Examining susceptibility and resistance phenotypes to enhance understanding of the genetic basis of major coronary artery disease in type 1 diabetes

Active Project Grant Awarded Last action

Award ID
R01HL161879
Recipient
Awarding agency
Obligated
$3,594,190

Award facts

Completion date 87% complete
Funding agency
National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health, Department of Health and Human Services
Place of performance
Pennsylvania, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
People with type 1 diabetes (T1D) are at dramatically increased risk of developing coronary artery disease (CAD), but the reasons for this excess risk compared to the background population are not fully understood. There is a critical need to identify people at risk of major CAD events early in their T1D natural history and to develop new therapeutic interventions to reduce CAD risk and burden. While prior studies have examined associations between genetic variants and CAD in T1D, a lack of strong candidate genes remains. This lack is at least partially due to the fact that case-control designs using low-precision phenotypes to maximize sample size and which disregard within-phenotype heterogeneity have been the most common approach to studying the genetic basis of vascular complications in T1D to date. Likewise, while IT is well established that inflammatory and immune response biomarkers are associated with CAD risk in general and that levels of these biomarkers are elevated in T1D, the association between such markers and CAD has not been comprehensively studied in T1D. Inflammatory and immune response biomarkers are intermediate phenotypes that hold potential to help uncover novel pathways to CAD in T1D and may be promising treatment targets. Thus, our hypotheses are that unidentified genetic variants associated with CAD susceptibility or resistance exist and that networks of inflammatory and immune response biomarkers are associated with CAD and may mediate inflammatory/immune response gene-CAD associations. Our approach will be to first refine the CAD phenotype definition to one that better reflects the genetic etiology of CAD susceptibility and resistance in T1D. Specifically, studying highly specific "discordant" risk factor-CAD phenotype subgroups may help uncover novel pathways to CAD development in T1D. Our approach will increase precision of both genetic sequencing (by using whole genome sequencing) and CAD phenotype definitions. We will also measure a comprehensive proteomic panel of 92 targeted biomarkers and derive networks of related markers to assess their associations with CAD and the degree to which those networks mediate associations between CAD and genes involved in inflammation/immune response. We will utilize data and specimens from the epidemiology of diabetes complications (EDC) study, a well-characterized T1D cohort with >30 years of follow-up and deep phenotyping, allowing US to comprehensively examine many intermediate phenotypes (i.e., traditional risk factors and novel biomarkers) in gene-to-CAD pathways. Furthermore, we will replicate the findings from this discovery analyses in external cohorts. With this approach we expect to uncover evidence of novel pathways that account for a proportion of unexplained CAD risk in T1D and point to new intervention targets.

Transactions

Action Obligated Date
Amendment $327,064
Amendment $319,386
Amendment $403,786
Amendment $623,143
Amendment $623,143
Amendment $648,834
Original award $648,834

Subawards

Subrecipient Amount Awarded
Rector & Visitors Of The University Of Virginia Examining Susceptibility and Resistance Phenotypes to Enhance Understanding of the Genetic Basis of Major Coronary Artery Disease in Type 1 Diabetes $174,096
Subrecipient not on record $178,728
Rector & Visitors Of The University Of Virginia $130,503
Rector & Visitors Of The University Of Virginia $88,741

Quick answers

Who received award R01HL161879?

R01HL161879 was awarded to University Of Pittsburgh - Of The Commonwealth System Of Higher Education by National Heart Lung and Blood Institute (National Institutes of Health) on July 27, 2022.

How much is award R01HL161879 worth?

$3,594,190 has been obligated on R01HL161879.

Which agency awarded R01HL161879?

National Heart Lung and Blood Institute (National Institutes of Health) awarded R01HL161879, with funding from National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health).

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