We propose to study genetic determinants of atherosclerosis in diabetes on the inflammatory and endothelia dysfunction pathways that mediate the vessels' response to atherogenic factors.
Our aim i s to determine whether variability in 20 genes belonging to these pathways is related to the risk of coronary heart disease (CHD) among men and women diagnosed with type 2 diabetes in two large ongoing prospective studies, the Nurses' Health Study (NHS) and Health Professionals' Follow-up Study (HPFS). We propose to do so by combining two complementary approaches that are made possible by the recent advances in our knowledge of the human genome and high-throughput genotyping technologies. We will directly target functional variants in the coding regions of the candidate genes, but will also investigate the association between CHD and ancestral haplotypes at each locus.
Our specific aims are: 1. To identify novel variants in 10 candidate genes of the inflammatory, and endothelial dysfunction pathways that have not been systematically screened for polymorphisms by targeted resequencing; 2. To assess the relationship between, functional variants in 20 candidate genes in the inflammatory and endothelial dysfunction pathways and risk of CHD among subjects with diabetes of the NHS and HPFS cohorts; 3. To identify the subset of polymorphisms that best capture the overall genetic variability at each locus (haplotype tagging SNPs or htSNPs) and investigate the association between CHD risk and the haplotypes defined by these htSNPs; 4. To examine individual SNPs as well as haplotypes in relation to biochemical markers of inflammation and endothelial activation such as CRP, ICAM-1, VCAM-1, E-selectin, and TNF-a in diabetic individuals; and 5. To examine gene-environment interactions in relation to CHD risk in diabetic subjects. By 2006, an estimated 820 cases of CHD will have been confirmed among diabetic men and women in the blood cohorts. The large size, prospective design, high follow-up rates, detailed and reliable long-term lifestyle and outcome information, and the availability of blood specimens make these cohorts a valuable and unique resource for studying genetic determinants of accelerated atherosclerosis in diabetic patients. Knowledge of such markers would provide valuable opportunities for prevention and intervention in this high-risk population as well as in the general population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071981-04
Application #
7111637
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Sholinsky, Phyliss
Project Start
2003-09-17
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2008-08-31
Support Year
4
Fiscal Year
2006
Total Cost
$614,815
Indirect Cost
Name
Harvard University
Department
Nutrition
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
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Heianza, Yoriko; Sun, Dianjianyi; Smith, Steven R et al. (2018) Changes in Gut Microbiota-Related Metabolites and Long-term Successful Weight Loss in Response to Weight-Loss Diets: The POUNDS Lost Trial. Diabetes Care 41:413-419
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Sun, Dianjianyi; Li, Xiang; Heianza, Yoriko et al. (2018) History of Asthma From Childhood and Arterial Stiffness in Asymptomatic Young Adults: The Bogalusa Heart Study. Hypertension 71:928-936
Wang, Tiange; Heianza, Yoriko; Sun, Dianjianyi et al. (2018) Improving adherence to healthy dietary patterns, genetic risk, and long term weight gain: gene-diet interaction analysis in two prospective cohort studies. BMJ 360:j5644
Heianza, Yoriko; Sun, Dianjianyi; Ma, Wenjie et al. (2018) Gut-microbiome-related LCT genotype and 2-year changes in body composition and fat distribution: the POUNDS Lost Trial. Int J Obes (Lond) 42:1565-1573
Sun, Dianjianyi; Heianza, Yoriko; Li, Xiang et al. (2018) Genetic, epigenetic and transcriptional variations at NFATC2IP locus with weight loss in response to diet interventions: The POUNDS Lost Trial. Diabetes Obes Metab 20:2298-2303
Goni, Leticia; Sun, Dianjianyi; Heianza, Yoriko et al. (2018) A circadian rhythm-related MTNR1B genetic variant modulates the effect of weight-loss diets on changes in adiposity and body composition: the POUNDS Lost trial. Eur J Nutr :
Heianza, Yoriko; Sun, Dianjianyi; Li, Xiang et al. (2018) Gut microbiota metabolites, amino acid metabolites and improvements in insulin sensitivity and glucose metabolism: the POUNDS Lost trial. Gut :
McKeown, Nicola M; Dashti, Hassan S; Ma, Jiantao et al. (2018) Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis. Diabetologia 61:317-330

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