Mitochondrial Haplogroups Modify the Risk of Developing Hypertrophic Cardiomyopathy in a Danish Population

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in genes coding for proteins involved in sarcomere function. The disease is associated with mitochondrial dysfunction. Evolutionarily developed variation in mitochondrial DNA (mtDNA), defining mtDNA haplogroups and haplogroup clusters, is associated with functional differences in mitochondrial function and susceptibility to various diseases, including ischemic cardiomyopathy. We hypothesized that mtDNA haplogroups, in particular H, J and K, might modify disease susceptibility to HCM. Mitochondrial DNA, isolated from blood, was sequenced and haplogroups identified in 91 probands with HCM. The association with HCM was ascertained using two Danish control populations. Haplogroup H was more prevalent in HCM patients, 60% versus 46% (p = 0.006) and 41% (p = 0.003), in the two control populations. Haplogroup J was less prevalent, 3% vs. 12.4% (p = 0.017) and 9.1%, (p = 0.06). Likewise, the UK haplogroup cluster was less prevalent in HCM, 11% vs. 22.1% (p = 0.02) and 22.8% (p = 0.04). These results indicate that haplogroup H constitutes a susceptibility factor and that haplogroup J and haplogroup cluster UK are protective factors in the development of HCM. Thus, constitutive differences in mitochondrial function may influence the occurrence and clinical presentation of HCM. This could explain some of the phenotypic variability in HCM. The fact that haplogroup H and J are also modifying factors in ischemic cardiomyopathy suggests that mtDNA haplotypes may be of significance in determining whether a physiological hypertrophy develops into myopathy. mtDNA haplotypes may have the potential of becoming significant biomarkers in cardiomyopathy.

Genetics of hypertrophic cardiomyopathy: A review of current state

“…It has been described that haplogroup H has higher mitochondrial oxidative damage because this haplogroup is the highest VO2max consumer, in contrast with haplogroup J, which it is the lowest. Therefore, haplogroup H constitutes a susceptibility factor while haplogroup J constitutes a protective factor for HCM …”

“…Therefore, haplogroup H constitutes a susceptibility factor while haplogroup J constitutes a protective factor for HCM. 96 13 | THERAPEUTIC IMPLICATIONS Current therapeutics for HCM patients are based on symptomatic alleviation and depend on the clinical features. The pharmacotherapy is mainly based on beta-blockers, calcium channel blockers and disopyramide.…”

Whole mitochondrial genome genetic diversity in an Estonian population sample

“…The analysis of mitochondrial DNA (mtDNA) has been implemented in molecular anthropology [1], evolutionary biology [2], medical genetics [3,4], and human identity testing [5]. Strictly maternal inheritance, lack of recombination and high mutation rate make mtDNA a viable marker system for assessing genetic relationships among individuals or groups.…”

Mitochondrial haplogroups are associated with hypertrophic cardiomyopathy in the Indian population

“…Mitochondrial DNA (mtDNA) haplogroups have been associated with various diseases, including ischaemic (Fernandez-Caggiano et al, 2012), dilated (Fernandez-Caggiano et al, 2013) and hypertrophic cardiomyopathy (HCM) (Castro et al, 2006;Hagen et al, 2013). These studies were all performed on European populations.…”