comparator population groups were 552 individuals of European ancestry and 1962 of Han Chinese ancestry. Levels of circulating MHC Class I Polypeptide-related sequence A (MICA) were measured by ELISA. Fifty-four CNV regions (CNVRs) appearing in at least 10 individuals were detected, of which seven common CNVRs were specific to or amplified in Polynesian people. A burden test of these seven revealed associations of insertion/deletion with gout (OR = 1.80 [1.01; 3.22], P = 0.046). Individually testing of the seven CNVRs for association with gout revealed nominal association of CNVR1 with gout in Western Polynesian (Chr6: 31.36–31.45 Mb, OR = 1.72 [1.03; 2.92], P = 0.04), CNVR6 in the meta-analyzed Polynesian sample sets (Chr1: 196.75–196.92 Mb, OR = 1.86 [1.16; 3.00], P = 0.01) and CNVR9 in Western Polynesian (Chr1: 189.35–189.54 Mb, OR = 2.75 [1.15; 7.13], P = 0.03). Analysis of European gout genetic association data demonstrated a signal of association at the CNVR1 locus that was an expression QTL for MICA. The most common CNVR (CNVR1) includes deletion of the MICA gene, encoding an immunomodulatory protein. Expression of MICA was reduced in the serum of individuals with the deletion. In summary, we provide evidence for the association of CNVR1 containing MICA with gout in Polynesian peoples, implicating class I MHC-mediated antigen presentation in gout.