In a previous genome-wide linkage scan for genes predisposing to type 2 diabetes mellitus (T2DM) in the Pima Indians, we obtained the strongest evidence for linkage with markers on chromosome 1q21-q23. Subsequently, the 1q linkage of T2DM has been replicated in several, diverse populations. Our strategy to search for the underlying diabetes susceptibility gene(s) has been based on two complementary approaches: 1) systematic analysis of densely spaced single nucleotide polymorphisms (SNPs); and 2) investigation of candidate genes within the linked region for variants/mutations. So far, over 100 candidate genes have been/are being analyzed by sequencing in a subset of diabetic and non-diabetic Pimas. Informative SNPs are tested for association with diabetes, and their effect on the linkage is also evaluated. More recently, an international collaborative Chromosome 1 Consortium has been established by uniting several of the groups which detected T2DM linkage on 1q, with the goal to facilitate search for the underlying diabetes gene(s). This startegy involves analysis of over 5000 subjects from five populations (including about 1000 Pimas), and so far this effort has led to genotyping of over 2000 SNPs within an initial interval of 13 Mb spanning the linkage peak in most populations. ? We found a few areas showing nominal association with T2DM and so far analyzed extensively a ~200 kilobase region in which multiple SNPs showed the strongest association with the disesase, and also could explain about 25% of the original linkage. Although we detected numerous variants, this strategy did not help to identify the putative causative variant. This area is fairly conserved between human and other species, and therefore an experimental animal model (such as knockout mice) may be needed to assess the functional relevance of the variants in this region. ? As the 13 Mb region may not include the causative mutation (the whole linked region is over 30 Mb long), more SNPs has been (or are being) genotyped to expand the analyzed region. We just received an additional 1000 SNPs genotyped by the Consortium and their analysis is in progress. This will provide us with approximately 3500 SNPs (including over 500 SNPs that were genotyped here in Phoenix), giving a density range of one SNP per every 5-25 kb. We anticipate that the results obtained with these SNPs will help to prioritize region(s) which are likely to harbor the diabetes gene(s), and will narrow down the area of interest for further thorough molecular genetic analysis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK069073-09
Application #
7337552
Study Section
(PECR)
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2006
Total Cost
Indirect Cost
Name
U.S. National Inst Diabetes/Digst/Kidney
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Ma, Lijun; Hanson, Robert L; Que, Lorem N et al. (2007) Variants in ARHGEF11, a Candidate Gene for the Linkage to Type 2 Diabetes Mellitus on Chromosome 1q, Are Nominally Associated With Insulin Resistance and Type 2 Diabetes Mellitus in Pima Indians. Diabetes :
Chu, Winston S; Das, Swapan Kumar; Wang, Hua et al. (2007) Activating transcription factor 6 (ATF6) sequence polymorphisms in type 2 diabetes and pre-diabetic traits. Diabetes 56:856-62
Muller, Yunhua Li; Hanson, Robert L; Zimmerman, Collin et al. (2007) Variants in the Ca V 2.3 (alpha 1E) subunit of voltage-activated Ca2+ channels are associated with insulin resistance and type 2 diabetes in Pima Indians. Diabetes 56:3089-94
Ma, Lijun; Hanson, Robert L; Que, Lorem N et al. (2007) Variants in ARHGEF11, a candidate gene for the linkage to type 2 diabetes on chromosome 1q, are nominally associated with insulin resistance and type 2 diabetes in Pima Indians. Diabetes 56:1454-9
Fu, Mao; Sabra, Mona M; Damcott, Coleen et al. (2007) Evidence that Rho guanine nucleotide exchange factor 11 (ARHGEF11) on 1q21 is a type 2 diabetes susceptibility gene in the Old Order Amish. Diabetes 56:1363-8
Zeggini, Eleftheria; Damcott, Coleen M; Hanson, Robert L et al. (2006) Variation within the gene encoding the upstream stimulatory factor 1 does not influence susceptibility to type 2 diabetes in samples from populations with replicated evidence of linkage to chromosome 1q. Diabetes 55:2541-8
Thameem, Farook; Farook, Vidya S; Bogardus, Clifton et al. (2006) Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians. Diabetes 55:839-42
Thameem, Farook; Farook, Vidya S; Yang, Xiaolin et al. (2004) The transcribed endosulfine alpha gene is located within a type 2 diabetes-linked region on 1q: sequence and expression analysis in Pima Indians. Mol Genet Metab 81:16-21
Thameem, Farook; Yang, Xiaolin; Permana, Paska A et al. (2003) Evaluation of the microsomal glutathione S-transferase 3 (MGST3) locus on 1q23 as a Type 2 diabetes susceptibility gene in Pima Indians. Hum Genet 113:353-8
Wolford, J K; Bogardus, C; Ossowski, V et al. (2000) Molecular characterization of the human PEA15 gene on 1q21-q22 and association with type 2 diabetes mellitus in Pima Indians. Gene 241:143-8

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