Meta-Analysis of Molecular Association Studies: Vitamin D Receptor Gene Polymorphisms and BMD as a Case Study

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Abstract
With the rise of molecular and genetic epidemiology, molecular association studies are increasingly common; however, meta-analysis of these studies has been a neglected area. This study performed a meta-analysis of the association of the vitamin D receptor (VDR) gene polymorphisms and BMD. We also highlight methodological issues that need to be resolved. With the rise of molecular and genetic epidemiology, molecular association studies are increasingly common; however, meta-analysis of these studies has been a neglected area. This study performed a meta-analysis of the association of vitamin D receptor (VDR) gene polymorphisms and BMD/osteoporosis and highlights methodological issues. Studies published from 1994 to 2001 were identified through Medline using PubMed software. The reference lists of the articles retrieved were also reviewed. Where eligible papers had insufficient information, we contacted authors by mail (up to three mailings) for additional information. Any observational study, which tested the association between VDR BsmI genotypes and either BMD or osteoporosis at the femoral neck or spine in adult women, was included in the review. Data were extracted independently by two reviewers (AT and JA) using a standardized data extraction form. The B allele was significantly associated with BMD at the spine; it seemed to follow a recessive model, with the BB genotype having lower BMD than Bb/bb genotypes at baseline, which led to greater bone mineral loss over time. Highlighted methodological lessons included the need to check Hardy-Weinberg equilibrium and the importance of exploring heterogeneity, pooling data in a manner that is sensitive to genetic models, and avoiding multiple comparisons. With the proliferation of molecular association studies, there will be an increased need to quantify the magnitude of the risk associated with genetic polymorphisms. This will likely entail meta-analytic methods, and this meta-analysis highlights some of the methodological issues that will need to be resolved.