<p>Mitochondrial DNA D-loop sequencing reveals obesity variants in an Arab population</p>

Abstract

Background: The association of mitochondrial DNA (mtDNA) variations with obesity has been investigated in diverse populations across the world. However, such obesity-associated mtDNA examinations are rarely conducted in Arab populations. Materials and methods: We re-sequenced mtDNA displacement loop (D-loop) region of 395 Arab individuals of Kuwait. We categorized the individuals based on their BMI scores as obese (n=232; BMI ≥30 kg/m 2 ), overweight (n=110; BMI ≥25 kg/m 2 and <30 kg/m 2 ), and lean (n=53; BMI <25 kg/m 2 ). We performed all the statistical tests by combining obese and overweight individuals in one group. Association analyses were conducted applying Fisher's exact test and logistic regression model. Results: We identified that the mtDNA variations m.73A>G, and m.523delAC were positively correlated with obesity, while m.310T>C, and m.16318A>T were negatively associated. All these variants, except m.16318A>T, remain statistically significant after adjusting for age and gender. We found that the variant m.73A>G increases the likelihood of being obese by 6-fold, whereas haplogroup H decreases the probability of being obese in Arab individuals of Kuwait. Haplotype analysis revealed that a haplotype, A263G-C309CT-T310C, defining the H2a clade of H haplogroup, reduces the probability of being obese. Conclusion: Our study reports, for the first time, the obesity-related mtDNA variants in Arabs of Kuwait. Based on the mtDNA D-loop region variations, we detected particular variants and haplogroup that are related with increased and decreased probability of being obese in the Kuwait Arab population.

Polycystic ovary syndrome and mitochondrial dysfunction

“…The changes in mtDNA D-loop and copy numbers may be a heritable risk factor for PCOS in South Indian women [85]. Several mtDNA D-loop variants and haplogroups have reportedly been associated with obesity in different ethnic populations [98]. For example, D-loop variants m.16292C > T and m.16189 T > C are associated with obesity in Germany [99].…”

Mitochondrial haplogroup J associated with higher risk of obesity in the Qatari population

“…A recent study 17 reported a higher frequency of haplogroup H in the control group (BMI < 25 kg/m 2 ) compared with the group with overweight and obesity (BMI > 25 kg/m 2 ) among Arabs living in Kuwait. The frequency of haplogroup H in our Qatar study cohort was slightly higher in the group without obesity; nevertheless, the difference was not significant compared with the group with obesity, which might be due to differences in the admixture of Arab ethnicities in the region.…”

“…None of the reported associations involving mitochondrial DNA variants and obesity passes the Bonferroni corrected P-value thresholds. The threshold value for BMI (30 kg/m 2 ) used to define the obesity and no obesity/control groups differs from that used in previous obesity studies using mtDNA [14][15][16][17]29,[34][35][36] . We set a higher threshold for BMI in our study mainly because of the low number of lean BMI individuals in the cohort (the mean BMI value of the cohort was 32.7 ± 6.8 kg/m 2 ) and the desire to balance the sample sizes of the 2 groups; however, the mean BMI value in the group without obesity was borderline (26.5 ± 2.6 kg/m 2 ), and that of the group with obesity was much higher (at 36.5 ± 5.7 kg/ m 2 ).…”

“…Furthermore, the mitochondrial haplogroup T has been suggested to increase the risk of obesity in 2 independent association studies on Austrian 14 and Southern Italian 15 populations. Maternal haplogroups X and H have been proposed to reduce the risk of obesity in Caucasians of northern European origin in the United States (US) 16 as well as in Arabs living in Kuwait 17 , respectively. It is worth noting that these studies on maternal haplogroups were performed using variants that were extracted either from genome-wide genotype data generated using BeadChips in genome-wide association studies or from sequencing partial sections of the mitochondria genome using Sanger sequencing.…”

Delineation of Mitochondrial DNA Variants From Exome Sequencing Data and Association of Haplogroups With Obesity in Kuwait

“…These findings have led to studies that have evaluated whether mitochondrial dysfunction in obesity is due to inherited sequence variations. Several mitochondrial variants and haplogroups have been associated with obesity in different ethnicities ( Yang et al, 2011 ; Grant et al, 2012 ; Nardelli et al, 2013 ; Flaquer et al, 2014 ; Knoll et al, 2014 ; Ebner et al, 2015 ; Veronese et al, 2018 ; Eaaswarkhanth et al, 2019 ). The genotyping data used in these studies were from the mitochondrial control region ( Nardelli et al, 2013 ; Ebner et al, 2015 ; Veronese et al, 2018 ; Eaaswarkhanth et al, 2019 ) and/or extracted from GWASs ( Yang et al, 2011 ; Grant et al, 2012 ; Flaquer et al, 2014 ; Knoll et al, 2014 ).…”