Mitochondrial DNA haplogroup distribution within Leber hereditary optic neuropathy pedigrees

Leber hereditary optic neuropathy (LHON; OMIM#535000) is a mitochondrial genetic disease thatcauses blindness in young adults, with anestimated minimum prevalence of 3.2 per 100 000 in thenorth east of England.1 It classically presents as bilateralsubacute loss of central vision due to the focalneurodegeneration of the retinal ganglion cell layer.Over 95% of cases are principally due to one of three‘‘primary’’ mtDNA point mutations: 3460GRA, 11778GRA,and 14484TRC, all of which involve genes that encodecomplex I subunits of the mitochondrial respiratorychain. However, less than ,50% of male and ,10% offemale LHON carriers will develop the optic neuropathy.2 3This marked incomplete penetrance and gender biasclearly indicates that additional genetic and/or environmentalfactors are required for the phenotypic expressionof the pathogenic mtDNA mutations in LHON. However,these secondary factors remain poorly defined at the presenttime.There has recently been considerable interest in thepossible role of the mtDNA background on the phenotypicexpression of mitochondrial genetic disorders. Thehypothesis is that on their own, some polymorphisms areselectively ‘‘neutral’’ but that in specific combinations,they act in a synergistic, deleterious manner withestablished pathogenic mtDNA mutations to increase therisk of disease expression or to produce a more severeclinical outcome.4 The following nucleotide substitutionsare found at a higher frequency in LHON patientsrelative to controls:5–7 4216TRC, 4917ARG, 9804GRA,9438GRA, 13708GRA, 15257GRA, and 15812GRA.Phylogenetic analysis has shown that 4216TRC,13708GRA, 15257GRA, and 15812GRA all cluster on aspecific mtDNA background, haplogroup J, which is one ofthe nine haplogroups that define populations ofEuropean ancestry.8 9 Several studies have subsequentlyfound that LHON pedigrees that harbour the 11778GRAand 14484TRC mutations are apparently not randomlydistributed along the phylogenetic tree, but tend toshow a preferential association with haplogroup J (table 1).It has therefore been argued that these polymorphicvariants interact with the primary mtDNA mutations,increasing the risk of visual loss among LHON carriers.However, the potential pathogenic role of these so-called‘‘secondary’’ mtDNA mutations in LHON is still controversial.All the association studies published so far involved arelatively small number of pedigrees collected over a widegeographical area by centres with a specialist interest inLHON, thereby raising the possibility of ascertainment bias.To investigate further the presumed association betweenprimary LHON mutations and haplogroup J, we determinedthe haplogroup distribution of a rigorously defined,population based LHON cohort from the north east ofEngland, and carried out a systematic statistical review ofthe literature.