1.
Association of Uric Acid with Incident Metabolic Syndrome in a Japanese General Population.
Sumiyoshi, H, Ohyama, Y, Imai, K, Kurabayashi, M, Saito, Y, Nakamura, T
International heart journal. 2019;(4):830-835
Abstract
Uric acid is associated with cardiovascular disease (CVD) and its risk factors. Here, we examined the association between the serum uric acid level and incident metabolic syndrome in a Japanese general population. This retrospective, observational study was based on data obtained from an annual health checkup program in Gunma Prefecture, Japan. We evaluated 14,793 participants who did not use antihypertensive or antidiabetic medications and did not present with CVD or metabolic syndrome at the study baseline in 2009. Metabolic syndrome was defined as per the Japanese diagnostic criteria. A discrete proportional hazards regression model was used to evaluate the association between the serum uric acid level at baseline and the incident metabolic syndrome through 2012 and was adjusted for age, gender, waist circumference, systolic and diastolic blood pressure, fasting blood glucose, high-density lipoprotein cholesterol, and triglyceride. At baseline, the average age of the participants was 48.9 years, who were comprised of 40% women. The mean serum uric acid level at baseline was 5.3 ± 1.4 mg/dL. During the three-year follow-up, 7% of the cohort (n = 1,031) developed metabolic syndrome. The uric acid level was strongly associated with incident metabolic syndrome in the multivariable model (adjusted hazard ratio: 1.10; 95% confidence interval, 1.04-1.17; P < 0.01 per 1 mg/dL increase for uric acid). Higher uric acid levels were independently associated with a greater risk of incident metabolic syndrome in a Japanese general population.
2.
Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals.
Nakatochi, M, Kanai, M, Nakayama, A, Hishida, A, Kawamura, Y, Ichihara, S, Akiyama, M, Ikezaki, H, Furusyo, N, Shimizu, S, et al
Communications biology. 2019;:115
Abstract
Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10-8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci-TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A-are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout.
3.
The effects of URAT1/SLC22A12 nonfunctional variants, R90H and W258X, on serum uric acid levels and gout/hyperuricemia progression.
Sakiyama, M, Matsuo, H, Shimizu, S, Nakashima, H, Nakamura, T, Nakayama, A, Higashino, T, Naito, M, Suma, S, Hishida, A, et al
Scientific reports. 2016;:20148
Abstract
Urate transporter 1 (URAT1/SLC22A12), a urate transporter gene, is a causative gene for renal hypouricemia type 1. Among several reported nonsynonymous URAT1 variants, R90H (rs121907896) and W258X (rs121907892) are frequent causative mutations for renal hypouricemia. However, no case-control study has evaluated the relationship between gout and these two variants. Additionally, the effect size of these two variants on serum uric acid (SUA) levels remains to be clarified. Here, 1,993 primary gout patients and 4,902 health examination participants (3,305 males and 1,597 females) were genotyped with R90H and W258X. These URAT1 variants were not observed in any gout cases, while 174 subjects had the URAT1 variant in 2,499 health examination participants, respectively (P = 8.3 × 10(-46)). Moreover, in 4,902 health examination participants, the URAT1 nonfunctional variants significantly reduce the risk of hyperuricemia (P = 6.7 × 10(-19); risk ratio = 0.036 in males). Males, having 1 or 2 nonfunctional variants of URAT1, show a marked decrease of 2.19 or 5.42 mg/dl SUA, respectively. Similarly, females, having 1 or 2 nonfunctional variants, also evidence a decrease of 1.08 or 3.89 mg/dl SUA, respectively. We show that URAT1 nonfunctional variants are protective genetic factors for gout/hyperuricemia, and also demonstrated the sex-dependent effect size of these URAT1 variants on SUA (P for interaction = 1.5 × 10(-12)).