This investigation is the only one from the UK that has sought an association between BMP2 gene polymorphisms and BMD and susceptibility to osteoporosis. As far as we know this is the first such investigation carried out exclusively in men with idiopathic osteoporosis. However, the power of this study is low; therefore any conclusions drawn should be treated with caution. Post hoc power analysis, calculated using a Quanto programme and based on observed allele frequencies, sample size, and odds ratios, showed that the study had 67% power to detect an odds ratio of 1.50 (moderate level) and above. In order to achieve an odds ratio of 1.25 one would require a case-control sample size of 507 individuals in each group. In the original Icelandic study a significant effect of BMP2 gene SNP1 polymorphism, Ser37Ala, was demonstrated in a cohort of 201 subjects, comprising 153 controls and 58 subjects with fracture [4
]. Just like the earlier observation we too found it to be a rare variant in our cohort with an allele frequency of 1.25% for Ala37. In previous reports, the allele frequency for Ala37 in the Icelandic cohort was 0.8% in controls and 3% to 4.9% in osteoporotic patients and 2.5% in the Rotterdam study. However, unlike the Icelandic study, we did not see a significant association or increase in the relative risk (RR) with the SNP1 genotype. In our cohort we did not see any GT or TT genotypes of the rare variant of the SNP2 genotype that arises from Ala94Ser. The gene frequency for SNP3 polymorphism, due to Arg190Ser variants, constituting three genotypes, TT (Arg190Arg), AT (Arg190Ser), and AA (Ser190Ser), was akin to earlier reports in European populations. In both male controls and men with osteoporosis the genotypes were in Hardy-Weinberg equilibrium. In addition to studying the association of the BMP2 to risk of fracture and BMD, in a subset of subjects we also investigated the association of the genotype with annual bone loss at the lumbar spine, total femoral, and femoral neck. Both initial BMD as well as annual change in the BMD showed no association with the BMP2 genotype. This could be partly due to allele frequency differences in different geographical and gender cohorts. In our study we observed a higher frequency of susceptible T (Ser) allele (64% in patients and 59% in controls) which is comparable to HAPMAP frequencies (58%–73% in European populations), but other populations like Turkish, Korean, and African populations show a lower frequency [13
The desirability of having a large cohort for SNP studies investigating polygenic disease association with putative candidate genes with phenotype or disease state is well established. This is due to the fact that in a polygenic disorder like osteoporosis many genes make a small, but significant contribution towards the attainment and maintenance of BMD. Therefore, many genes may be involved in the pathogenesis of osteoporosis and risk of osteoporotic fractures. In view of this small contribution of a large number of genes, the contribution of the genotypic influence is likely to be more clearly demonstrated in a sufficiently large cohort with the required level of statistical power. It is, however, becoming increasingly evident that the association of a large number of candidate gene SNPs with BMD and osteoporosis risk shows race-, geography- and gender-related differences [3
]. We would also contend that, if a given genotype does make a substantial contribution to the attainment and maintenance of BMD and pathophysiology of disease then it should be possible to demonstrate such effects even in smaller homogenous cohorts. Indeed, in the original study on BMP2 the genotype association with osteoporosis was established in a small cohort [4
]. We have been able to demonstrate associations of some novel genotypes in smaller cohorts and which were subsequently verified in much larger studies [5
There have been only a handful of studies following the first report of bone morphogenetic protein 2 (BMP2) as a susceptibility gene for osteoporotic fractures and low BMD in Icelandic and Danish populations [9
]. Even these relatively few studies of polymorphisms, within the BMP2 gene in relation to bone mineral density (BMD) and fracture, have produced inconsistent findings [4
]. Neither a Rotterdam study of a large population-based cohort of Dutch whites nor a study in healthy American whites could find any contribution to BMD by variations in BMP2 genotypes [7
]. On the other hand, a SNP- and haplotype-based US family study showed highly suggestive associations with BMP2 [5
]. In another analysis on a European cohort, variation in BMP2 genotype showed no association with BMD; it did, however, find a role in aspects of bone quality, which may be age and site dependent [9
]. The 3′ region of the gene was significantly associated with the ultrasound parameters speed of sound and stiffness. Similarly in Turkish women study BMP2 polymorphisms did not substantially contribute to lumbar spine bone mineral density [14
]. Overall, association studies have shown that Arg190Ser SNP is not associated with BMD in different populations and the initial study may have been a false positive association. Alternatively, it is entirely possible that the association may show gender-related variation, as the initial study had shown association in females and our study was carried out in an exclusively male population.
In conclusion, in a BMP2 candidate gene polymorphism study in the UK, comprising osteoporotic men and male control subjects, there were no genotypic or haplotypic effects on phenotype and fracture risk identified.