Mitochondrial haplogroups modify the risk of developing hypertrophic cardiomyopathy in a Danish population.
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.
Department of Clinical Biochemistry and Immunology, Statens Serum Institut, Copenhagen, Denmark.
Christian M
CM
Hagen
Frederik H
FH
Aidt
Paula L
PL
Hedley
Morten K
MK
Jensen
Ole
O
Havndrup
Jørgen K
JK
Kanters
Johanna C
JC
Moolman-Smook
Severin O
SO
Larsen
Henning
H
Bundgaard
Michael
M
Christiansen
D000328:Adult; D000368:Aged; D002312:Cardiomyopathy, Hypertrophic / Q000453:epidemiology* / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D003718:Denmark / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics; D010802:Phylogeny; D012307:Risk Factors
D004272:DNA, Mitochondrial