Abstract
Recent studies have shown that mtDNA background could affect the clinical expression of Leber hereditary optic neuropathy (LHON). We analyzed the mitochondrial DNA (mtDNA) variation of 304 Chinese patients with m.11778G>A (sample #1) and of 843 suspected LHON patients who lack the three primary mutations (sample #2) to discern mtDNA haplogroup effect on disease onset. Haplogroup frequencies in the patient group was compared to frequencies in the general Han Chinese population (n = 1,689; sample #3). The overall matrilineal composition of the suspected LHON population resembles that of the general Han Chinese population, suggesting no association with mtDNA haplogroup. In contrast, analysis of these LHON patients confirms mtDNA haplogroup effect on LHON. Specifically, the LHON sample significantly differs from the general Han Chinese and suspected LHON populations by harboring an extremely lower frequency of haplogroup R9, in particular of its main sub-haplogroup F (#1 vs. #3, P-value = 1.46×10−17, OR = 0.051, 95% CI: 0.016–0.162; #1 vs. #2, P-value = 4.44×10−17, OR = 0.049, 95% CI: 0.015–0.154; in both cases, adjusted P-value <10−5) and higher frequencies of M7b (#1 vs. #3, adjusted P-value = 0.001 and #1 vs. #2, adjusted P-value = 0.004). Our result shows that mtDNA background affects LHON in Chinese patients with m.11778G>A but not suspected LHON. Haplogroup F has a protective effect against LHON, while M7b is a risk factor.
Highlights
The three primary mutations (m.3460G.A in the MT-ND1 gene, m.11778G.A in the MT-ND4 gene, and m.14484T.C in the MT-ND6 gene) on mitochondrial DNA have been identified to be the essential factors for Leber hereditary optic neuropathy (LHON, OMIM 535000)
The mitochondrial DNA (mtDNA) control region sequence variations for each patient are listed in the online Tables S2 and S3, and the sequences can be retrieved from GenBank under the Accession Numbers HM632037–HM632340 and HM632341–HM633183
Many studies reported that mtDNA background affects the expression of human disorders [33,34,35,36,37], some positive findings could respond to false positives [38]
Summary
The three primary mutations (m.3460G.A in the MT-ND1 gene, m.11778G.A in the MT-ND4 gene, and m.14484T.C in the MT-ND6 gene) on mitochondrial DNA (mtDNA) have been identified to be the essential factors for Leber hereditary optic neuropathy (LHON, OMIM 535000). Our previous study of Chinese families with m.11778G.A showed that haplogroup M7b192 could increase the risk of vision loss but haplogroup M8a might produce a protective effect [15]. Frequencies of haplogroups M7b192 and M8a are not significantly altered in LHON pedigrees compared to the normal controls despite their apparent background effect on the penetrance [15]. This pattern is quite different from that of European patients, in which there is an internal consistency of the haplogroup association, namely, haplogroup J is present at an increased frequency in LHON families with m.11778G.A and m.14484T.C, and subdivisions of this haplogroup show increased penetrance [5]. Insufficient sampling (limited statistical power), and/or potential population stratification may account for the lack of internal consistency in our observation [15]
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