Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, People's Republic of China.
Department of Biochemistry, University of Otago, Dunedin 9054, New Zealand.
Hum Mol Genet. 2022 Oct 28;31(21):3757-3768. doi: 10.1093/hmg/ddac094.
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 copy number variation (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 major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) were measured by enzyme-linked immunosorbent assay. Fifty-four CNV regions (CNVRs) appearing in at least 10 individuals were detected, of which seven common (>2%) CNVRs were specific to or amplified in Polynesian people. A burden test of these seven revealed associations of insertion/deletion with gout (odds ratio (OR) 95% confidence interval [CI] = 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 quantitative trait locus 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 people, implicating class I MHC-mediated antigen presentation in gout.
在新西兰（Aotearoa New Zealand）的毛利人和太平洋（波利尼西亚）人群中，痛风的患病率特别高。在这里，我们研究了常见的人口特异性拷贝数变异（CNV）对新西兰波利尼西亚人群痛风的贡献。对来自新西兰波利尼西亚有（n=1196）和没有（n=1249）痛风的个体的微阵列生成的全基因组基因型数据进行了分析。比较人群组包括 552 名欧洲血统个体和 1962 名汉族血统个体。通过酶联免疫吸附试验测量循环中主要组织相容性复合体（MHC）I 类多肽相关序列 A（MICA）的水平。检测到至少 10 个人出现的 54 个 CNV 区域（CNVR），其中 7 个常见（>2%）CNVR 仅存在于或在波利尼西亚人中扩增。对这些 7 个 CNVR 的负担测试显示插入/缺失与痛风有关（比值比（OR）95%置信区间[CI]为 1.80[1.01；3.22]，P=0.046）。对 7 个 CNVR 与痛风的关联进行单独测试显示，在西方波利尼西亚人中，CNVR1 与痛风有名义上的关联（Chr6：31.36-31.45 Mb，OR=1.72[1.03；2.92]，P=0.04），在荟萃分析的波利尼西亚样本集中，CNVR6 与痛风有关（Chr1：196.75-196.92 Mb，OR=1.86[1.16；3.00]，P=0.01），而在西方波利尼西亚人中，CNVR9 与痛风有关（Chr1：189.35-189.54 Mb，OR=2.75[1.15；7.13]，P=0.03）。对欧洲痛风遗传关联数据的分析表明，CNVR1 位点存在与痛风相关的信号，该信号是 MICA 的表达数量性状基因座。最常见的 CNVR（CNVR1）包含 MICA 基因的缺失，该基因编码一种免疫调节蛋白。缺失个体的血清中 MICA 的表达减少。总之，我们提供了证据表明，包含 MICA 的 CNVR1 与波利尼西亚人的痛风有关，提示 I 类 MHC 介导的抗原呈递与痛风有关。
