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- mitochondrial DNA
- dementia with Lewy bodies
- Alzheimer disease
- neurodegenerative disease
We are grateful to Professor Poulton and Dr Das for clarifying their definition of the 16189 variant. In our study we determined the allele status at position 16189 of mitochondrial DNA (mtDNA), and found no evidence of an association between the 16189C polymorphic sequence variant and late onset dementia.1 The title of our manuscript therefore reflects our observations and does not need to be corrected. Part of the confusion seems to have arisen because of different definitions of the “16189 variant” in the literature.
The standard “Cambridge” reference mtDNA sequence2,3 has a run of cytosine residues from nucleotide position (np) 16184 to 16193 interrupted by a thymidine residue at nucleotide position 16189. In approximately 12% of the UK population, there is a T→C substitution at np 16189.1 In most individuals this results a tract of 10 C residues (polyC tract). This sequence is unstable and is associated with length variation of the polyC tract, probably because of slippage during genome replication,4 generating larger and smaller polyC tracts within the same individual during life (heteroplasmy).4 However, occasional individuals have other polymorphisms between np 16184 and 16193, which appear to stabilise the tract and do not lead to the generation of length variants.4 We suggest a more accurate definition should be used when referring to the homopolymeric C tract that is present in the majority of individuals with the T16189C substitution. The term “mtDNA 16184-93 polyC tract” will hopefully prevent confusion in the future.
Poulton and Das comment on the results of our logistic regression analysis (table 1 in our paper1), and suggest that individuals with homopolymeric tract length heteroplasmy have a 2.2 fold increased risk of developing Alzheimer’s disease (AD) compared with controls. This would imply an association between their definition of the 16189 variant and late onset dementia. However, the confidence intervals for the relative risk of 2.2 are 0.85 to 5.81, comfortably including 1. The relative risk is therefore not statistically significant and does not support a link between AD and homopolymeric length tract heteroplasmy.
In our original study,1 we measured homopolymeric tract length heteroplasmy using a trimmed PCR approach with a fluorescent forward primer. However, not all individuals with a 16184-93 polyC tract also have length heteroplasmy. Therefore, to address the concerns of Poulton and Das experimentally, we directly sequenced the relevant region of mtDNA in all of the cases and controls that harboured the 16189C variant in our original study,1 using an established protocol.5 The frequency of the mtDNA 16184-93 polyC tract in our original control population corresponded to values reported in other studies6,7 (table 1); 59% of control individuals with the T16189C polymorphic variant had a 16184-93 polyC tract, corresponding to publicly available control sequence data (http://www.genpat.uu.se/mtDB/). We found no evidence of an association between AD or dementia with Lewy bodies and 16184-93 polydC tract in a cohort or neuropathologically defined cases and controls, either by logistic regression analysis, or by directly comparing cases and controls with Fisher’s exact test (table 1).
D M Turnbull and P F Chinnery receive support from the Wellcome Trust and the Alzheimer’s Research Trust.
Conflict of interest: none declared
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