Evaluate the effects of serum urate level on bone mineral density: a genome-wide gene-environment interaction analysis in UK Biobank cohort

Abstract

Introduction: Serum urate is associated with BMD and may be a protective factor. However, the exact association and mechanism are still unclear. We performed a genome-wide gene-environmental interaction study (GWGEIS) to explore the interaction effects between gene and urate on BMD, using data from the UK Biobank cohort.

Methods: A total of 4575 participants for femur total BMD, 4561 participants for L1-L4 BMD, and 237799 participants for heel BMD were included in the present study. Linear regression models were used to test for associations between urate and BMD (femur total BMD, L1-L4 BMD, heel BMD) by R software. GWGEIS was conducted by PLINK 2.0 using a generalize linear model, adjusted for age, sex, weight, smoking behavior, drinking behavior, physical activity and 10 principle components for population structure.

Results: Results showed that urate was positively associated with femur total BMD, L1-L4 BMD and heel BMD and similar findings were observed in both the male and female subgroups. GWGEIS identified 261 genome-wide significant (P < 5.00 × 10^-8) SNP × urate interaction effects for femur total BMD (rs8192585 in NOTCH4, rs116080577 in PBX1, rs9409991 in COL5A1), 17 genome-wide significant SNP × urate interaction effects for heel BMD (rs145344540 in PDE11A and rs78485379 in DKK2), 17 suggestive genome-wide SNP × urate interaction effects (P < 1.00 × 10^-5) for L1-L4 BMD (rs10977015 in PTPRD). We also detected genome-wide significant and suggestive SNP × urate interaction effects for BMD in both the male and female subgroups.

Conclusions: This study reported several novel candidate genes, and strengthen the evidence of the interactive effects between gene and urate on the variations of BMD.

Keywords: Bone mineral density (BMD); Genes; Genetics; Genome-wide gene–environmental interaction study; Serum urate.