Sex Differences in Urate Handling

Abstract

Hyperuricemia, or elevated serum urate, causes urate kidney stones and gout and also increases the incidence of many other conditions including renal disease, cardiovascular disease, and metabolic syndrome. As we gain mechanistic insight into how urate contributes to human disease, a clear sex difference has emerged in the physiological regulation of urate homeostasis. This review summarizes our current understanding of urate as a disease risk factor and how being of the female sex appears protective. Further, we review the mechanisms of renal handling of urate and the significant contributions from powerful genome-wide association studies of serum urate. We also explore the role of sex in the regulation of specific renal urate transporters and the power of new animal models of hyperuricemia to inform on the role of sex and hyperuricemia in disease pathogenesis. Finally, we advocate the use of sex differences in urate handling as a potent tool in gaining a further understanding of physiological regulation of urate homeostasis and for presenting new avenues for treating the constellation of urate related pathologies.

Estimation of non-additive genetic variance in human complex traits from a large sample of unrelated individuals

“…Previous studies 36,37 have suggested that urate concentration is a trait on the low spectrum of polygenicity and controlled by three main genes and two large effect QTLs on chromosome 4. Moreover, urate concentration also displays sex-specific effects and heritability 38 . Analysis performed on each sex separately (with a 3 fold IVW meta-analysis for REML) confirmed a larger estimated heritability in females under HE and 0.354 ± 0.005 under REML) than in males under HE and 0.237 ± 0.006 under REML), and a significant dominance variance for females only under HE analysis (, P = 1.4e-3 for females, and ±, P = 3.9e-1 for males).…”

“…Altogether, low polygenicity of urate concentration combined with substantial sex differences in the genetic architecture on chromosome 4 constitute strong departure from assumptions underlying the consistency of HE and REML estimators. There is also prior evidence of female sex hormones effects on urate concentration 38 , which we did not accounted for in our analysis, and further investigations of the sex-specific genetic architecture of the trait are needed. Finally, we detected significant dominance deviation ( P < 5e-8) at two SNPs on chromosome 1 (top hit for rs12124078, a SNP associated with kidney function 39 ) and 4 (larger signal with top hit for rs9998811 located in SLC2A9 gene region 36 ), ( Supplementary Figure 7 ) although the total dominance variance explained by these two SNPs remains very small .…”

How Are We Managing Patients with Hyperuricemia and Gout: A Cross Sectional Study Assessing Knowledge and Attitudes of Primary Care Physicians?

“…The final product of purine and protein metabolism in humans is uric acid. Hyperuricemia is defined as an excess of serum uric acid which may lead to the precipitation of uric acid crystals [1,2]. In around 90% of persons with hyperuricemia, there is an insufficient excretion of urate in the kidneys indicating a genetic predisposition [1].…”

“…In around 90% of persons with hyperuricemia, there is an insufficient excretion of urate in the kidneys indicating a genetic predisposition [1]. Moreover, serum uric acid levels show a strong heritable component [2]. Other causes include increased endogenous purine production and the consumption of high-purine diets [1].…”

Roma Ethnicity and Sex-Specific Associations of Serum Uric Acid with Cardiometabolic and Hepatorenal Health Factors in Eastern Slovakian Population: The HepaMeta Study

“…Endogenous estradiol appears to decrease uric acid levels by lowering the post-secretory tubular reabsorption of uric acid [ 22 ]. Notably, estrogen may play a role in the regulation of expression or activity of uric acid transporters, specifically ABCG2 and SLC2A9; estrogen could mediate either direct transcriptional regulation of the transporter genes or activate transporter-specific transcription factors, including HNF4α [ 23 ]. Thus, using sex as a biological variable may provide key insights into understanding uric acid handling [ 24 ].…”