Abstract
BackgroundBMI is a strong indicator of complications from type I diabetes, especially under intensive treatment.MethodsWe have genotyped 435 type 1 diabetics using Illumina Infinium Omni Express Exome-8 v1.4 arrays and performed mitoGWAS on BMI. We identified additive interactions between mitochondrial and nuclear variants in genes associated with mitochondrial functioning MitoCarta2.0 and confirmed and refined the results on external cohorts: the Framingham Heart Study (FHS) and GTEx data. Linear mixed model analysis was performed using the GENESIS package in R/Bioconductor.ResultsWe find a borderline significant association between the mitochondrial variant rs28357980, localized to MT-ND2, and BMI (β = − 0.69, p = 0.056). This BMI association was confirmed on 1889 patients from FHS cohort (β = − 0.312, p = 0.047). Next, we searched for additive interactions between mitochondrial and nuclear variants. MT-ND2 variants interacted with variants in the genes SIRT3, ATP5B, CYCS, TFB2M and POLRMT. TFB2M is a mitochondrial transcription factor and together with TFAM creates a transcription promoter complex for the mitochondrial polymerase POLRMT. We have found an interaction between rs3021088 in MT-ND2 and rs6701836 in TFB2M leading to BMI decrease (inter_pval = 0.0241), while interaction of rs3021088 in MT-ND2 and rs41542013 in POLRMT led to BMI increase (inter_pval = 0.0004). The influence of these interactions on BMI was confirmed in external cohorts.ConclusionsHere, we have shown that variants in the mitochondrial genome as well as additive interactions between mitochondrial and nuclear SNPs influence BMI in T1DM and general cohorts.
Highlights
Body mass index (BMI) is a strong indicator of complications from type I diabetes, especially under intensive treatment
We looked closer into these interactions and found that variant rs3021088 of MT-ND2 gene interacted with variants in TFB2M and POLMRT genes, both of which are necessary for mitochondrial transcription
For SIRT3 we have found an interaction between mitochondrial variant localized to 5460 position (MAF 10.1%) and two nuclear variants – rs11602954 (p = 0.03) and rs11606393 (p = 0.028)
Summary
BMI is a strong indicator of complications from type I diabetes, especially under intensive treatment. Mitochondria are organelles whose main role is energy production. They are the only organelles that contain their own genome. The mitochondrial genome is a double stranded 16.5 kb long molecule which resembles that of an alpha-. Among them 13 code for polypeptides, while the remainder - 2 rRNAs (12S and 16S) and 22 tRNAs – are necessary for mitochondrial protein synthesis. All 13 mRNAs code for subunits of oxidative phosphorylation (OXPHOS) complexes. The rest of the peptides needed to build the electron transport chain (ETC), as well as to maintain mitochondrial functioning, are nuclear-encoded [2]. It has been shown that mitochondrial function correlates with cells’ metabolic state and can influence obesity [3]
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