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Shared genetic regulatory networks for cardiovascular disease and type 2 diabetes in multiple populations of diverse ethnicities in the United States.

ABSTRACT: Cardiovascular diseases (CVD) and type 2 diabetes (T2D) are closely interrelated complex diseases likely sharing overlapping pathogenesis driven by aberrant activities in gene networks. However, the molecular circuitries underlying the pathogenic commonalities remain poorly understood. We sought to identify the shared gene networks and their key intervening drivers for both CVD and T2D by conducting a comprehensive integrative analysis driven by five multi-ethnic genome-wide association studies (GWAS) for CVD and T2D, expression quantitative trait loci (eQTLs), ENCODE, and tissue-specific gene network models (both co-expression and graphical models) from CVD and T2D relevant tissues. We identified pathways regulating the metabolism of lipids, glucose, and branched-chain amino acids, along with those governing oxidation, extracellular matrix, immune response, and neuronal system as shared pathogenic processes for both diseases. Further, we uncovered 15 key drivers including HMGCR, CAV1, IGF1 and PCOLCE, whose network neighbors collectively account for approximately 35% of known GWAS hits for CVD and 22% for T2D. Finally, we cross-validated the regulatory role of the top key drivers using in vitro siRNA knockdown, in vivo gene knockout, and two Hybrid Mouse Diversity Panels each comprised of >100 strains. Findings from this in-depth assessment of genetic and functional data from multiple human cohorts provide strong support that common sets of tissue-specific molecular networks drive the pathogenesis of both CVD and T2D across ethnicities and help prioritize new therapeutic avenues for both CVD and T2D.

SUBMITTER: Shu L

PROVIDER: S-EPMC5634657 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Shared genetic regulatory networks for cardiovascular disease and type 2 diabetes in multiple populations of diverse ethnicities in the United States.

Shu Le L Chan Kei Hang K KHK Zhang Guanglin G Huan Tianxiao T Kurt Zeyneb Z Zhao Yuqi Y Codoni Veronica V Trégouët David-Alexandre DA Yang Jun J Wilson James G JG Luo Xi X Levy Daniel D Lusis Aldons J AJ Liu Simin S Yang Xia X

PLoS genetics 20170928 9

Cardiovascular diseases (CVD) and type 2 diabetes (T2D) are closely interrelated complex diseases likely sharing overlapping pathogenesis driven by aberrant activities in gene networks. However, the molecular circuitries underlying the pathogenic commonalities remain poorly understood. We sought to identify the shared gene networks and their key intervening drivers for both CVD and T2D by conducting a comprehensive integrative analysis driven by five multi-ethnic genome-wide association studies ...[more]

PMID: 28957322

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Project description:Cardiovascular disease (CVD) death rates are much higher in blacks than whites in the United States. It is unclear how CVD risk and events are distributed among blacks versus whites and how interventions reduce racial disparities.We developed risk models for fatal and for fatal and nonfatal CVD using 8 cohorts in the United States. We used 6154 adults who were 50 to 69 years of age in the National Health and Nutrition Examination Survey 1999 to 2012 to estimate the distributions of risk and events in blacks and whites. We estimated the total and disparity impacts of a range of population-wide, targeted, and risk-based interventions on 10-year CVD risks and event rates.Twenty-five percent (95% confidence interval [CI], 22-28) of black men and 12% (95% CI, 10-14) of black women were at ?6.67% risk of fatal CVD (almost equivalent to 20% risk of fatal or nonfatal CVD) compared with 10% (95% CI, 8-12) of white men and 3% (95% CI, 2-4) of white women. These high-risk individuals accounted for 55% (95% CI, 49-59) of CVD deaths among black men and 42% (95% CI, 35-46) in black women compared with 30% (95% CI, 24-35) in white men and 18% (95% CI, 13-22) in white women. We estimated that an intervention that treated multiple risk factors in high-risk individuals could reduce black-white difference in CVD death rate from 1659 to 1244 per 100 000 in men and from 1320 to 897 in women. Rates of fatal and nonfatal CVD were generally similar between black and white men. In women, a larger proportion of women were at ?7.5% risk of CVD (30% versus 19% in whites), and an intervention that targeted multiple risk factors among this group was estimated to reduce black-white differences in CVD rates from 1688 to 1197 per 100 000.A substantially larger proportion of blacks have a high risk of fatal CVD and bear a large share of CVD deaths. A risk-based intervention that reduces multiple risk factors could substantially reduce overall CVD rates and racial disparities in CVD death rates.

Dataset Information

Shared genetic regulatory networks for cardiovascular disease and type 2 diabetes in multiple populations of diverse ethnicities in the United States.

Publications

Shared genetic regulatory networks for cardiovascular disease and type 2 diabetes in multiple populations of diverse ethnicities in the United States.

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