Aotearoa New Zealand Māori and Pacific Population-amplified Gout Risk Variants: CLNK Is a Separate Risk Gene at the SLC2A9 Locus

Abstract

Objective The Māori and Pacific (Polynesian) population of Aotearoa New Zealand (NZ) has a high prevalence of gout. Our aim was to identify potentially functional missense genetic variants in candidate inflammatory genes amplified in frequency that may underlie the increased prevalence of gout in Polynesian populations. Methods A list of 712 inflammatory disease-related genes was generated. An in silico targeted exome set was extracted from whole genome sequencing data in people with gout of various ancestral groups (Polynesian, European, East Asian; n = 55, 780, 135, respectively) to identify Polynesian-amplified common missense variants (AF > 0.05). Candidate functional variants were tested for association with gout by multivariable-adjusted regression analysis in 2,528 individuals of Polynesian ancestry. Results We identified 26 variants common in the Polynesian population and uncommon in the European and East Asian populations. Three of the 26 population-specific variants were nominally associated with the risk of gout (rs1635712, KIAA0319, ORmeta = 1.28, Pmeta = 0.028; rs16869924, CLNK, ORmeta = 1.37, Pmeta = 0.0017; rs2070025, FGA, ORmeta = 1.34, Pmeta = 0.017). The CLNK variant, within the established SLC2A9 gout locus, was genetically-independent of the association signal at SLC2A9. Conclusion We provide nominal evidence for the existence of population-amplified genetic variants conferring risk of gout in Polynesian populations. Polymorphisms in CLNK have previously been associated with gout in other populations, supporting our evidence for association of this gene with gout.

A Polynesian-specific missense CETP variant alters the lipid profile

“…Importantly, this variant and the accumulating evidence of the presence of other population-specific trait-associated variants 21 , 61 , 62 , 63 , 64 , 65 emphasizes the significance of population-specific variation and its influence on disease traits. Comprehensive evaluations of genome-wide genetic variation in Māori and Pacific populations are long overdue, 66 essential for improvement in health outcomes, 19 and critical for equity in genomics and healthcare as we move toward an era of personalized medicine grounded in genetics.…”

Association of Gout Polygenic Risk Score With Age at Disease Onset and Tophaceous Disease in European and Polynesian Men With Gout

“…The Aus/NZ European cohort also included non-gout controls. Three Polynesian cohorts were also included in this study, largely sourced from the Genetics of Gout in Aotearoa study (21,22) (Table 1 and Supplementary Tables 1 and 2). These 3 cohorts included 1 West Polynesian cohort and 2 East Polynesian cohorts.…”

Trends in the Contribution of Genetic Susceptibility Loci to Hyperuricemia and Gout and Associated Novel Mechanisms

“…The allele “G" of CLNK SNP (rs2041215 and rs1686947) was identified as susceptibility genes for gout in the Chinese population by using dominant model (OR 1.66; 95% CI 1.04–2.63; p = 0.031) (OR 2.19; 95% CI 1.38–3.46; p = 0.001) and additive model (OR 1.39; 95% CI 1.00–1.93; p = 0.049) (OR 1.67; 95% CI 1.19–2.32; p = 0.003), respectively ( Jin et al, 2015 ). A CLNK SNP (rs16869924) within the established SLC2A9 gout-associated locus was shown to increase the risk of gout in Polynesian and Chinese Tibetan individuals, genetically independent on the SLC2A9 association signal ( Lan et al, 2016 ; Ji et al, 2021 ). It is hypothesized that CLNK mainly regulates B-cell development and activation and co-mediates the formation of immune complexes through the STAT signaling pathway to promote gout, as suggested be a combination of related studies ( Siniachenko et al, 1984 ; Wang et al, 2002 ; Marrero et al, 2006 ).…”