Population Heterogeneity in the Genetic Control of Serum Urate
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
References (43)
- et al.
Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia
Am J Hum Genet
(2008) - et al.
Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide study
Lancet
(2008) - et al.
GLUT1 and GLUT9 as major contributors to glucose influx in HepG2 cells identified by a high sensitivity intramolecular FRET glucose sensor
Biochim Biophys Acta
(2008) - et al.
Association between intronic SNP in urate-anion exchanger gene, SLC22A12, and serum uric acid levels in Japanese
Life Sci
(2006) - et al.
Asymptomatic hyperuricemiaRisks and consequences in the Normative Aging Study
Am J Med
(1987) - et al.
Type 1 sodium-dependent phosphate transporter (SLC17A1 protein) is a Cl (-)-dependent urate exporter
J Biol Chem
(2010) Genomewide association studies and assessment of the risk of disease
N Engl J Med
(2010)- et al.
The human genome and understanding of common disease: current technologies
Cell Mol Life Sci
(2007) - et al.
Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis
Nat Genet
(2010) - et al.
Hyperuricaemia, gout and kidney function in New Zealand Māori men
Br J Rheumatol
(1984)
Polynesian women are also at risk for hyperuricaemia and gout because of a genetic defect in renal urate handling
Br J Rheumatol
The genetics of renal excretion of urate in man
Ann Rheum Dis
Segregation analysis of serum uric acid in the NHLBI Family Heart Study
Hum Genet
The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts
PLoS Genet
SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout
Nat Genet
SLC2A9 influences uric acid concentrations with pronounced sex-specific effects
Nat Genet
Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in old order Amish
Arthritis Rheum
Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout
Proc Natl Acad Sci U S A
Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population
Sci Translational Med
Functional analysis of SNPs variants of BCRP/ABCG2
Pharm Res
Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations
PLos Genet
Cited by (27)
Mathematical modeling analysis of hepatic uric acid disposition using human sandwich-cultured hepatocytes
2020, Drug Metabolism and PharmacokineticsCitation Excerpt :Among uric acid transporters expressed in hepatocytes, OAT2 was disregarded in the present study, since OAT2 transports uric acid uni-directionally into the cells and does not contribute to sinusoidal efflux to systemic circulation from hepatocytes [6]. In addition, all these transporters have been suggested to associate with SUA level and/or incidence of gout by genome-wide association studies [29–32]. In mice, Glut9 is expressed on the sinusoidal membrane of hepatocytes and greatly affects uric acid disposition by exhibiting hyperuricaemic and hyperuricosuric state in liver-specific Glut9 knockout mice [13].
Gout – An update of aetiology, genetics, co-morbidities and management
2018, MaturitasCitation Excerpt :More recently discovered is the contribution of decreased function of the ABCG2 transporter in the gut contributing to hyperuricaemia [6]. Genetic variation makes a substantial contribution to the variation seen in the prevalence of gout across different ethnic groups [7,8]. Recent developments in gout genetics include the discovery of an association between reduced mitochondrial genetic copy number and gout [9].
Hyperuricemia, Acute and Chronic Kidney Disease, Hypertension, and Cardiovascular Disease: Report of a Scientific Workshop Organized by the National Kidney Foundation
2018, American Journal of Kidney DiseasesCitation Excerpt :The lower range of urate concentrations, described in people consuming traditional non-Western diets, is 2 to 4 mg/dL (120-240 μM).4 Serum urate concentrations are higher in industrialized populations (3-8 mg/dL [180-480 μM]), reflecting diets richer in purines and fructose (both of which generate urate), greater alcohol intake, increased prevalence of factors that reduce kidney urate excretion (eg, insulin resistance, renal vasoconstriction associated with hypertension, and decreased kidney function),4 and interpopulation genetic differences.5 In humans, serum urate is excreted by the kidney (two-thirds) and gut (one-third).
Epidemiology of Gout and Hyperuricemia
2018, GoutGenomic Influences on Hyperuricemia and Gout
2017, Rheumatic Disease Clinics of North AmericaGout: Joints and beyond, epidemiology, clinical features, treatment and co-morbidities
2014, MaturitasCitation Excerpt :Gout is a disease with strong environmental influences, but also substantial genetic risk factors, and intriguing new evidence has demonstrated interactions between genetic risk factors and dietary influences. While an accurate estimate of the heritability of gout is elusive, it is clear that there are substantial genetic influences of the risk of gout [17]. Heritability of the critical precursor hyperuricaemia is very high at 60–90% [18,19].