Significant interaction between LRP2 rs2544390 in intron 1 and alcohol drinking for serum uric acid levels among a Japanese population

Abstract

A genome-wide association study identified that LRP2 rs2544390 in intron 1 was associated with serum uric acid (SUA) levels among Japanese, as well as polymorphisms of SLC22A12, ABCG2, and SLC2A9. This study aimed to confirm the association of rs2544390 C/T with SUA, as well as another LRP2 polymorphism (rs3755166 G/A) in the promoter. Subjects were 5016 health checkup examinees (3409 males and 1607 females) aged 35 to 69years with creatinine<2.0mg/dL. The subjects with SLC22A12 258WW, SLC2A9 rs11722228C allele, ABCG2 126QQ and 141Q allele (2546 males and 1199 females) were selected for analysis. Mean SUA was 6.03mg/dL for CC, 6.18mg/dL for CT, and 6.19mg/dL for TT among males (p=0.012), and 4.49mg/dL, 4.45mg/dL, and 4.42mg/dL among females (not significant), respectively. No association was observed for rs3755166. The association with rs2544390 was stronger among male drinkers. The odds ratio of drinking ≥5/week relative to no drinking for hyperuricemia (SUA≥7mg/dL and/or under medication for hyperuricemia) was 1.11 (95% confidence interval, 0.67-1.84) among CC males, 1.75 (1.22-2.51) among CT males, and 3.13 (1.80-5.43) among TT males. The interaction terms with drinking ≥5/week were 1.56 (p=0.156) for CT and 2.87 (p=0.005) for TT. This was the first report on the interaction between LRP2 genotype and alcohol drinking for SUA. Since the low density lipoprotein-related protein 2 (megalin) encoded by LRP2 is a multi-ligand endocytic receptor expressed in many tissues including the kidney proximal tubules, the association/interaction remained to be confirmed both epidemiologically and biologically.