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Variants of the TCF7L2 gene are associated with beta cell dysfunction and confer an increased risk of type 2 diabetes mellitus in the ULSAM cohort of Swedish elderly men
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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2007 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 50, no 9, 1852-1857 p.Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis:

In a population-based cohort of elderly men with well-defined phenotypes and biochemical markers related to type 2 diabetes mellitus, we analysed two single nucleotide polymorphisms (SNPs), rs7903146 and rs12255372, in the transcription factor 7-like 2 gene (TCF7L2), which are associated with an increased risk of type 2 diabetes mellitus.

Materials and methods:

The 1,142 subjects were from the population-based Uppsala Longitudinal Study of Adult Men cohort study (see http://www.pubcare.uu.se/ULSAM/ , last accessed in May 2007). Insulin sensitivity was assessed using a euglycaemic-hyperinsulinaemic clamp; fasting intact and 32-33 split proinsulin, immunoreactive insulin and specific insulin were measured in plasma samples. The SNPs rs7903146 and rs12255372 were genotyped using a fluorescent homogeneous single base extension assay. The SNP genotypes were analysed against diabetes prevalence at age 70 using logistic regression and against quantitative biochemical measures using linear regression analysis.

Results:

We replicated the association with type 2 diabetes mellitus for both SNPs in this cohort of elderly males. The highest significant odds ratio (2.15, 95% CI 1.20-3.85) was found for SNP rs7903146. The odds ratio for SNP rs12255372 was 1.69 (95% CI 1.20-2.39). Both TCF7L2 SNPs were found to be significantly associated with plasma proinsulin when adjusting for insulin sensitivity, both in the whole cohort and when the diabetic subjects were excluded. Analysis for fasting plasma insulin or insulin sensitivity did not give significant results.

Conclusions/interpretation:

The association between the risk alleles of the two SNPs studied and levels of proinsulin in plasma, identified when adjusting for insulin sensitivity using euglycaemic-hyperinsulinaemic clamp measurements in this study, is an important novel finding.

Place, publisher, year, edition, pages
2007. Vol. 50, no 9, 1852-1857 p.
Keyword [en]
Impaired fasting glucose, Impaired glucose tolerance, Proinsulin, Single base primer extension, Single nucleotide polymorphisms, TCF7L2, Transcription factor 7-like 2 gene, Type 2 diabetes mellitus, Uppsala Longitudinal Study of Adult Men
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96369DOI: 10.1007/s00125-007-0746-5ISI: 000248771800010PubMedID: 17618413OAI: oai:DiVA.org:uu-96369DiVA: diva2:170923
Available from: 2007-11-02 Created: 2007-11-02 Last updated: 2012-02-29Bibliographically approved
In thesis
1. Analysis of Complex Genetic Traits in Population Cohorts using High-throughput Genotyping Technology
Open this publication in new window or tab >>Analysis of Complex Genetic Traits in Population Cohorts using High-throughput Genotyping Technology
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Most human traits and common diseases have a complex genetic makeup involving more than one gene. The work presented in this thesis investigates standing body height and the common disease type 2 diabetes mellitus (T2DM). In study I we analyzed two single nucleotide polymorphisms (SNPs) in the TCF7L2 gene that had been shown to be associated with T2DM. Analysis was performed in the ULSAM population cohort of ~1500 males. We were able to replicate the association to type 2 diabetes and in addition to that we made a novel find, showing association between the risk alleles and increased proinsulin levels. In study II we analyzed four genes identified to be associated with T2DM in a genome-wide association study. We analyzed SNPs in these genes in the ULSAM population cohort and found an association between SNPs in the HHEX gene and insulin responses and insulin levels.

The aim of studies III-V was to identify genes affecting normal variation in standing body height. Using a candidate gene approach in study III, 17 genes were screened in the ULSAM population cohort using SNPs. A suggestive association of the ESR1 gene with height was found and confirmed as significant in males from the PIVUS population cohort. In study IV, as a part of the GenomEUtwin project, we performed genetic fine mapping of a linked locus for body height on the X-chromosome. By analyzing 1377 SNPs in 780 Finnish twins, we mapped a region spanning 65kb of this locus with linkage to body height in males. This region contains the GPC3 and PHF6 genes that have known connections to syndromes were standing body height is affected. In study V significant linkage and association to standing body height in males was found for the COL1A11 gene, using population cohorts from Finland and Iceland.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 56 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 287
Keyword
Molecular medicine, SNP, TCF7L2, HHEX, COL11A1, ESR1, body height, type 2 diabetes mellitus, proinsulin, ULSAM, complex genetic trait, genotyping technology, Molekylärmedicin
Identifiers
urn:nbn:se:uu:diva-8291 (URN)978-91-554-7007-4 (ISBN)
Public defence
2007-11-24, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:00
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Available from: 2007-11-02 Created: 2007-11-02Bibliographically approved

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Zethelius, BjörnSyvänen, Ann-ChristineBerne, Christian

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