Mitochondrial Genetic Variants Identified to Be Associated with BMI in Adults

The worldwide epidemic of diabetes and metabolic syndrome in the last few decades cannot be fully accounted for only by changes in the lifestyle factors, such as sedentary lifestyle and overeating. Besides genetic factors, there must be other causes to explain this rapid change. They could not be infectious in nature and induce insulin resistance as key biochemical abnormality. Mitochondrial dysfunction could be underlying mechanism behind the insulin resistance, thus metabolic syndrome. Then there have been increasing number of reports suggesting that chronic exposure to and accumulation of endocrine disrupting chemicals (EDCs), especially so-called the persistent organic pollutants (POPs) within the body might be associated with metabolic syndrome. Combining two concepts, we developed new "EDCs-induced mitochondrial dysfunction hypothesis of metabolic syndrome". In this review we suggest that classifying those chemicals into 5 groups might be clinically useful considering their removal or avoidance; POPs, non-persistent organic pollutants, heavy metals, air pollutants and drugs. We will also discuss briefly how those insights could be applied to clinical medicine.

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“…A recent survey on the mitochondrial genetic variants among Europeans revealed significant association with BMI, but not with T2DM [22].…”

Section: Genetic Cause (S) Of Metabolic Syndromementioning

confidence: 94%

Metabolic syndrome and the environmental pollutants from mitochondrial perspectives

Kim

Lee

2014

Rev Endocr Metab Disord

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“…However, when all chips are considered together, good overall coverage of the mitochondrial genome is obtained. 39 Genotype calling algorithms may be controversial when applied to mtSNPs due to the heteroplasmy effect. The mtDNA tend to be heterogenous in the sense that different mitochondria of an individual may have different genotypes, such that genotype at an mtSNP may not be restricted to zero, one or two minor alleles.…”

Section: Methodsmentioning

confidence: 99%

“…This issue affects the possibility of estimating genotypes and makes calling algorithms useless. Therefore, whenever one intends to identify susceptibility genes located in the mtDNA, we recommend accounting for heteroplasmy using individual-level allele frequencies obtained from the intensity values 39 or sequencing data rather than genotypes calls obtained by algorithms that were designed for nuclear SNPs.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial genetic variants identified to be associated with posttraumatic stress disorder

et al. 2015

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Despite the fact that mitochondrial dysfunctions are increasingly recognized as key components in stress-related mental disorders, very little is known about the association between posttraumatic stress disorder (PTSD) and mitochondrial variants. To identify susceptibility mitochondrial genes for PTSD, we analyzed a total number of 978 mitochondrial single-nucleotide polymorphisms (mtSNPs) in a sample of 1238 individuals participating in the KORA (Cooperative Health Research in the Region of Augsburg) study. Participants were classified with ‘no PTSD', ‘partial PTSD' or ‘full PTSD' by applying the Posttraumatic Diagnostic Scale and the Impact of Event Scale. To assess PTSD–mtSNP association while taking heteroplasmy into account, we used the raw signal intensity values measured on the microarray and applied linear regression. Significant associations were obtained between full versus no PTSD and two mtSNPs; mt8414C→T (β=−0.954±0.06, Padjusted=0.037) located in adenosine triphosphate (ATP) synthase subunit 8 (MT-ATP8) and mt12501G→A (β=−1.782±0.40, Padjusted=0.015) located in the NADH dehydrogenase subunits 5 (MT-ND5). Heteroplasmy for the two variants towards a larger number of the respective minor alleles increases the risk of having PTSD. NADH dehydrogenase and ATP synthase are both linked to the regulation of reactive oxygen species. Our results highlight the important role of the mitochondrial genome among the factors that contribute to the risk of PTSD. Mitochondrial genetic variants may be more important than has previously been assumed, leading to further insights regarding effects of existing medications, or even to the development of innovative treatments. As this is the first mitochondrial genome-wide association study for PTSDs, further analyses are needed to follow up on the present findings.

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“…Previous studies have already associated variants in these genes with obesity. A paper from 2014 has shown, apart from associations with two other positions, an association between three variants in complex I genes– MT-ND1, MT-ND2 and MT-ND4L [23]. Moreover, the variant C5178A in MT-ND2 gene was shown to lead to lower incidence of autoimmune diabetes.…”

Section: Discussionmentioning

confidence: 99%

Title: “Mitochondrial GWAS and Association of Nuclear - Mitochondrial Epistasis with BMI in T1DM Patients”

Ludwig-Słomczyńska

Seweryn

Kapusta

et al. 2018

Preprint

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UM, KC, PG and ŁD gathered study cohort and phenotypic data; EWO and MTM supervised 22 cohort construction; AHLS and EP performed genotyping; AHLS, MTS and PK analyzed and 23 interpreted data; AHLS, MTS, PK and PPW wrote the paper; AHLS and PPW and guarantors 24 of this work. All authors contributed to critical revision of the manuscript and approved its 25 publication. Abstract 27Mitochondria are organelles whose main role is energy production and might influence obesity. 28They are the only organelles with their own genome. Here we have genotyped 435 patients with 29 type 1 diabetes using Illumina Infinium Omni Express Exome-8 v1.4 arrays and performed 30 mitoGWAS on BMI. We have analyzed additive interactions between mitochondrial and 31 nuclear variants in genes known to be associated with mitochondrial functioning 32 (MitoCarta2.0) and confirmed and refined the results on external cohorts -Framingham Heart 33 Study (FHS) and GTEx data. The linear mixed model analysis was performed using the 34 GENESIS package in R/Bioconductor We have found a nominal association between 35 rs28357980 localized to MT-ND2 and BMI (β=-0.69, p=0.056). This was confirmed on 1889 36 patients from FHS cohort (β =-0.312, p=0.047). Next, we have searched for additive 37interactions between mitochondrial and nuclear variants. MT-ND2 variants interacted with 38 variants in SIRT3, ATP5B, CYCS, TFB2M and POLRMT genes. TFB2M is a mitochondrial 39 transcription factor and together with TFAM creates transcription promoter complex for 40 mitochondrial polymerase POLRMT. We have found that the interaction between rs3021088 41 of MT-ND2 gene and rs6701836 in TFB2M has led to BMI decrease (inter_pval=0.0241), while 42 interaction of rs3021088in MT-ND2 and rs41542013 in POLRMT gene led to BMI increase 43 (inter_pval=0.0004). The influence of these interactions on BMI was confirmed on external 44 cohorts. Here, we have shown that variants in mitochondrial genome as well as additive 45 interactions between mitochondrial and nuclear SNPs influence BMI in T1DM and general 46 cohorts. 48Author summary: 49 Obesity is an epidemic of our times. It is known that it results from an imbalance between 50 energy intake and its expenditure, while mitochondria are organelles whose main role is energy 3 51 production. They are the only organelles that contain their own genome. Thus, we have 52 genotyped 435 patients with type 1 diabetes and looked on single mitochondrial variant 53 influence as well as on additive interactions between mitochondrial and nuclear variants which 54 might affect BMI. Our analysis has shown, that rs28357980 localized to MT-ND2 is associated 55 with BMI. Next, we looked whether variants in this gene, which builds complex I of the electron 56 transport chain, might interact with nuclear variants and together they modify obesity risk. We 57 focused mainly on mitochondrial biogenesis and found that interactions between variants in 58 TFB2M (rs6701836) or POLRMT (rs41542013) and MT-ND2 (rs3021088) affect patients 59 BMI. TFB2M is a mit...

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Mitochondrial Genetic Variants Identified to Be Associated with BMI in Adults

Cited by 37 publications

References 47 publications

Metabolic syndrome and the environmental pollutants from mitochondrial perspectives

Metabolic syndrome and the environmental pollutants from mitochondrial perspectives

Mitochondrial genetic variants identified to be associated with posttraumatic stress disorder

Title: “Mitochondrial GWAS and Association of Nuclear - Mitochondrial Epistasis with BMI in T1DM Patients”

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