Association between novel polymorphisms in COL1A1 gene and osteoporosis-related phenotypes

Abstract

Background: Osteoporosis is a common disease with a strong genetic component and the COLIA1 gene is an important candidate for susceptibility. Previous studies have focused on three polymorphisms in the 5′ flank of COL1A1. It is unclear however whether other SNP within COL1A1 might be associated with osteoporosis. Methods:We genotyped 25 common sequence variations selected from the Hapmap database (MAF>0.001) covering the COL1A1 gene and 10 kb upstream and downstream flanking sequences in the Rotterdam Study population (n=6383), which included 998 subjects with non-vertebral fracture; 265 with hip fracture and 354 with vertebral fracture. Genotyping was performed using the Sequenom iPLEX gold genotyping array. Results: Several SNP were associated with fractures and/or BMD. Three SNP were associated with non-vertebral fracture in males, independent of age and BMI, but the association appeared to be driven by the rs2857396 located in intron 30 (MAF=0.16, P=0.006, odds ratio [OR]=1.35, 95% CI: 1.09–1.68). The rs2075554 located in intron 11 was associated with hip fracture in both genders independent of age, BMI and femoral neck BMD (MAF=0.13, P=0.005, OR=1.79, 95% CI: 1.23–2.86). This SNP is in complete LD with rs2075555 which was previously associated with femoral neck width in the Framingham Study. Other associations for each trait were as follows: hip fracture, rs2586494 (both genders, MAF=0.13), p=0.003; vertebral fracture, rs2696247 (both genders, MAF=0.14), p=0.006; and femoral neck BMD, rs16948767 (females only, MAF=0.008), p=0.004. There was no association between the promoter polymorphisms and fracture, but an association was observed with femoral neck BMD in females (p=0.035). Conclusion: We have identified several novel genetic variants within the COL1A1 gene which are associated with osteoporosisrelated phenotypes, distinct from those previously identified. This study confirms that genetic variation at the COL1A1 locus predisposes to osteoporosis, but further functional studies will be required to uncover the molecular basis of these associations.