The role of genetic susceptibility in T2DM is well established. In the previous funding period, we mapped T2DM to chromosome 1q21-q23 by linkage in multigenerational Utah families. These results were confirmed by parallel studies in Pima Indians, Amish and French families, and English sib pairs. Several markers within this region show promising associations with T2DM. Three hypotheses are proposed: 1) a single locus or haplotype on 1q21-q23 increases diabetes susceptibility in multiple populations; 2) additional susceptibility loci will be apparent by conditioning on the 1q21 locus; 3) the 1q21-q23 susceptibility locus alters gene expression in fat and muscle. A comprehensive, complementary strategy is proposed to address these hypotheses and to compensate for the weaknesses inherent in any single approach. This strategy incorporates a close collaboration with other laboratories with evidence for linkage. First, a dense marker map will be constructed to test linkage disequilibrium by placing 1000 single nucleotide polymorphisms (SNPs) and 75 microsatellites over a 15 Mb region. Initial typing will use a pooled typing strategy, followed by confirmation in individual case control samples and typing of additional SNPs. Second, a positional candidate strategy will be pursued by identifying candidate genes on 1q21-q23 both by known function and by expression in diabetes-related tissues. Candidates will be sought also through differential expression in sib pairs discordant for diabetes. Each candidate gene will be screened extensively for variation in exons, flanking regions, and intronic sequences proximal to exons. Variants identified will be tested in case control studies, first using a pooled strategy with subsequent confirmation in individual samples. For variants that are associated with T2DM in either linkage disequilibrium or candidate gene studies, all closely spaced markers will be typed in multigenerational families to establish haplotypes. Markers will be tested for family-based association, haplotype sharing, decay of haplotype sharing, and association with evidence for linkage. Finally, using the associated variant or haplotype for 1q21-q23, 2-locus conditional search methods will be used to identify additional linked regions. Regions of suggestive linkage will be identified from all Caucasian genome scans, and microsatellite marker density increased to 3-5 cM in Utah families. Functional candidates at each region will be identified and screened for variation. Multiple conditional search methods will be tested and compared. The proposed studies have a strong likelihood of finding the 1q21-q23 susceptibility locus and begin to explore other loci.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK039311-16
Application #
6621083
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Mckeon, Catherine T
Project Start
1988-05-01
Project End
2006-11-30
Budget Start
2002-12-11
Budget End
2003-11-30
Support Year
16
Fiscal Year
2003
Total Cost
$300,880
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Das, S K; Ma, L; Sharma, N K (2015) Adipose tissue gene expression and metabolic health of obese adults. Int J Obes (Lond) 39:869-73
Das, Swapan Kumar; Sharma, Neeraj Kumar; Zhang, Bin (2015) Integrative network analysis reveals different pathophysiological mechanisms of insulin resistance among Caucasians and African Americans. BMC Med Genomics 8:4
Sharma, Neeraj K; Varma, Vijayalakshmi; Ma, Lijun et al. (2015) Obesity Associated Modulation of miRNA and Co-Regulated Target Transcripts in Human Adipose Tissue of Non-Diabetic Subjects. Microrna 4:194-204
Das, Swapan Kumar; Sharma, Neeraj Kumar (2014) Expression quantitative trait analyses to identify causal genetic variants for type 2 diabetes susceptibility. World J Diabetes 5:97-114
Mondal, Ashis K; Sharma, Neeraj K; Elbein, Steven C et al. (2013) Allelic expression imbalance screening of genes in chromosome 1q21-24 region to identify functional variants for Type 2 diabetes susceptibility. Physiol Genomics 45:509-20
Ma, Lijun; Murea, Mariana; Snipes, James A et al. (2013) An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects. PLoS One 8:e56193
Sharma, Neeraj K; Langberg, Kurt A; Mondal, Ashis K et al. (2013) Phospholipid biosynthesis genes and susceptibility to obesity: analysis of expression and polymorphisms. PLoS One 8:e65303
Elbein, Steven C; Gamazon, Eric R; Das, Swapan K et al. (2012) Genetic risk factors for type 2 diabetes: a trans-regulatory genetic architecture? Am J Hum Genet 91:466-77
Mondal, Ashis K; Das, Swapan K; Varma, Vijayalakshmi et al. (2012) Effect of endoplasmic reticulum stress on inflammation and adiponectin regulation in human adipocytes. Metab Syndr Relat Disord 10:297-306
Baral, Aradhita; Kumar, Pankaj; Halder, Rashi et al. (2012) Quadruplex-single nucleotide polymorphisms (Quad-SNP) influence gene expression difference among individuals. Nucleic Acids Res 40:3800-11

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