SLC2A9 and Hyperuricemia: A Locus-Wide Association Study To Identify Population-Specific Genetic Variants In New Zealand Māori and Pacific People

Abstract

Hyperuricemia, pathologically defined as the presence of an elevated level of serum urate, is a prerequisite for gouty arthritis. The solute carrier family 2 member 9 (SLC2A9) gene that encodes a urate transporter tops the list of hyperuricemic genes. It is a key genetic determinant of serum urate levels and explains about 3% of urate variance. Gout is highly prevalent in the New Zealand Māori and other Polynesian populations. As an attempt to understand the reason for this increased prevalence, this study focused on the identification and characterisation of Polynesian-specific genetic variants within the SLC2A9 locus conferring susceptibility to hyperuricemia.

The SLC2A9 locus was resequenced in 809 individuals (Polynesian, n = 440 and European, n = 369) comprising hyperuricemic cases and normouricemic controls. All Polynesians were from New Zealand while Europeans were from New Zealand and the United States. Association analysis was carried out to identify variants within the SLC2A9 locus that confer risk for hyperuricemia. Multiple adjusted logistic regression analysis was carried out using R version 3.4.1. A number of data visualization techniques and variant annotation tools were used to interpret and represent data and variant annotations.

A total of 3963 variants was identified within the locus, of which 25 and 53 variants displayed nominal significance (p-value ≤ 0.05) with hyperuricemia in the East and West Polynesians, respectively. These significant signals were further analysed. Five variants were chosen for replication via genotyping (VAR_CHR4_9914056, rs373311989, VAR_CHR4_9452283, VAR_CHR4_10160679 and VAR_CHR4_10457448). The A allele of VAR_CHR4_9914056, located in intron 7 of the SLC2A9 gene, was found to be associated with hyperuricemia in the East Polynesians in the Discovery Cohort (adjusted OR = 28.30, POR = 0.003) and the association was successfully replicated in the larger independent Replication Cohort, although with a relatively smaller effect size (adjusted OR = 2.93, POR = 0.004).

The variants prioritized for replication were also tested for the association with gout in Polynesians. The A allele of the intergenic variant, VAR_CHR4_10160679, showed a significant protective association with gout both during discovery (adjusted OR = 0.04, POR = 0.03) and replication (adjusted OR = 0.32, POR = 0.01) in West Polynesians. The region containing this variant (4:10120364 – 4:10494666) displayed variation in the haplotype structure in Polynesians compared to Europeans, as revealed by haplotype analysis and visualization.

This research was conducted to provide a greater insight into the genetic causes of gout and understand the reason for the higher prevalence of hyperuricemia in Polynesians. The work signifies the usefulness of targeted resequencing, especially in a bespoke fashion, in studying the genetic basis of a trait/disease that is highly prevalent in a particular population and further evinces the association of non-coding variants in the SLC2A9 locus, mapping to the human 4p16.1 chromosomal region, with hyperuricemia and gout in Polynesians. The study also demonstrates the utility of data visualization tools and techniques in exploratory big data analysis. The identification of the Polynesian-specific hyperuricemia-associated variant can be applied in precision medicine and public health genomics to improve health outcomes for the target population.