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Predictive value of 8 genetic loci for serum uric acid concentration.

ABSTRACT: AIM:To investigate the value of genomic information in prediction of individual serum uric acid concentrations. METHODS:Three population samples were investigated: from isolated Adriatic island communities of Vis (n=980) and Korcula (n=944), and from general population of the city of Split (n=507). Serum uric acid concentration was correlated with the genetic risk score based on 8 previously described genes: PDZK1, GCKR, SLC2A9, ABCG2, LRRC16A, SLC17A1, SLC16A9, and SLC22A12, represented by a total of 16 single-nucleotide polymorphisms (SNP). The data were analyzed using classification and regression tree (CART) and general linear modeling. RESULTS:The most important variables for uric acid prediction with CART were genetic risk score in men and age in women. The percent of variance for any single SNP in predicting serum uric acid concentration varied from 0.0%-2.0%. The use of genetic risk score explained 0.1%-2.5% of uric acid variance in men and 3.9%-4.9% in women. The highest percent of variance was obtained when age, sex, and genetic risk score were used as predictors, with a total of 30.9% of variance in pooled analysis. CONCLUSION:Despite overall low percent of explained variance, uric acid seems to be among the most predictive human quantitative traits based on the currently available SNP information. The use of genetic risk scores is a valuable approach in genetic epidemiology and increases the predictability of human quantitative traits based on genomic information compared with single SNP approach.

SUBMITTER: Gunjaca G

PROVIDER: S-EPMC2829178 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Predictive value of 8 genetic loci for serum uric acid concentration.

Gunjaca Grgo G Boban Mladen M Pehlić Marina M Zemunik Tatijana T Budimir Danijela D Kolcić Ivana I Lauc Gordan G Rudan Igor I Polasek Ozren O

Croatian medical journal 20100201 1

<h4>Aim</h4>To investigate the value of genomic information in prediction of individual serum uric acid concentrations.<h4>Methods</h4>Three population samples were investigated: from isolated Adriatic island communities of Vis (n=980) and Korcula (n=944), and from general population of the city of Split (n=507). Serum uric acid concentration was correlated with the genetic risk score based on 8 previously described genes: PDZK1, GCKR, SLC2A9, ABCG2, LRRC16A, SLC17A1, SLC16A9, and SLC22A12, repr ...[more]

PMID: 20162742

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Project description:BackgroundHyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout.MethodsGenome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p<5.0 x 10(-8)) or the Rotterdam cohort (p<1.0 x 10(-7)) were evaluated with gout. The results obtained in white participants were combined using meta-analysis.FindingsThree loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7.0 x 10(-168) and 2.9 x 10(-18) for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2.5 x 10(-60) and 9.8 x 10(-4)), and rs1165205 in SLC17A3 (p=3.3 x 10(-26) and 0.33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0.59 per T allele, 95% CI 0.52-0.68, p=7.0 x 10(-14)), rs2231142 (1.74, 1.51-1.99, p=3.3 x 10(-15)), and rs1165205 (0.85, 0.77-0.94, p=0.002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1.71, 1.06-2.77, p=0.028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272-351 mumol/L in the Framingham cohort, 269-386 mumol/L in the Rotterdam cohort, and 303-426 mumol/L in white participants of the ARIC study) and gout (frequency 2-13% in the Framingham cohort, 2-8% in the Rotterdam cohort, and 1-18% in white participants in the ARIC study).InterpretationWe identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout.

Project description:ObjectiveSerum uric acid is the end-product of purine metabolism and at high levels is a risk factor for several human diseases including gout and cardiovascular disease. Heritability estimates range from 0.32 to 0.63. Genome-wide association studies (GWAS) provide an unbiased approach to identify loci influencing serum uric acid. Here, we performed the first GWAS for serum uric acid in continental Africans, with replication in African Americans.MethodsAfricans (n = 4126) and African Americans (n = 5007) were genotyped on high-density GWAS arrays. Efficient mixed model association, a variance component approach, was used to perform association testing for a total of ~ 18 million autosomal genotyped and imputed variants. CAVIARBF was used to fine map significant regions.ResultsWe identified two genome-wide significant loci: 4p16.1 (SLC2A9) and 11q13.1 (SLC22A12). At SLC2A9, the most strongly associated SNP was rs7683856 (P = 1.60 × 10-44). Conditional analysis revealed a second signal indexed by rs6838021 (P = 5.75 × 10-17). Gene expression and regulatory motif data prioritized a single-candidate causal variant for each signal. At SLC22A12, the most strongly associated SNP was rs147647315 (P = 6.65 × 10-25). Conditional analysis and functional annotation prioritized the missense variant rs147647315 (R (Arg) > H (His)) as the sole causal variant. Functional annotation of these three signals implicated processes in skeletal muscle, subcutaneous adipose tissue and the kidneys, respectively.ConclusionsThis first GWAS of serum uric acid in continental Africans identified three associations at two loci, SLC2A9 and SLC22A12. The combination of weak linkage disequilibrium in Africans and functional annotation led to the identification of candidate causal SNPs for all three signals. Each candidate causal variant implicated a different cell type. Collectively, the three associations accounted for 4.3% of the variance of serum uric acid.

Project description:Objective:There is no consensus on the role of abnormal uric acid (UA) levels in the prognosis of patients undergoing hemodialysis. We therefore aimed to investigate the effects of changes in UA concentration on the risk of all-cause death and cardiac death in such patients. Method:In this retrospective cohort study, patients admitted to two hemodialysis centers performing maintenance hemodialysis (MHD) in Wuhan First Hospital and Fourth Hospital Hemodialysis Center from January 1, 2007, to October 31, 2017, were included. Results:In all, 325 patients undergoing MHD aged 59.7 ± 14.7 years, including 195 men (60%), were enrolled, with a median follow-up of 37 months. Serum UA (p < 0.001) was significantly higher in the surviving group than in the death group. No significant difference was found in UA variability (p < 0.001) was significantly higher in the surviving group than in the death group. No significant difference was found in UA variability (p < 0.001) was significantly higher in the surviving group than in the death group. No significant difference was found in UA variability (p < 0.001) was significantly higher in the surviving group than in the death group. No significant difference was found in UA variability (p < 0.001) was significantly higher in the surviving group than in the death group. No significant difference was found in UA variability (p < 0.001) was significantly higher in the surviving group than in the death group. No significant difference was found in UA variability (p < 0.001) was significantly higher in the surviving group than in the death group. No significant difference was found in UA variability (p < 0.001) was significantly higher in the surviving group than in the death group. No significant difference was found in UA variability (. Conclusion:Low UA levels were closely related to all-cause mortality in patients undergoing MHD. Although UA levels had no significant effect on cardiac death, they had a good predictive value for long-term prognosis in patients on MHD.

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Predictive value of 8 genetic loci for serum uric acid concentration.

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Predictive value of 8 genetic loci for serum uric acid concentration.

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