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

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.