X‐linkage does not account for the absence of father–son similarity in plasma uric acid concentrations

Abstract

Plasma uric acid concentration aggregates in families, and this similarity has been suggested to be due, in part, to multiple shared genes. Men have higher plasma uric acid concentrations than women and are affected with gout nine times more frequently. Rare forms of hyperuricemia and gout are due to mutations of X-linked genes (HPRT1 and PRPS1). Given these observations, we tested the hypothesis that normal variation in plasma uric acid levels would display a pattern of familial similarity consistent with X-linkage in 892 individuals from 196 obese but otherwise healthy families. As predicted by X-linked inheritance, fathers and sons showed no resemblance in plasma uric acid concentration (r = 0.013, NS), while all other pairings showed moderate-to-strong familial resemblance (ranging from 0.167, P < 0.01, parent-offspring to 0.415, sister-sister, P < 0.01). We then tested the hypothesis that loci along the X chromosome would influence plasma uric acid concentration. We conducted both single-point and multipoint linkage analyses using 17 X-linked markers spaced at approximately 9 cm intervals to determine whether allele sharing among sibs was related to sib similarity in plasma uric acid concentrations (n = 1,100 sib pairs). We found no regions of the X chromosome that cosegregated with plasma uric acid concentrations (P > 0.05). We conclude that variation in genes on the X chromosome contribute little to normal variation in plasma uric acid concentrations.

The genetics of hyperuricaemia and gout

“…24 In one study of twins, the heritability of the renal clearance of urate was ~60%, whereas the estimated heritability of FEua was ~87%. 25 Other studies have shown that serum urate levels have a substantial heritable component (~40%).…”

TT genotype of rs2941484 in the human HNF4G gene is associated with hyperuricemia in Chinese Han men

“…Elevated levels of uric acid were found to be associated with inflammation, oxidative stress, insulin resistance, dysglycemia, endothelial dysfunction, vascular, renal and cardiac stiffness, cardiac diastolic dysfunction, renal hyperfiltration and proteinuria [19–21]. Studies of twins and families have shown the inheritance for both hyperuricaemia and excretion of urate via the kidneys [22]. In one study in twins, the heritability of the renal clearance of urate was 60% to 87% [23].…”

Pathogenesis of hyperuricemia: Recent advances

“…Rare forms of hyperuricemia and gout are caused by mutations of X-linked genes (HPRT and PRPS). All of these data suggest that genes responsible for uric acid regulation might reside on the X chromosome [7].…”

“…In a study of 892 obese members from 196 families, Reed and Price [7] found that variations in genes on the X chromosome contributed little to the normal variation in plasma uric acid concentration. They tested the hypothesis that loci along the X chromosome would influence the plasma uric acid concentration but found no regions that cosegregated with the plasma uric acid concentrations.…”