Elsevier

Seminars in Nephrology

Volume 31, Issue 5, September 2011, Pages 420-425
Seminars in Nephrology

Population Heterogeneity in the Genetic Control of Serum Urate

https://doi.org/10.1016/j.semnephrol.2011.08.005Get rights and content

Summary

Scanning of the genome in Caucasian cohorts for genes that control serum urate levels have revealed eight confirmed associations. Knowledge of genetic control of serum urate in other populations can be extrapolated from the study of gout, a condition of extreme hyperuricemia; three urate transport genes (SLC2A9, ABCG2, and SLC17A1/NPT1) have been studied in diverse populations (Caucasian, Asian, and Polynesian). Between-population heterogeneity is evident in allele frequency and association with gout, notably within Polynesian populations, which are defined by a geographic region and shared ancestry but also characterized by migratory events that create bottlenecks and alter genetic structure in the founder populations. Despite the large genome-wide studies in Caucasians, only 5% of the variance in serum urate levels has been explained. A more complete picture will be revealed by very large meta-analyses of genome-wide association scans in Caucasian and in other populations with less genetic heterogeneity than Caucasians.

Section snippets

Genetic Influences on Serum Urate Levels in Caucasians

Rates of renal clearance of uric acid are known to vary between ethnic groups,4, 5 and twin studies have shown that renal clearance of uric acid has a considerable heritable proportion (60%),6 and follows a complex non-Mendelian pattern of inheritance.7 Li et al8 first reported an association of the SLC2A9 (GLUT9) gene with serum urate concentrations in Italian cohorts, and this rapidly was replicated in a number of other GWAS for serum urate concentrations in population-based cohorts.9, 10, 11

Gout as a Condition of Hyperuricemia

Nearly all knowledge generated regarding genetic control of serum urate levels has been derived from the Caucasian GWAS described earlier, aside from the previously described African American analysis.13 To review the role of the newly identified genes in genetics of serum urate levels in other ancestral groups, we have focused on gout as a model of severe hyperuricemia, with hyperuricemia being defined as a serum urate level greater than 7 mg/dL in men and greater than 6 mg/dL in women. A

SLC2A9

Population heterogeneity in genetic association with gout is clearly evident at SLC2A9 (Table 1). In the case of the intronic variants there is genetic association in Caucasian, New Zealand Pacific Island, and New Zealand Māori people.24 New Zealand Māori and, to a lesser extent, Pacific Island people living in New Zealand, are admixed populations, predominantly with Caucasians. Study of tightly linked groups of markers (haplotypes) suggests that the association at this SLC2A9 locus is driven

ABCG2

With the notable exception of New Zealand Māori, there is consistent and strong association of the Q141K (rs2231142) variant of ABCG2 with gout in Caucasian, Asian, and Pacific Island people (Table 1),16, 33, 34, 35 with ORs ranging from 1.7 in Han Chinese to 2.8 in Pacific Island people living in New Zealand. In contrast to the SLC2A9 variants discussed earlier, there is strong evidence that Q141K is the causative variant in Caucasians; rs2231142 is the most associated genetic variant in the

NPT1

The NPT1 (SLC17A1; sodium-phosphate transporter 1) gene encodes for a urate transporter expressed in the apical membrane of renal tubule cells.37 In contrast to SLC2A9 and ABCG2 there is consistent evidence for association of NPT1 with gout across populations (OR, 1.3-1.7), despite considerable variation in frequency of the risk allele (Table 1). One likely etiologic variant is T269I (rs1165196); this variant is associated with gout in a Japanese sample set,38 and the NPT1 variant associated

Gender-Gene Interactions at SLC2A9 and ABCG2

The influence of the intronic variants of SLC2A9 on serum urate levels is stronger in women than men in most,8, 9, 10, 12, 13 but not all,11 Caucasian sample sets. However, there is no convincing gender bias reported for SLC2A9 in gout, this could be owing to either the smaller gout sample sets studied or, more likely, given that SLC2A9 determines serum urate levels, where a gender effect is observed, and that gout is a condition of extreme serum urate levels in both men and women, a gender

Concluding Remarks

Data from the three genes (SLC2A9, ABCG2, and NPT4), summarized in Table 1, indicate heterogeneity in genetic control of gout and, by inference, serum urate levels, between Caucasian, Asian, and Polynesian populations. At the three genes, there is no correlation between the frequency of the risk allele and the frequency of gout (Table 1), although such an observation needs to be qualified with the acknowledgement that environments differ between the various populations. We are only scratching

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