Background/Purpose: Consumption of drinks sweetened with sugar or high fructose corn syrup increases both serum urate levels and the risk for gout. SLC2A9 encodes a renal urate transporter that exchanges uric acid for glucose and fructose. Genetic variants in SLC2A9 explain 3.5% of the variation in serum urate levels in European Caucasian (EC) populations and are strongly associated with gout in EC and New Zealand (NZ) Maori and Pacific Island (Polynesian) people. Because SLC2A9 transports both uric acid and simple hexose sugars we tested the hypothesis that SLC2A9 genotype and sugar-sweetened beverage (SSB) consumption interact to determine the risk for gout.

Methods: NZ survey data from 1623 people with and without gout were used. Gout was determined by ARA preliminary classification criteria. SSB consumption was self-reported, including fruit juice, where one unit of drink was defined as a can or large glass. Data from the Atherosclerosis Risk in Communities (ARIC) study were also used (6003 EC controls and 153 primary gout cases determined by self-report). Two ancestral groups were studied; EC (NZ and ARIC) and NZ Polynesian. The NZ samples were genotyped for SLC2A9 single nucleotide polymorphism (SNP) rs11942223 using Taqman® technology. The ARIC samples had previously been genotyped for surrogate marker rs6449173. STATA v8.0 statistical software was used, with an interaction term included in the logistic regression analysis, derived from the ratio of the estimated odds ratio (OR) comparing exposed (≥4 SSB/day) and unexposed (<4 SSB/day) rs11942223 risk allele (T) homozygotes with the estimated OR comparing exposed and unexposed people positive for the rs11942223 protective allele (C).

Results: The risk of gout associated with consuming ≥4 SSB/day without stratification by genotype was similar to the increased genetic risk observed in the T-allele homozygous groups (Table). However the normally protective C-allele conferred a considerable increase in risk for gout in individuals exposed to ≥4 SSB/day (for example OR increased from 0.51 to 4.93 in Polynesian. The genotype by interaction term (ORI) was significant in Polynesian (ORI=5.31, P=0.043) but not in EC (ORI =5.31, P=0.087) (all adjusted by sample set, age, sex, BMI). Combining the two groups revealed significant evidence for interaction (ORI=4.74, P=0.003).

Conclusion:

When exposed to high SSB consumption individuals with the normally gout-protective allele at rs11942223 have a considerably elevated risk of gout. Our data suggest that SLC2A9-mediated uric acid transport is physiologically influenced by excess simple sugars derived from SSB, with excess SSB consumption negating the gout-risk discrimination normally mediated by rs11942223.  

Table. Risk of gout for ≥4 SSB/day stratified by genotype at SLC2A9

	European Caucasian			Polynesian (Maori/Pacific Island)
	Obs	OR [95% CI]1	P	Obs	OR [95% CI]	P
≥4 SSB/day group unstratified	6735	1.88 [0.87-4.07]	0.11	1020	2.02 [1.37-2.98]	4.2×10-4
T-allele homozygous, <4 SSB/day	6685	1.00	–	951	1.00	­-
C-allele positive, <4 SSB/day		0.63 [0.47-0.84]	0.002		0.51 [0.28-0.93]	0.027
T-allele homozygous, ≥4 SSB/day		1.18 [0.48-2.91]	0.71		1.82 [1.19-2.77]	0.005
C-allele positive, ≥4 SSB/day		3.91 [0.74-20.70]	0.11		4.93 [1.14-21.33]	0.033

1. ORs were adjusted by BMI, age, sex, data set.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/epistatic-interaction-between-solute-carrier-2a9-genotype-and-sugar-sweetened-beverage-consumption-in-the-determination-of-gout-risk/