Introduction & Objective: Previous work showed that genetic polymorphisms of the nuclear gene Klotho (KL), were associated with longevity and altered risk of various aging-related diseases. However, genetic variations of KL specifically associated with diabetes have not been published. In this study, we assessed the association of KL SNPs with diabetes, and performed a demonstration of identifying mitochondrial genetic variants that interact with KL SNPs to modulate diabetes risk.
Methods: We used the data from 10,121 participants of the Health and Retirement Study (70.3% non-Hispanic White, 60% women), a prospective observational study including adults aged 50 year and older from the United States. First, we performed single gene-wide association scan to identify KL SNPs associated with diabetes. Next, we performed a nuclear mitochondrial interaction test (NuMIT) in which we use an identified KL SNP from the gene-wide scan to evaluate potential interactions with 85 mitochondrial SNPs in relation to diabetes. All analyses were run separately within ethnic group and by sex.
Results: The prevalence of diabetes in non-Hispanic Whites was 23.8%. A KL SNP rs9563121 was associated with lower prevalence of diabetes in non-Hispanic white women (OR 0.86; P = 0.020), but this association was not significant in men or in other ethnic groups. A NuMIT analysis identified eight mitochondrial SNPs which showed significant interactions with rs9563121 in relation to diabetes. Most strikingly, MitoG15929A diminished the potential beneficial effect of KL rs9563121 on diabetes in women. In addition, in men with the MitoG15929A variant, KL rs9563121 was associated with higher prevalence of diabetes.
Conclusion: The NuMIT approach revealed significant interactions between mitochondrial and nuclear DNA variants of KL. Furthermore, MitoG15929A may be a critical risk modifier for diabetes in a sex-dependent manner.
T. Oh: None. T.E. Arpawong: None. H. Kumagai: None. K. Yen: None. E. Crimmins: None. P. Cohen: None.
