Cardiometabolic phenotypes and mitochondrial DNA copy number in two cohorts of UK women

Abstract

The mitochondrial genome is present at variable copy number between individuals. Mitochondria are vulnerable to oxidative stress, and their dysfunction may be associated with cardiovascular disease.The association of mitochondrial DNA copy number with cardiometabolic risk factors (lipids, glycaemic traits, inflammatory markers, anthropometry and blood pressure) was assessed in two independent cohorts of European origin women, one in whom outcomes were measured at mean (SD) age 30 (4.3) years (N = 2278) and the second at 69.4 (5.5) years (N = 2872). Mitochondrial DNA copy number was assayed by quantitative polymerase chain reaction. Associations were adjusted for smoking, sociodemographic status, laboratory factors and white cell traits.Out of a total of 12 outcomes assessed in both cohorts, mitochondrial DNA copy number showed little or no association with the majority (point estimates were close to zero and nearly all p-values were > 0.01). The strongest evidence was for an inverse association in the older cohort with insulin (standardised beta [95%CI]: − 0.06, [− 0.098, − 0.022], p = 0.002), but this association did not replicate in the younger cohort.Our findings do not provide support for variation in mitochondrial DNA copy number having an important impact on cardio-metabolic risk factors in European origin women.

Association of mitochondrial DNA copy number with cardiometabolic diseases in a large cross-sectional study of multiple ancestries

“…Because low mtDNA CN was associated with older age and reported to be associated with increased cardiometabolic disease risk, 15-17,28 we reported beta estimates as the change in an outcome variable in response to 1 s.d. lower mtDNA CN in all of analyses.…”

“…17 A more recent study in two independent cohorts of women of European ancestry (n=2,278, mean age 30 years; and n=2,872, mean age 69 years), however, failed to detect significant associations between mtDNA CN and cardiometabolic risk factors including systolic blood pressure (SBP), diastolic blood pressure (DBP), HDL, LDL, TRIG, and glucose levels. 18 Given inconsistent findings in previous studies and the central role of mtDNA in metabolism, we set out to investigate the association between mtDNA CN and several cardiometabolic risk factors in seven US cohorts representing several ancestries with whole genome sequencing (WGS) and extensive cardiometabolic phenotyping. We also included individuals with Whole Exome Sequencing (WES) from the UK Biobank for validation.…”

“…16 A more recent study in two independent cohorts of women of European origin (n=2,278, mean age 30 years; and n=2,872, mean age 69 years), however, failed to detect significant associations between mtDNA CN and CMD risk factors including systolic blood pressure (SBP), diastolic blood pressure (DBP), HDL, LDL, TRIG, and glucose levels. 17…”

“…18 we report beta estimates as the change in an outcome variable in response to 1 s.d. lower mtDNA CN in all of analyses.…”

Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences

“…In one large WGS study of mitochondrial genome copy number (MT-CN) in 2077 Sardinians, Ding et al estimated the heritability of MT-CN at 54% and detected significant associations between MT-CN and both waist circumference and waist–hip ratio, but found no association with body mass index (BMI) [ 15 ]. Another large study (N = 5150) found virtually no evidence of association between qPCR-measured MT-CN and any of several cardiometabolic phenotypes [ 23 ]. The only exception was an inverse association with insulin that was identified in one cohort but did not survive meta-analysis across cohorts.…”