AUTHOR=Topless Ruth K. , Flynn Tanya J. , Cadzow Murray , Stamp Lisa K. , Dalbeth Nicola , Black Michael A. , Merriman Tony R. 

TITLE=Association of SLC2A9 genotype with phenotypic variability of serum urate in pre-menopausal women

JOURNAL=Frontiers in Genetics

VOLUME=6

YEAR=2015

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2015.00313

DOI=10.3389/fgene.2015.00313

ISSN=1664-8021

ABSTRACT=<p>The <italic>SLC2A9</italic> gene, that encodes a renal uric acid reuptake transporter, has genetic variants that explain ∼3% of variance in urate levels. There are previous reports of non-additive interaction between <italic>SLC2A9</italic> genotype and environmental factors which influence urate control. Therefore, our aim was to further investigate the general phenomenon that such non-additive interactions contribute to genotype-specific association with variance at <italic>SLC2A9</italic>. Data from 14135 European individuals were used in this analysis. The measure of variance was derived from a ranked inverse normal transformation of residuals obtained by regressing known urate-influencing factors (sex, age, and body mass index) against urate. Variant <italic>rs6449173</italic> showed the most significant effect on serum urate variance at <italic>SLC2A9</italic> (<italic>P</italic> = 7.9 × 10<sup>-14</sup>), which was maintained after accounting for the effect on average serum urate levels (<italic>P</italic> = 0.022). Noting the stronger effect in a sub-cohort that consisted of pre-menopausal women and younger men, the participants were stratified into males and pre-menopausal and post-menopausal women. This revealed a strong effect on variance in pre-menopausal women (<italic>P</italic> = 3.7 × 10<sup>-5</sup>) with a weak effect in post-menopausal women (<italic>P</italic> = 0.032) and no effect in men (<italic>P</italic> = 0.22). The T-allele of <italic>rs6449173</italic>, which associates with increased urate levels, was associated with the greater variance in urate. There was a non-additive interaction between <italic>rs6449173</italic> genotype and female gender in control of serum urate levels that was driven by a greater increase in urate levels associated with the T-allele in women. Female hormones, and/or other factors they influence or are associated with (such as iron levels, temperature, testosterone) interact with <italic>SLC2A9</italic> genotype in women to determine urate levels. The association of <italic>SLC2A9</italic> with greater variance in pre-menopausal women may reflect the cyclical changes resulting from menstruation.</p>