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TCF7L2 polymorphisms are associated with type 2 diabetes in northern Sweden
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. (Sofia Mayans)
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
Department of Medicine, Sunderby Hospital, Luleå.
Show others and affiliations
2007 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 3, 342-346 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2007. Vol. 15, no 3, 342-346 p.
Keyword [en]
association, diabetes, polymorphism, TCF7L2, Case-Control Studies, Diabetes Mellitus; Type 2/*genetics, Family, Female, Genetic Predisposition to Disease, Humans, Male, Polymorphism; Single Nucleotide, Sweden, TCF Transcription Factors/*genetics
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Medical Genetics Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:umu:diva-22329DOI: 10.1038/sj.ejhg.5201773ISI: 000244406200013PubMedID: 17245407OAI: oai:DiVA.org:umu-22329DiVA: diva2:214483
Available from: 2009-05-05 Created: 2009-05-05 Last updated: 2014-10-13Bibliographically approved
In thesis
1. Genetic studies of diabetes in northern Sweden
Open this publication in new window or tab >>Genetic studies of diabetes in northern Sweden
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes mellitus represents a group of metabolic disorders caused by both environmental and genetic factors. The two most common forms of diabetes are type 2 diabetes (T2D) and type 1 diabetes (T1D). T2D is associated with obesity and the disease is caused by insulin resistance and pancreatic b-cell dysfunction. T1D is an autoimmune disease in which the insulin- producing b-cells in the pancreas are destroyed by infiltration of lymphocytes.

The aim of this thesis was to identify genes conferring susceptibility to diabetes. This was approached using genetic methods, both linkage and association studies, within the population of northern Sweden.

The northern Swedish population is well suited for genetic studies of familial forms of disease, since an internal expansion of the northern Swedish population, coupled with a low frequency of immigration and a high frequency of consanguineous marriages, has resulted in a relatively homogeneous gene pool. This simplified genetic background increases the probability of identifying genes contributing to disease.

The family-based material used for the type 2 diabetes studies (papers I and II) consisted of 231 individuals from 59 families originating in northern Sweden. The type 2 diabetes case-control material (papers I and II) consisted of 872 cases and 857 matched controls, all from northern Sweden. In paper I we performed a genome-wide linkage scan, seeking T2D susceptibility loci. Linkage to the previously identified Calpain-10 region was found, however, association studies in the case-control material revealed no association to the CAPN10 gene. Using both the family-based and the case-control material, we were able to confirm the association of polymorphisms in the TCF7L2 gene to T2D in the population of northern Sweden (paper II).

CTLA-4 is a negative regulator of T cell activity, belonging to the CD28 co-stimulatory receptor family. Numerous reports, including our own, have associated CTLA-4 variants with T1D as well as other autoimmune diseases, such as autoimmune thyroid disease (AITD). Allelic variation in the 3ÚTR of the CTLA-4 gene was associated to human T1D and this variant has also been suggested to affect the level of mRNA encoding the soluble form of the molecule (sCTLA-4). We confirmed the association of allelic variation in the 3ÚTR of the CTLA-4 gene in a T1D/AITD case-control material from northern Sweden, consisting of 104 individuals with ATID, 149 individuals with T1D and 865 matched controls. However, we were unable to identify any correlation between allelic variants in the 3ÚTR of the CTLA-4 gene and expression of sCTLA-4 (paper III).

Based on recently published genome-wide association (GWA) scans, 33 single-nucleotide polymorphisms (SNPs) located within 16 genes were selected for an association analysis in T1D/AITD families from northern Sweden. The T1D/AITD family-based material consisted of 253 cases and 206 healthy individuals from 97 northern Swedish families. Analysis revealed association to T1D for SNPs in PTPN22, COL1A2, IL-2Ra and INS. In addition, SNPs in CTLA-4, IL-2 and C12orf30 were shown to be associated to AITD (paper IV).

Together, these results underpin the notion that the population of northern Sweden is well suited for the detection of genes involved in complex diseases. The use of our more restricted patient material, compared to materials used in published GWA scans, enables the discovery of disease associated genes in a more cost effective manner and show that our population is capable of detecting general susceptibility genes.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2008. 88 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1216
Keyword
Diabetes, families, genetic, association, SNP, linkage, TCF7L2, CTLA-4, Calpain-10
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-1920 (URN)978-91-7264-637-7 (ISBN)
Public defence
2008-12-05, Sal B, 1D, Norrlands Universitetssjukhus 9 trappor, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2010-01-18Bibliographically approved

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Mayans, SofiaÅgren, ÅsaEliasson, MatsHolmberg, Dan

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European Journal of Human Genetics
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)Medical GeneticsEndocrinology and Diabetes

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