Human Molecular Genetics, 2002, Vol. 11, No. 13 1581-1583
© 2002 Oxford University Press
Type 2 diabetes is associated with a common mitochondrial variant: evidence from a population-based case–control study
1Department of Paediatrics and Statistics, University of Oxford, Oxford, UK and 2Department of Public Health and Primary Care, Institute of Public Health, Cambridge University, Cambridge, UK
Received March 22, 2002; Accepted April 23, 2002
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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Variants in mitochondrial DNA (mtDNA) could be associated with type 2 diabetes because ATP plays a critical role in the production and release of insulin. Diabetes can be precipitated both by mtDNA mutations and by exposure to mitochondrial poisons. The risk of inheriting diabetes from an affected mother is greater than that from an affected father, but this is not explained by maternally inherited diabetes and/or deafness (MIDD) caused by the 3243G : C mtDNA point mutation, which accounts for less than 0.5% of cases of diabetes. A common mtDNA variant (the 16189 variant) is positively correlated with blood fasting insulin, but there are no definitive studies demonstrating that it is associated with diabetes. We demonstrated a significant association between the 16189 variant and type 2 diabetes in a population-based case–control study in Cambridgeshire, UK (n=932, odds ratio=1.61 (1.0–2.7, P=0.048), which was greatly magnified in individuals with a family history of diabetes from the father's side (odds ratio=
; P<0.001). |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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Type 2 diabetes is a multifactorial disorder in which variants in mitochondrial DNA (mtDNA) could play a role. While diabetes is a major feature in certain mtDNA diseases, pathogenic mtDNA mutations have only been identified in a tiny minority of diabetics. We have previously described a common mitochondrial variant that is associated with raised fasting insulin concentrations in several populations (1,2) and with maternal restraint of fetal growth (3). We sought to determine whether this mtDNA variant is significantly associated with proven type 2 diabetes in a case–control study.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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552 patients aged 45–76 years with type 2 diabetes were randomly selected from general practitioner diabetes registers in Cambridgeshire, UK and were invited to attend for this case–control study. Presence of type 2 diabetes was based on clinical criteria: onset of diabetes after the age of 30 years without treatment with insulin in the first year after diagnosis. 552 controls were recruited at random from the same population sampling frames, individually matched to cases for age, sex and GP practice. Diabetes was excluded in controls by medical record search and by glycated haemoglobin measurement less than 6%. Anthropometric measures were performed in light clothing using standardized methods. Detailed medical history was recorded by structured interviews, and alcohol consumption and smoking were assessed. The study received ethical approval from the Cambridge Local Research Ethics Committee, and participants provided informed consent.
The 16189 variant arises when a T16189C transition results in a poly(dC) tract in the large non-coding region of mtDNA, near to control sequences for replication and transcription. The majority of UK Caucasians with the variant are homoplasmic for the T16189C transition, with a tract length of 10 C residues. This may generate heteroplasmic length variation, each individual having a range of tract lengths, including a minority of mtDNAs with tract lengths of 9 and 11. Heteroplasmic length variation of the homopolymeric tract becomes more pronounced with tracts whose modal length is over 10. In this study, the 16189 variant was identified by PCR restriction enzyme analysis of blood DNA as previously described (1). We did not quantitate the proportion of wild-type and variant mtDNAs in the heteroplasmic individuals, because the numbers that were heteroplasmic were too small to be analysed separately. Results were obtained for 932 individuals (463 cases and 469 controls). The individuals who were not typed (n=172) were not systematically different from the cohort who were typed for the 16189 variant. All PCR products positive for the 16189 variant were sequenced and analysed using Staden mutation detection software in order to assign them to a mtDNA haplogroup (Table 2). Genotyping was undertaken blinded to case–control assignation.
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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The overall characteristics of the patients and controls are shown in Table 1. The 16189 variant was found more commonly in the cases (46 of 463, 9.9%) than the controls (30 of 469, 6.4%). The odds ratio for the association between the 16189 variant and diabetes was 1.61 (1.0–2.7, P=0.048). The frequencies of the 16189 variant and of type 2 diabetes are a great deal higher than any mtDNA disease described hitherto.
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As expected, a greater proportion of the cases than controls reported having a maternal or paternal family history of diabetes (Table 1). We would have anticipated that maternal family history would have had a larger effect than paternal, because there appears to be an intrauterine diabetogenic effect in mice with toxin-induced diabetes, but this was not the case.
The analysis of the 16189 variant was repeated, stratifying by the presence of a maternal or paternal history of diabetes. Of the 77 cases with a paternal history of diabetes, 11 had the 16189 variant (14.3%), and this variant was found in 8 out of the 85 people with a maternal family history (9.4%). Thus, the 16189 variant was not found to a greater degree among cases with a maternal family history compared with those with a paternal history (P=0.47).
Among people without a paternal history of diabetes, the risk of diabetes in those with the 16189 variant was 1.48. However, all 11 individuals with both a paternal history and the 16189 variant were cases, i.e. the odds ratio was infinite (P<0.001). There was no evidence of a difference in the association between the 16189 variant and diabetes between those who did and those who did not have a maternal history of diabetes.
We estimate that the population-attributable risk percentage, or the proportion of cases of type 2 diabetes attributable to this variant, would be 3.76%. An association of similar magnitude has been described in abstract form in a Chinese study (4), but this study was unlikely to have been population-based and no information was available on the selection of controls, the adequacy of matching or on mitochondrial haplotypes. Given that the frequency of this variant was 20% in their control population, the population-attributable risk percentage would be 11%. This common variant is present in a significant proportion of those with type 2 diabetes worldwide (5), with a prevalence of 93% in Polynesians and 50% in Pima Indians. This suggests that the 16189 variant could have a substantially larger effect on the prevalence of type 2 diabetes than the commonest diabetogenic mtDNA mutation described hitherto (6,7), which underlies less than 0.5% of type 2 diabetes in UK Caucasians (8).
mtDNA is unique in that its haplotype indicates its maternal origins. By using the most parsimonious neighbour-joining tree, it is possible to determine whether a particular polymorphism is likely to have arisen once or several times in a given population. Using this approach to define mtDNA haplogroups, it is clear that the 16189 variant has arisen many times independently (9). Haplotype analysis using an adaptation of the Richards et al. (9) classification demonstrated that the distribution of the 16189 variant within the different mtDNA haplogroups was similar in patients and controls (Table 2). Hence, the association between the 16189 variant and diabetes is not due to a single mitochondrial founder. This analysis takes the question of ethnicity into account; indeed, only one of the 16189 positive individuals was non-Caucasian (one case within haplogroup T). These data are consistent with a previous report that there was no single mitochondrial founder in type 2 diabetes (10). The fact that the 16189 variant has arisen several times on independent mtDNA haplotypes makes the association with type 2 diabetes compelling. Thus, our data suggest that it is the 16189 variant per se, rather than some other mtDNA mutation in cis, that is associated with diabetes. Furthermore, we have previously reported a positive association between the incidence of the 16189 variant and diabetes between ethnic groups (11). This and the independent occurrence of the 16189 variant on diverse mitochondrial DNA backgrounds among the diabetics suggests that the association of the 16189 variant with diabetes is not due to co-segregation with a diabetogenic nuclear gene. The association is biologically plausible. The 16189 variant lies close to control sequences within the large non-coding region. Previous investigators have demonstrated that proteins bind close to this region (12). The presence of the 16189 variant may alter DNA bending and hence could influence interactions between bound proteins controlling either mitochondrial DNA replication or transcription. We are currently studying the effects of the 16189 variant on mtDNA synthesis and maintenance. Preliminary data suggest that the 16189 variant results in a modest reduction in mtDNA copy number compared with nuclear DNA, which might have a mildly detrimental effect on respiratory chain function in ß cells (J. Poulton, unpublished).
In addition to describing the underlying association between 16189 and diabetes, we were also able to examine the extent to which the risk associated with this variant was affected by having a parental history of diabetes. We were unable to identify an excess of the 16189 variant among those individuals who reported having a maternal history of diabetes. However, all of the 11 individuals who both reported having a paternal family history of diabetes and had the 16189 variant were cases. This would suggest that nuclear genetic factor(s) inherited from the father increased the background risk of the maternally inherited mitochondrial variant considerably. Such an interaction is biologically plausible, since paternal history of diabetes is associated with low birthweight (13) and the 16189 variant is associated with thinness at birth (3). In addition, a nucleo-mitochondrial interaction has been described in age-related hearing loss in mice (14). If so, the 16189 variant might be a risk factor for other multifactorial conditions whose phenotypes may be seen as features of mitochondrial disease. Previously, we have shown that the 16189 variant is associated with a 2–3-fold increased risk of idiopathic sporadic dilated cardiomyopathy in both UK Caucasians and black Africans (15). Secondly, the 16189 variant appears to exacerbate thinness at birth in babies apparently nutritionally deprived in utero, who subsequently exhibit ‘catch-up’ growth (3). In both of these multifactorial phenotypes, the 16189 variant interacts to magnify the effect of other risk factors. Hence, in addition to the univariate association of the variant with diabetes, its effect in combination with family history provides the third example of such an interaction. Taken together, the findings suggest that the 16189 variant may have a presumably detrimental effect on mitochondrial function, and that this in turn influences the cellular response to other stresses in two significant multifactorial diseases.
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ACKNOWLEDGEMENTS |
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We thank the patients and their physicians for cooperation with the study. We thank Professor S. O'Rahilly for suggesting the study and Professor E.R. Moxon for his support. J.P. is a Royal Society University Research Fellow and N.J.W. is an MRC Clinician Scientist Fellow. Financial support for the mitochondrial studies was from The Wellcome Trust, Diabetes UK and the MRC.
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FOOTNOTES |
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* To whom Correspondence should be addressed at: Department of Paediatrics, John Radcliffe Hospital, Room 4406, Headington, Oxford OX3 9DU, UK. Tel.: +44 (0)1865 221067; Fax: +44 (0)1865 220479
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