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Transient receptor potential cation channel, subfamily M, members 6 (TRPM6) and 7 (TRPM7), have been implicated in inflammatory disorders including diabetes, a major source of morbidity and mortality in developing and Western society. We hypothesized that gene variation of TRPM6 and TRPM7 may play a role in type 2 diabetes mellitus (T2DM) Using a case-control population sample of the Boston metropolitan area (all whites, 455 controls and 467 cases), we assessed the relationship of 29 TRPM6 and 11 TRPM7 tag-single nucleotide polymorphisms (SNPs) with (1) several diabetes-related intermediate phenotypes (fasting insulin levels, fasting glucose levels, hemoglobin A1c, and homeostatic model assessment) and (2) the presence of T2DM. All SNPs examined were in Hardy-Weinberg equilibrium. Overall, genotype distributions were similar between cases and controls. Linear regression analysis, adjusted for potential risk factors/confounders, showed no evidence of an association of any SNPs tested with the aforementioned diabetes-related intermediate phenotypes after correcting for multiple testing. Marker-by-marker multivariable logistic regression analysis showed no evidence of an association of any SNPs tested with the presence of T2DM after correcting for multiple testing. Continued investigation using an entropy-blocker-defined haplotype-based approach showed similar null findings. If corroboration occurs in future large prospective investigations, then the present investigation further suggests that TRPM6 and TRPM7 gene variation may not be useful predictors for T2DM risk assessment. [ABSTRACT FROM AUTHOR]