Common genetic variants on bone morphogenetic protein receptor type IB (BMPR1B) gene are predictive for carotid intima-media thickness

Abstract

Background: Bone morphogenetic proteins (BMP) 2 and 4 are implicated in the development of atherosclerosis. However, the relationships between the proteins, their main receptors and carotid intima-media thickness (cIMT), a predictive preclinical phenotype of atherosclerosis, have not been established. Methods and Results: We screened and validated the relationships of single-nucleotide polymorphisms (SNPs) on BMP2, BMP4, BMPR1A, BMPR1B, and BMPR2 with thicker cIMT by 2 independent case-control studies that used different subject selection methods. Among 200 screened SNPs, 12 on BMPR1B were regarded as candidate genetic markers (P-value <5.0×10 -4 ). After combining the discovery and validation studies and adjusting for traditional cardiovascular risk factors, rs4456963*G, rs4235438*T, rs2522530*T, and rs3796433*C showed significant higher odds ratios (ORs) of having thicker cIMT (adjusted ORs: 1.50-1.56; all P-values <2.5×10 -4 ). Multivariate analyses showed that rs4456963 and rs3796433 were significantly independent determinants of cIMT thickening. The corresponding multivariate-adjusted ORs for rs4456963*G and rs3796433*C alleles were 1.50 (95% confidence interval (CI): 1.22-1.84) and 1.50 (95% CI: 1.23-1.82), respectively. Interaction between rs4456963 and rs3796433 was evident by the significantly higher OR (8.16, 95% CI: 3.12-21.3) for subjects with the GG-CC genotype. The rs4456963*G and rs3796433*C showed positively linear trends with severity of carotid atherosclerosis. Conclusions: We identified 2 SNPs on BMPR1B showing significantly independent correlations with thicker cIMT. The study provides invaluable evidence supporting that BMPR1B is closely related to carotid atherosclerosis and a potential target for the development of therapeutic agents for atherosclerotic disease.