Although there are advances in understanding the pathogenesis of multiple myeloma, its causes remainelusive. Risk is increased by 1.5-3-fold in family members of cases, suggesting a genetic contribution. It ispossible that plasma cell growth factors and proteins important in B cell differentiation may contribute to riskby increasing the pool of plasma cells available for transformation to myeloma. In prior SPORE supportedpilot studies, we found evidence linking polymorphisms (i.e., 'SNP's) in genes that control two importantplasma cell growth factors, interleukin (IL)-6 and insulin-like growth factor (IGF)-1, with susceptibility tomultiple myeloma. In addition, we found positive associations between polymorphisms of certain DNA repairgenes and multiple myeloma risk. These studies had strong prior hypotheses but small sample sizes, andthus the possibility of false positive results is a. concern. Furthermore, since multiple myelomadisproportionately affects African-Americans and Hispanics (to a lesser degree), it is important to conductstudies in a multi-ethnic setting, whereas the pilot studies included relatively few ethnic minorities. Thereforewe propose to confirm these preliminary findings in a larger multi-ethnic sample of 559 cases and 885controls from 5 separate studies with existing DNA samples, including the Health Professionals Follow-upStudy, Nurse's Health Study, and the USC-Hawaii Multi-ethnic Cohort Study, and two population-basedcase-control studies. We will include several genes in plasma cell growth and B cell differentiationpathways. In choosing the SNPs to examine in this study, we will take into account the ethnic diversity of theparticipating study populations, as well as considerations related to the structure of the genes of interest. Wehave developed a powerful software program to choose polymorphisms based on those considerations fromHapMap, and we will genotype 1,536 SNPs in 25 genes using well-validated, efficient genotyping technologythrough the DSC Genotyping Core Facility. We will examine the association of variation in individual geneswith myeloma risk, accounting for correlations between SNPs. We will also interact with other SPOREprojects to interrogate the function of any SNPs that we observe to be associated with risk. We believe thisproject enhances the overall value of the SPORE by contributing to the understanding of geneticsusceptibility to multiple myeloma, needed for the development of both treatment and prevention strategies.
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