Identification of CDC42BPG as a novel susceptibility locus for hyperuricemia in a Japanese population

Mol Genet Genomics. 2018 Apr;293(2):371-379. doi: 10.1007/s00438-017-1394-1. Epub 2017 Nov 9.

Abstract

Chronic kidney disease and hyperuricemia are serious global health problems. Recent genome-wide association studies have identified various genetic variants related to these disorders. However, most studies have been conducted in a cross-sectional manner. To identify novel susceptibility loci for chronic kidney disease or hyperuricemia, we performed longitudinal exome-wide association studies (EWASs), using ~ 244,000 genetic variants and clinical data of Japanese individuals who had undergone annual health checkups for several years. After establishing quality controls, the association of renal function-related traits in 5648 subjects (excluding patients with dialysis and population outliers) with 24,579 single nucleotide variants (SNVs) for three genetic models (P < 3.39 × 10- 7) was tested using generalized estimating equation models. The longitudinal EWASs revealed novel relations of five SNVs to renal function-related traits. Cross-sectional data for renal function-related traits in 7699 Japanese subjects were examined in a replication study. Among the five SNVs, rs55975541 in CDC42BPG was significantly (P < 4.90 × 10- 4) related to the serum concentration of uric acid in the replication cohort. We also examined the SNVs detected in our longitudinal EWASs with the information on P values in GKDGEN meta-analysis data. Four SNVs in SLC15A2 were significantly associated with the estimated glomerular filtration rate in European ancestry populations, although these SNVs were related to the serum concentration of uric acid with borderline significance in our longitudinal EWASs. Our findings indicate that CDC42BPG may be a novel susceptibility locus for hyperuricemia.

Keywords: Chronic kidney disease; Creatinine; Estimated glomerular filtration rate; Generalized estimating equation; Hyperuricemia; Uric acid.

MeSH terms

  • Asian People / genetics
  • Cohort Studies
  • Cross-Sectional Studies
  • Female
  • Genetic Predisposition to Disease / ethnology
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study / methods
  • Glomerular Filtration Rate
  • Humans
  • Hyperuricemia / blood
  • Hyperuricemia / ethnology
  • Hyperuricemia / genetics*
  • Japan
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Protein Serine-Threonine Kinases / genetics*
  • Uric Acid / blood

Substances

  • Uric Acid
  • CDC42BPG protein, human
  • Protein Serine-Threonine Kinases