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- Horikawa, Y, et al.
(författare)
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Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus
- 2000
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 26:2, s. 163-175
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10 (CAPN10). This finding suggests a novel pathway that may contribute to the development of type 2 diabetes.
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- Ma, Lijun, et al.
(författare)
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Association analysis of Krüppel-like factor 11 variants with type 2 diabetes in Pima Indians
- 2008
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - Chevy Chase : Endocrine society. - 0021-972X .- 1945-7197. ; 93:9, s. 3644-3649
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Krüppel-like factor 11 (KLF11) is a transcription factor of the zinc finger domain family that has been shown to regulate expression of the insulin gene. An initial study reported that a KLF11 variant predicting a Q62R was associated with type 2 diabetes (T2D) in French Caucasians; however, subsequent studies have failed to identify an association between this variant and T2D in subjects from a similar Northern-European ancestry. OBJECTIVE: We sought to determine whether the Q62R or other variants within KLF11 were associated with T2D in Pima Indians, a population with an extremely high prevalence of this disease.DESIGN, SETTING, AND SUBJECTS: KLF11 was sequenced in 24 Pima Indians to identify potentially novel variants. There were 18 variants genotyped in a family-based sample of 1337 Pima Indians to analyze the linkage disequilibrium pattern of this gene and identify representative variants. Four representative variants were further genotyped in a population-based sample of 3501 full-heritage Pima Indians for association analyses. Among these subjects, 413 had undergone metabolic studies when they were nondiabetic to measure traits that predict T2D.RESULTS: Neither the Q62R nor any other common variant in KLF11 was associated with T2D in the Pima population. In addition, no variant was associated with insulin secretion or insulin-stimulated glucose disposal rate.CONCLUSIONS: Common variation in KLF11 variation does not appear to influence the population-based risk for developing T2D among full-heritage Pima Indians. Thus, KLF11 is unlikely to play a major role in the etiology of T2D among this Native American population.
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- Ma, Lijun, et al.
(författare)
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Evaluation of A2BP1 as an Obesity Gene
- 2010
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 59:11, s. 2837-2845
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-A genome-wide association study (GWAS) in Pima Indians (n = 413) identified variation in the ataxin-2 binding protein 1 gene (A2BP1) that was associated with percent body fat. On the basis of this association and the obese phenotype of ataxin-2 knockout mice, A2BP1 was genetically and functionally analyzed to assess its potential role in human obesity. RESEARCH DESIGN AND METHODS-Variants spanning A2BP1 were genotyped in a population-based sample of 3,234 full-heritage Pima Indians, 2,843 of whom were not part of the initial GWAS study and therefore could serve as a sample to assess replication. Published GWAS data across A2BP1 were additionally analyzed in French adult (n = 1,426) and children case/control subjects (n = 1,392) (Meyre et al. Nat Genet 2009;41:157-159). Selected variants were genotyped in two additional samples of Caucasians (Amish, n = 1,149, and German children case/control subjects, n = 998) and one additional Native American (n = 2,531) sample. Small interfering RNA was used to knockdown A2bp1 message levels in mouse embryonic hypothalamus cells. RESULTS-No single variant in A2BP1 was reproducibly associated with obesity across the different populations. However, different variants within intron 1 of A2BP1 were associated with BMI in full-heritage Pima Indians (rs10500331, P = 1.9 x 10(-7)) and obesity in French Caucasian adult (rs4786847, P = 1.9 x 10(-10)) and children (rs8054147, P = 9.2 x 10(-6)) case/control subjects. Reduction of A2bp1 in mouse embryonic hypothalamus cells decreased expression of Atxn2, Insr, and Mc4r. CONCLUSIONS-Association analysis suggests that variation in A2BP1 influences obesity, and functional studies suggest that A2BP1 could potentially affect adiposity via the hypothalamic MC4R pathway. Diabetes 59:2837-2845, 2010
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