Association of the A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 gene with bone mineral density and fracture risk in Maltese postmenopausal women

Abstract

INTRODUCTION: The Low-density lipoprotein receptor-related protein 5 (LRP5) is involved in osteoblast differentiation, making it an important determinant of bone mass and strength. The single nucleotide polymorphism, SNP (C>T) at position 1330 in exon 18 results in a missense substitution of alanine to valine (A1330V) which has been associated with low bone mineral density (BMD) and increased fracture risk.

AIM: To investigate the influence of the A1330V polymorphism on BMD and different low-trauma fractures in Maltese postmenopausal women.

METHODOLOGY: 1043 women between 40 and 79 years were recruited and their BMD measured by dual-energy X-ray absorptiometry. Subjects without a history of a fragility fracture were subdivided in three groups: normal (n=223), osteopenic (n=271), and osteoporotic (n=282) according to their BMD. The remaining 267 were fracture cases who had a normal (n=12), osteopenic (n=107) or osteoporotic BMD (n=148). Genotyping was performed by polymerase-chain reaction and restriction enzyme digest.

RESULTS: The genotype distributions were as follows: normal controls CC (78%), CT (21%), TT(1%); osteopenic subjects CC (78%), CT (20%), TT (2%); osteoporotic subjects CC (68%), CT (28%), TT (4%); and fracture cases CC (69%), CT (27%), TT (4%). In the total study group, the A1330V SNP was associated with reduced lumbar spine BMD (TT: age-adjusted Odds ratio, OR 3.7 [95% Confidence Interval 1.2-11.0], p=0.02; CT: OR 1.6 [1.1-2.4], p=0.01) and to a lesser extent reduced femoral neck BMD (TT: OR 2.8 [0.9-8.7], p=0.07; CT: OR 1.7 [1.2-2.6], p=0.01). Women without a fracture history had an increased risk of osteoporosis when carrying one or both copies of the minor allele T (CT: OR 1.6 [1.0-2.4], p=0.04; TT: OR 10.6 [1.4-80.5], p=0.03). No significant difference was observed between osteopenic subjects (without fractures) and normal controls. When comparing fracture cases to normal controls, women carrying CT/TT genotypes had an increased fracture risk than women with the CC genotype (CT: 1.6 [1.0-2.4], p=0.05; TT: OR of 8.3 [1.0-67.0], p=0.05). All fracture cases homozygous for the T allele had an osteopenic or osteoporotic BMD; fracture risk was partly attenuated by BMD adjustment (TT: OR 2.5 [0.2-27.7], p=0.45) and remained unchanged in carriers of the A1330V SNP (CT: OR 1.4 [0.7-2.8] p=0.31). The TT genotype was the most common among subjects with a wrist, humerus or hip fracture; however the difference was not significant (p>0.05).

CONCLUSION: The results indicate that the A1330V polymorphism is associated with reduced BMD and increased fracture susceptibility in Maltese postmenopausal women.