This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.OBJECTIVE: Coronary artery calcification (CAC) is an integral part of atherosclerotic plaque and is an independent predictor of cardiac events. The mortality risk from cardiovascular disease (CVD) in diabetic patients is 2-5 fold greater compared to the general population. The development of diabetic nephropathy (DN) leads to further acceleration of atherosclerosis and a significant increase in morbidity and mortality from CVD. As diabetic patients progress from microalbuminuria to overt proteinuria and ultimately to end stage renal disease (ESRD), there is a parallel increase in death rate from CVD. In this study, we plan to evaluate the atherosclerotic burden by measuring CAC by Multidetector Computed Tomography (MDCT) and to conduct a genetic epidemiological investigation of CAC in a minority population prone to complex disease phenotypes including type 2 diabetes mellitus (T2DM), DN, and CVD.RESEARCH PLAN AND METHODS: We are one of eight Participating Investigation Centers (PICs) of the Family Investigation of Nephropathy of Diabetes (FIND) study, which aims to localize genes for DN using concordant and discordant sibpair analytical approach. Our center completed recruitment of 1200 subjects ascertained from 320 families of Mexican American origin. A majority of thes families are nuclear in nature, composed mainly of sibships with varying sizes. The proband contains diabetic siblings with various phenotypes: normoalbuminuria, microalbuminuria and macroalbuminuria are included in the study. Also included in the study are the nondiabetic siblings of the probands. The overall hypothesis of this proposal is that susceptibility to the development and the severity of CAC in patients with DM and DN has genetic predisposition.In this proposal, we plan to recall all available participants of the FIND subpopulation ascertained by the San Antonio PIC: 1) to measure prevalence and severity of CAC; 2) to determine its heritability; 3) to identify chrmomsomal regions harboring CAC susceptibility genes using genome wide scan and linkage approaches; 3a) Detect initial evidence of linkage to CAC susceptibility loci across the traits, and already available FIND-San Antonio PIC genome scan data; 3b) Refine the initial screening using multipoint variance components method; 3c) Conduct multivariate linkage analysis to identify genetic locations with common genetic influences (pleiotropy) on a given trait-pair e.g., CAC and DM.; and 3d) Perform Oligogenic linkage analysis.CLINICAL
Diabetes mellitus is a common chronic illness that affects 10-16 million people in the U.S. and is associated with high levels of morbidity and mortality. The results from this project will clarify the contribution of genetic factors to the etiology of CAC. Specifically, this study will lead to the identification of genes that influence variation in CAC. Also, it will lead to the identification of susceptibility loci across the genome with common genetic influences on CAC and its correlated metabolic diseases such as DM and DN. The identification of susceptibility genes for CAC should increase the knowledge about the CVD risk for whom intensive preventive or therapeutic measures may be most beneficial. Screening and identifying patients at risk for CAC will contribute to the current efforts directed to reduce mortality and morbidity of cardiovascular disease.
Showing the most recent 10 out of 600 publications
