Tcf7 L2 Polymorphisms Are Associated With Type 2 Diabetes

2891 words - 12 pages

A recent study found association of one microsatellite and five single nucleotide polymorphisms (SNPs) in intron 3 of the TCF7L2 gene with type 2 diabetes (T2D) in the Icelandic, Danish and American populations. The aim of the present study was to investigate if those SNPs were associated to T2D in two (family- and population-based) cohorts from northern Sweden. We genotyped four of the associated SNPs in a case–control cohort consisting of 872 T2D cases and 857 controls matched with respect to age, sex and geographical origin and in a sample of 59 extended families (148 affected and 83 unaffected individuals). Here, we report replication of association between T2D and three SNPs in the case–control (rs7901695, P=0.003; rs7901346, P=0.00002; and rs12255372, P=0.000004) and two SNPs in the family-based (rs7901695, P=0.01 and rs7901346, P=0.04) samples from northern Sweden. This replication strengthens the evidence for involvement of TCF7L2 in T2D.

Type 2 diabetes (T2D) is a multifactorial disorder characterized by chronic hyperglycaemia resulting from pancreatic dysfunction and insulin resistance. It is a common disease with a complex pattern of inheritance, which most likely reflects the influence of multiple genetic and environmental factors.1, 2 Publication of several genome-wide scans has linked many loci to the development of T2D in different populations.3, 4, 5 Genes implicated in T2D have conferred modest risk6, 7, 8, 9 and replication efforts have sometimes been successful;10, 11 however, in many cases they have yielded inconsistent results.8, 12 We have previously reported linkage of T2D to chromosome 2 in families from northern Sweden12 and in the same study found weak linkage to 10q. A recent publication found association of one microsatellite and five single nucleotide polymorphisms (SNPs) in intron 3 of the transcription factor 7-like two gene (TCF7L2), localized to chromosome 10q, with T2D in the Icelandic, Danish and American populations.7 Moreover, recent functional data linked alleles in some of those SNPs to progression from a state of impaired glucose tolerance (IGT) to T2D.13
Based on this background, we set out to investigate if four SNPs in TCF7L2, which had been previously associated to T2D,7 were associated to T2D in both case–control and family-based samples from northern Sweden.
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Materials and methods
Both the family-based and the matched case–control samples were as described previously.12 Briefly, the family-based material consisted of 231 samples from 59 extended families (148 affected and 83 unaffected individuals), and the case–control material comprised 872 T2D cases and 857 controls matched with respect to age, sex and geographical origin. Diabetes diagnoses were confirmed by scrutinizing medical records regarding symptoms and blood glucose measurements, following 1999 World Health Organisation criteria.14 Individuals with fasting plasma glucose >7.0 mmol/l and 2-h oral glucose...

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