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. Cardiovascular disease (CVD) and type 2 diabetes (T2D) are two tightly interrelated diseases that are leading epidemics and causes of deaths around the world. Elucidating the mechanistic connections between the two diseases will offer critical insights for the development of novel therapeutic avenues to target both simultaneously. Because of the challenging complexity of CVD and T2D, involving numerous risk factors, multiple tissues, and multidimensional molecular alterations, few have attempted such an investigation. We herein report a comprehensive and in-depth data-driven assessment of the shared mechanisms between CVD and T2D by integrating genomics data from diverse human populations including African Americans, Caucasian Americans, and Hispanic Americans with tissue-specific functional genomics information. We identified shared pathways and gene networks informed by CVD and T2D genetic risks across populations, confirming the importance of well-established processes, as well as unraveling previously under-appreciated processes such as extracellular matrix, branched-chain amino acid metabolism, and neuronal system for both diseases. Further incorporation of tissue-specific regulatory networks pinpointed potential key regulators that orchestrate the biological processes shared between the two diseases, which were cross-validated using cell culture and mouse models. This study suggests potential new therapeutic targets that warrant further investigation for both CVD and T2D.

Some Shanghai Clinical Center f a role of Niemann-Pick type C1 (NPC1) for obesity traits. However, whether the loss-of-function mutations in NPC1 cause adiposity in humans remains unknown. We recruited 25 probands with rare autosomal-recessive Niemann-Pick type C (NP-C) disease and their parents in assessment of the effect of heterozygous NPC1 mutations on adiposity. We found that male NPC1+/− carriers had a significantly higher BMI than matched control subjects or the whole population-based control subjects. Consistently, male NPC1+/− mice had increased fat storage while eating a high-fat diet. We further conducted an in-depth assessment of rare variants in the NPC1 gene in young, severely obese subjects and lean control subjects and identified 17 rare nonsynonymous/frameshift variants in NPC1 (minor allele frequency <1%) that were significantly associated with an increased risk of obesity (3.40% vs. 0.73%, respectively, in obese patients and control subjects, P = 0.0008, odds ratio = 4.8, 95% CI 1.7–13.2), indicating that rare NPC1 variants were enriched in young, morbidly obese Chinese subjects. Importantly, participants carrying rare variants with severely damaged cholesterol-transporting ability had more fat accumulation than those with mild/no damage rare variants. In summary, rare loss-of-function NPC1 mutations were identified as being associated with human adiposity with a high penetrance, providing potential therapeutic interventions for obesity in addition to the role of NPC1 in the familial NP-C disease.

Background—: Although cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors, potential molecular mechanisms that may also be shared for these 2 disorders remain unknown. Methods and Results—: Using an integrative pathway and network analysis, we performed genome-wide association studies in 8155 blacks, 3494 Hispanic American, and 3697 Caucasian American women who participated in the national Women’s Health Initiative single-nucleotide polymorphism (SNP) Health Association Resource and the Genomics and Randomized Trials Network. Eight top pathways and gene networks related to cardiomyopathy, calcium signaling, axon guidance, cell adhesion, and extracellular matrix seemed to be commonly shared between CVD and T2D across all 3 ethnic groups. We also identified ethnicity-specific pathways, such as cell cycle (specific for Hispanic American and Caucasian American) and tight junction (CVD and combined CVD and T2D in Hispanic American). In network analysis of gene–gene or protein–protein interactions, we identified key drivers that included COL1A1, COL3A1 , and ELN in the shared pathways for both CVD and T2D. These key driver genes were cross-validated in multiple mouse models of diabetes mellitus and atherosclerosis. Conclusions—: Our integrative analysis of American women of 3 ethnicities identified multiple shared biological pathways and key regulatory genes for the development of CVD and T2D. These prospective findings also support the notion that ethnicity-specific susceptibility genes and process are involved in the pathogenesis of CVD and T2D.

Much remains unknown about the role of added sugar in relation to cardiovascular disease (CVD) and the relative contributions of sugar-sweetened beverages (SSB) or artificially sweetened beverages (ASB) to CVD risk. Among the 109,034 women who participated in Women’s Health Initiative, we assessed average intakes of added sugar, SSB and ASB, and conducted Cox regression to estimate the hazard ratios (HRs) and their 95% confidence intervals for CVD risk. The consistency of findings was compared to a network meta-analysis of all available cohorts. During an average of 17.4 years of follow-up, 11,597 cases of total CVD (nonfatal myocardial infarction, coronary heart disease (CHD) death, stroke, coronary revascularization, and/or incident heart failure) were confirmed. Added sugar as % energy intake daily (%EAS) at ≥15.0% was positively associated with total CVD (HR = 1.08 [1.01, 1.15]) and CHD (HR = 1.20 [1.09, 1.32]). There was also a higher risk of total CVD associated with ≥1 serving of SSB intake per day (HR = 1.29 [1.17, 1.42]), CHD (1.35 [1.16, 1.57]), and total stroke (1.30 [1.10, 1.53]). Similarly, ASB intake was associated with an increased risk of CVD (1.14 [1.03, 1.26]) and stroke (1.24 [1.04, 1.48]). According to the network meta-analysis, there was a large amount of heterogeneity across studies, showing no consistent pattern implicating added sugar, ASB, or SSB in CVD outcomes. A diet containing %EAS ≥15.0% and consuming ≥1 serving of SSB or ASB may be associated with a higher CVD incidence. The relative contribution of added sugar, SSB, and ASB to CVD risk warrants further investigation.