Thesis

The role of SLC2A9 Variants in Hyperuricemia and Gout

6 Jul 2005
Description

Gout is a debilitating arthritis caused by elevated levels of serum urate in the blood (hyperuricemia). The prevalence of gout is on the rise worldwide with particularly high rates of the disease present in Māori and Pacific populations in New Zealand (9.3-13.9% of Māori men and 14.9% of Pacific Island men affected). Genetic and environmental factors contribute to hyperuricemia and gout. The high rates of gout in some ethnic groups is thought to reflect genetic differences in serum urate regulation. Variation in the renal urate transporter gene, SLC2A9, has been associated with hyperuricemia and gout and recently with type 2 diabetes mellitus. A number of single nucleotide polymorphisms (SNPs) in SLC2A9 have been associated with hyperuricemia and gout, with rs11942223 found to be strongly associated across diverse ethnic populations. Previous studies have also found evidence for gene-environment interaction between SLC2A9 and sugar- sweetened beverage consumption contributing to gout.The aims of this study were to further characterise and identify causal variants within SLC2A9 and the underlying etiologic mechanisms such as gene-environment interaction using a case-control approach. Conditional analyses were carried out to test for association of SLC2A9 variants independent from the effect of rs11942223.It was also hypothesised that SNP-SNP interaction between non-synonymous SLC2A9 SNPs may be playing a role in gout. Analysis of Caucasian and Polynesian populations was performed to investigate potential molecular differences in gout pathology between ethnic groups.This study found evidence of eight independent associations of variants within SLC2A9 with gout in Caucasian (rs2280205, rs6820230, rs11942223, rs4529048, rs6811287, rs11934363, rs10008035 and rs6449144). Among these variants, rs2280205 and rs6820230 are non-synonymous SNPs. Rs2280205 was also associated with serum urate control independent of the allele at rs11942223 in Caucasian. The findings of this study support that of previous studies, with rs11942223 found to play a crucial role in the contribution of SLC2A9 to gout risk in Caucasian but not in Māori and Pacific populations where the prevalence of gout is high. This study suggests rs3733591, rs16890979, rs4529048 and rs6449144 may be better causal variant candidates in people of West Polynesian ancestry. Some evidence was found to suggest the influence of a common SLC2A9 copy number variant on gout in the East Polynesian ancestral group analysed. Furthermore there was evidence to support the hypothesis of SLC2A9 SNP-SNP interaction in both Caucasian and Pacific populations. None of the SNPs tested showed statistically significant evidence for gene-environment interaction with SSB consumption, although rs2280205 should be analysed in larger sample sets.

Publication Details
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Handle: 
http://hdl.Handle.net/10523/5046
Published year only: 
2005
6
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