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Variants in Common Multi-factorial Diseases

Important diseases associated with aging, such as diabetes, are linked to OriB variants both in mtDNA and in nuclear genes involved in mtDNA maintenance. MtDNA contributes to common diseases such as type 2 diabetes and dilated cardiomyopathy (the commonest cause for heart transplants in young people). We have studied a common polymorphic mtDNA variant (the so-called OriB variant, see below), which is present in 8% of UK Caucasians, 50% of Pima Indians and >95% of Polynesians. We have shown that the 16189 variant is associated with i) type 2 diabetes, ii) thinness up to middle life, iii) high placental weight, iv) iron loading in haemochromatosis , v) dilated cardiomyopathy and deafness. Investigators in other centres have confirmed the association with diabetes and with thinness, and have also shown that it is a risk factor for endometrial cancer and other multifactorial disorders. Unlike many other polymorphisms that have been implicated in type 2 diabetes, the variant is likely to have bona fide functional consequences because it has arisen many times independently in the various populations studied, excluding a founder effect. Furthermore we have preliminary evidence that the variant has functional effects on glucose uptake and mtDNA segregation in cultured cells.

Understanding the contribution of mtDNA to common diseases may lead to new therapies. Even a modest reduction would have profound implications on health expenditure, as diabetes and its complications are the sixth largest cost on the British National Health Service budget.

Technical Definition of the OriB Variant

ccccctcccc Wild type sequence

cccccccccc 16189 variant (9 to 14C in length)

ccccccctcc T16189C plus C16191T (EXCLUDED)

We defined the 16189 variant as the DNA sequence associated with an uninterrupted polydC tract of length 9-13, resulting from a T16189C transition. This may generate heteroplasmic length variation. Heteroplasmic length variation does not occur when the polymeric tract is interrupted by a c to t transition at several different sites but commonly at bp 16186 or 16192. Individuals with these additional polymorphisms are excluded from the definition of the 16189 variant that we use, because they no longer have a long homopolymeric c tract. The variant does not alter any coding sequences yet lies near to mtDNA control sequences which can explain its effects on mitochondrial function. In studies of disease associations with variants in this region we chose to investigate the 16189 variant rather than any other sequence change, because of the likely functional effects of the homopolymeric C tract and heteroplasmic length variation.