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Evolutionary dissection of mtDNA hg H: a susceptibility factor for hypertrophic cardiomyopathy
Christian M Hagen1,2, Joanna L Elson1,3, Paula L Hedley1
1Department for Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark.
Insights
Mitochondrial DNA haplogroup H may influence hypertrophic cardiomyopathy risk. Specific H subhaplogroups, particularly H3, show a different distribution in HCM patients compared to controls, suggesting a subtle genetic association.
Area of Science:
- Genetics
- Cardiology
- Mitochondrial DNA
Background:
- Mitochondrial DNA (mtDNA) haplogroup H is a known susceptibility factor for hypertrophic cardiomyopathy (HCM).
- Specific single nucleotide polymorphisms (SNPs) conferring this risk within haplogroup H remain unidentified.
- Haplogroup H comprises over 80 subhaplogroups, each defined by unique SNPs.
Purpose of the Study:
- To investigate if the distribution of mitochondrial DNA haplogroup H subhaplogroups differs between hypertrophic cardiomyopathy patients and control groups.
- To identify potential specific subhaplogroups of H associated with HCM risk.
Main Methods:
- Comparative analysis of mtDNA haplogroup H subhaplogroup distribution.
- Study included 55 HCM index cases and two Danish control groups (n=170, n=908).
- An independent cohort of 39 HCM index cases from Australia was used for replication.
Main Results:
- A distinct distribution of H subhaplogroups was observed between HCM patients and controls.
- Subhaplogroups H73 was absent in HCM patients but present in controls.
- A higher H3/H2 proportion was noted in HCM patients (1.7) compared to controls (0.45-0.54), replicated in the Australian cohort (1.5).
Conclusions:
- The distribution of mitochondrial DNA haplogroup H subhaplogroups shows subtle differences between HCM cases and controls.
- The specific pathogenic role of these subhaplogroup differences in HCM requires further functional investigation.
Abstract:
Mitochondrial DNA (mtDNA) haplogroup (hg) H has been reported as a susceptibility factor for hypertrophic cardiomyopathy (HCM). This was established in genetic association studies, however, the SNP or SNP's that are associated with the increased risk have not been identified. Hg H is the most frequent European mtDNA hg with greater than 80 subhaplogroups (subhgs) each defined by specific SNPs. We tested the hypothesis that the distribution of H subhgs might differ between HCM patients and controls. The subhg H distribution in 55 HCM index cases was compared to that of two Danish mtDNA hg H control groups (n = 170 and n = 908, respectively). In the HCM group, H and 12 different H subhgs were found. All these, except subhgs H73, were also found in both control groups. The HCM group was also characterized by a higher proportion of H3 compared to H2. In the HCM group the H3/H2 proportion was 1.7, whereas it was 0.45 and 0.54 in the control groups. This tendency was replicated in an independent group of Hg H HCM index cases (n = 39) from Queensland, Australia, where the H3/H2 ratio was 1.5. In conclusion, the H subhgs distribution differs between HCM cases and controls, but the difference is subtle, and the understanding of the pathogenic significance is hampered by the lack of functional studies on the subhgs of H.
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