Genetic-epidemiological analysis of hypouricemia from 4,993 Japanese on nonfunctional variants of URAT1/SLC22A12 gene.

Objectives Up to 0.3% of Japanese have hypouricemia. Most cases appear to result from a hereditary disease, renal hypouricemia (RHUC), which causes exercise-induced acute kidney injury and urolithiasis. However, to what extent RHUC accounts for hypouricemia is not known. We therefore investigated its frequency and evaluated its risks by genotyping a general Japanese population. Methods A cohort of 4,993 Japanese was examined by genotyping the nonfunctional variants R90H (rs121907896) and W258X (rs121907892) of URAT1/SLC22A12, the two commonest causative variants of RHUC in Japanese. Results Participants' fractional excretion of uric acid and risk allele frequencies markedly increased at lower SUA levels. Ten participants (0.200%) had a serum uric acid (SUA) level of ≤ 2.0 mg/dl and nine had R90H or W258X, likely to have RHUC. Logistic regression analysis revealed these URAT1 variants to be significantly and independently associated with the risk of hypouricemia and mild hypouricemia (SUA ≤ 3.0 mg/dl) as well as sex, age, and BMI, but these URAT1 variants were the only risks in the hypouricemia population (SUA ≤ 2.0 mg/dl). W258X was only the risk in males with SUA of ≤ 3.0 mg/dl. Conclusion Our study accurately reveals the prevalence of RHUC and provides genetic evidence for its definition (SUA ≤ 2.0 mg/dl). We also show that individuals with SUA of ≤ 3.0 mg/dl, especially males, are prone to RHUC. Our findings will help to promote a better epidemiological understanding of RHUC as well as more accurate diagnosis, especially in males with mild hypouricemia.