Nuclear Mitochondrial Interaction Test Reveals Sex-Dependent Mitochondrial SNPs Interacting with Klotho Variants on Diabetes Risk

Context The environmental or other genetic factors might influence the effect of Klotho (KL) on glucose metabolism.

We investigated mitochondrial genetic variants that interact with KL single nucleotide polymorphisms (SNPs) to modulate diabetes risk.

We used the data from 7,047 non-Hispanic white participants of the Health and Retirement Study, a prospective observational study including adults aged 50 years and older from the United States. First, we performed single gene-wide association scans to identify KL SNPs associated with diabetes. Next, we performed a nuclear-by-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.

We failed to identify a significant association between diabetes and the KL SNP in our single gene-wide association test. However, we identified a novel variant (KL rs9563121) which showed a trend of increasing klotho mRNA levels with each additional minor allele. A NuMIT analysis identified mitochondrial SNPs, which showed significant interactions with rs9563121 in relation to diabetes risk. MitoG15929A showed significant interactions with rs9563121 in both men and women. MitoG15929A diminished the potential beneficial effect of KL rs9563121 on diabetes risk in women. Among men with the MitoG15929A variant, KL rs9563121 was associated with higher prevalence of diabetes.

The NuMIT approach revealed significant interactions between mitochondrial and nuclear DNA variants of KL. Furthermore, MitoG15929A may have a role in the interaction between diabetes and KL in a sex-dependent manner. Competing Interest Statement The authors have declared no competing interest. Abbreviations - BH - Benjamini-Hochberg - FDR - False Discovery Rate - HRS - Health and Retirement Study - KL - Klotho - MA - Minor allele - MAF - Minor allele frequency - NuMIT - Nuclear-by-Mitochondrial Gene Interaction Test