Background/Purpose: Common variants within the uric acid transporter genes SLC22A11 (OAT4) and SLC22A12 (URAT1) have been associated with hyperuricaemia and gout in multiple populations, but these associations have been with intronic or intergenic variants with no obvious causal role in protein function. This research aimed to characterise the exonic sequences of SLC22A11 and SLC22A12 in European and Polynesian individuals and assess whether rare non-synonymous variants in these genes are causal of hyperuricemia.

Methods: The exonic regions of SLC22A11 and SLC22A12 were sequenced in 422 individuals with hyperuricemia or gout (Polynesian = 227, European = 195) and 386 individuals without hyperuricemia or gout (Polynesian = 213, European = 173). All non-synonymous variants were identified and analysed using burden testing methods. SIFT, Polyphen-2, and PROVEAN were used to predict the effect of these non-synonymous variants on protein function.

Results: Eighteen non-synonymous variants were identified in SLC22A11 and SLC22A12, of these sixteen were missense (SLC22A11 = 9, SLC22A12 = 7) and two were nonsense (SLC22A11 = 1, SLC22A12 = 1). The nonsense variant in SLC22A11 was found in one Māori woman and three European men, all with high serum urate levels (average = 8.55 mg/dL), whilst the SLC22A12 nonsense variant was found in a Tongan man with a normal serum urate level of 5.04 mg/dL. Burden analyses of all non-synonymous variants in the European cohort produced a significant burden of risk variants (P = 0.02) in SLC22A11, and a significant burden of protective variants in SLC22A12 (P = 0.01). The same effect was not seen in the Polynesian cohort (P = 0.29 and 0.73, respectively). Prediction of the functional effects of each of the missense variants suggests only three of the nine SLC22A11 variants, but six of the seven SLC22A12 variants, modify protein function.

Conclusion: Rare non-synonymous variants in both SLC22A12 and SLC22A11 significantly associate with hyperuricemia in European individuals. Our data confirm the protective effect of rare genetic variants in SLC22A12, encoding the uric acid transporter URAT1. This is the first time rare genetic variants in SLC22A11 have been implicated in causing hyperuricemia, and our findings challenge current understanding of OAT4 (SLC22A11) as a transporter that mediates renal uric acid reabsorption. Notably, the vast majority of missense variants in other solute transporters are neutral or loss-of-function¹. 1. Leabman et al. Proc Natl Acad Sci U S A 2003;100:5896-901.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/exon-sequencing-reveals-a-significant-burden-of-non-synonymous-variants-in-both-slc22a11-oat4-and-slc22a12-urat1-in-european-hyperuricemic-individuals/