Genomic atlas of the human plasma proteome.

Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.

Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis.

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

Integrating genetic, transcriptional, and biological information provides insights into obesity.

OBJECTIVE: Indices of body fat distribution are heritable, but few genetic signals have been reported from genome-wide association studies (GWAS) of computed tomography (CT) imaging measurements of body fat distribution. We aimed to identify genes associated with adiposity traits and the key drivers that are central to adipose regulatory networks. SUBJECTS: We analyzed gene transcript expression data in blood from participants in the Framingham Heart Study, a large community-based cohort (n up to 4303), as well as implemented an integrative analysis of these data and existing biological information. RESULTS: Our association analyses identified unique and common gene expression signatures across several adiposity traits, including body mass index, waist-hip ratio, waist circumference, and CT-measured indices, including volume and quality of visceral and subcutaneous adipose tissues. We identified six enriched KEGG pathways and two co-expression modules for further exploration of adipose regulatory networks. The integrative analysis revealed four gene sets (Apoptosis, p53 signaling pathway, Proteasome, Ubiquitin-mediated proteolysis) and two co-expression modules with significant genetic variants and 94 key drivers/genes whose local networks were enriched with adiposity-associated genes, suggesting that these enriched pathways or modules have genetic effects on adiposity. Most identified key driver genes are involved in essential biological processes such as controlling cell cycle, DNA repair, and degradation of regulatory proteins are cancer related. CONCLUSIONS: Our integrative analysis of genetic, transcriptional, and biological information provides a list of compelling candidates for further follow-up functional studies to uncover the biological mechanisms underlying obesity. These candidates highlight the value of examining CT-derived and central adiposity traits.

Using Human Genetics to Drive Drug Discovery: A Perspective.

The probability of success of developing medicines to treat human disease can be improved by leveraging human genetics. Different types of genetic data and techniques, including genome-wide association, whole-exome sequencing, and whole-genome sequencing, can be used to gain insight into human disease. Layering different types of genetic evidence from Mendelian disease, coding variants, and common variation can bolster support for a genetic target. Human knockouts offer the potential to perform reverse genetic screens in humans to identify physiologically relevant targets. Other components of a good genetic target include protective loss-of-function mutations, some degree of known biology, tractability, and a clean on-target safety profile. In addition to using human genetics to inspire new drug programs, phenome-wide association studies can be used to identify alternative indications or repurposing opportunities. This information can be combined into a 5-step approach for selecting a genetic target for validation, which is presented in detail in this review. Finally, current challenges in leveraging human genetics are highlighted, including the difficulties translating certain types of genetic data, relatively small number of bona fide disease-associated coding rare variants, and current sample sizes of large well-curated biobanks linked to comprehensive genetic information.

Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy.

The global nephrology community recognises the need for a cohesive plan to address the problem of chronic kidney disease (CKD). In July, 2016, the International Society of Nephrology hosted a CKD summit of more than 85 people with diverse expertise and professional backgrounds from around the globe. The purpose was to identify and prioritise key activities for the next 5-10 years in the domains of clinical care, research, and advocacy and to create an action plan and performance framework based on ten themes: strengthen CKD surveillance; tackle major risk factors for CKD; reduce acute kidney injury-a special risk factor for CKD; enhance understanding of the genetic causes of CKD; establish better diagnostic methods in CKD; improve understanding of the natural course of CKD; assess and implement established treatment options in patients with CKD; improve management of symptoms and complications of CKD; develop novel therapeutic interventions to slow CKD progression and reduce CKD complications; and increase the quantity and quality of clinical trials in CKD. Each group produced a prioritised list of goals, activities, and a set of key deliverable objectives for each of the themes. The intended users of this action plan are clinicians, patients, scientists, industry partners, governments, and advocacy organisations. Implementation of this integrated comprehensive plan will benefit people who are at risk for or affected by CKD worldwide.

Barriers to medication adherence and links to cardiovascular disease risk factor control: the Framingham Heart Study.

BACKGROUND: In the elderly, impaired cognition may weaken medication adherence and compromise treatment for cardiovascular disease (CVD). AIM: We examined risk factors for medication adherence and the relationship between adherence and levels of CVD risk factors among older participants with hypertension, dyslipidaemia and diabetes in the Framingham Heart Study. METHODS: The four-item Morisky Medication Adherence Scale was administered to 1559 participants, median age 70 years, 53% women. We created an adherence score, ranging from 0 to 4, with low adherence defined as a score ≥2. CVD risk factors were assessed using standard protocols. Cognition was measured using the Mini-Mental State Examination (MMSE) and depressive symptoms were measured using the Center for Epidemiologic Studies of Depression (CES-D) scale. RESULTS: Among participants who self-reported taking antihypertensive, lipid-lowering and/or hyperglycaemic medication(s), 12% (n = 191) had low medication adherence. The risk of low adherence increased by 45% (95% confidence interval (CI): 25-68%, P < 0.001) per five-unit increase in CES-D score. In participants taking antihypertensive medication (n = 1017), low adherence was associated with higher mean diastolic blood pressure (73 mmHg, 95% CI: 71-75 vs 71 mmHg, 95% CI: 70-71; P = 0.04) after adjusting for covariates. Among participants taking lipid-lowering medication (n = 937), low adherence was associated with higher mean low-density lipoprotein cholesterol (92 mg/dL, 95% CI: 87-96 vs 86 mg/dL, 95% CI: 84-88; P = 0.03). Low adherence was not associated with fasting plasma glucose (P = 0.10) or haemoglobin A1c (P = 0.68) in the subgroup of participants (n = 192) taking hypoglycaemic medication. CONCLUSIONS: Depressive symptoms might act as a barrier for medication adherence, which exacerbates CVD risk factors in older-aged adults.

Genome-Wide Association of CKD Progression: The Chronic Renal Insufficiency Cohort Study.

The rate of decline of renal function varies significantly among individuals with CKD. To understand better the contribution of genetics to CKD progression, we performed a genome-wide association study among participants in the Chronic Renal Insufficiency Cohort Study. Our outcome of interest was CKD progression measured as change in eGFR over time among 1331 blacks and 1476 whites with CKD. We stratified all analyses by race and subsequently, diabetes status. Single-nucleotide polymorphisms (SNPs) that surpassed a significance threshold of P<1×10-6 for association with eGFR slope were selected as candidates for follow-up and secondarily tested for association with proteinuria and time to ESRD. We identified 12 such SNPs among black patients and six such SNPs among white patients. We were able to conduct follow-up analyses of three candidate SNPs in similar (replication) cohorts and eight candidate SNPs in phenotype-related (validation) cohorts. Among blacks without diabetes, rs653747 in LINC00923 replicated in the African American Study of Kidney Disease and Hypertension cohort (discovery P=5.42×10-7; replication P=0.039; combined P=7.42×10-9). This SNP also associated with ESRD (hazard ratio, 2.0 (95% confidence interval, 1.5 to 2.7); P=4.90×10-6). Similarly, rs931891 in LINC00923 associated with eGFR decline (P=1.44×10-4) in white patients without diabetes. In summary, SNPs in LINC00923, an RNA gene expressed in the kidney, significantly associated with CKD progression in individuals with nondiabetic CKD. However, the lack of equivalent cohorts hampered replication for most discovery loci. Further replication of our findings in comparable study populations is warranted.

Sugar-Sweetened Beverage Consumption Is Associated With Change of Visceral Adipose Tissue Over 6 Years of Follow-Up.

BACKGROUND: Sugar-sweetened beverage (SSB) intake has been linked to abnormal abdominal adipose tissue. We examined the prospective association of habitual SSB intake and change in visceral adipose tissue (VAT) and subcutaneous adipose tissue. METHODS AND RESULTS: The quantity (volume, cm(3)) and quality (attenuation, Hounsfield Unit) of abdominal adipose tissue were measured using computed tomography in 1003 participants (mean age 45.3 years, 45.0% women) at examination 1 and 2 in the Framingham's Third Generation cohort. The 2 exams were ≈ 6 years apart. At baseline, SSB and diet soda intake were assessed using a valid food frequency questionnaire. Participants were categorized into 4 groups: none to <1 serving/mo (nonconsumers), 1 serving/mo to <1 serving/week, 1 serving/week to 1 serving/d, and ≥ 1 serving/d (daily consumers) of either SSB or diet soda. After adjustment for multiple confounders including change in body weight, higher SSB intake was associated with greater change in VAT volume (P trend<0.001). VAT volume increased by 658 cm(3) (95% confidence interval [CI], 602 to 713), 649 cm(3) (95% CI, 582 to 716), 707 cm(3) (95% CI, 657 to 757), and 852 cm(3) (95% CI, 760 to 943) from nonconsumers to daily consumers. Higher SSB intake was also associated with greater decline of VAT attenuation (P trend=0.007); however, the association became nonsignificant after additional adjustment for VAT volume change. In contrast, diet soda consumption was not associated with change in abdominal adipose tissue. CONCLUSIONS: Regular SSB intake was associated with adverse change in both VAT quality and quantity, whereas we observed no such association for diet soda.

Residential Proximity to Major Roadways, Fine Particulate Matter, and Hepatic Steatosis: The Framingham Heart Study.

We examined associations between ambient air pollution and hepatic steatosis among 2,513 participants from the Framingham (Massachusetts) Offspring Study and Third Generation Cohort who underwent a computed tomography scan (2002-2005), after excluding men who reported >21 drinks/week and women who reported >14 drinks/week. We calculated each participant's residential-based distance to a major roadway and used a spatiotemporal model to estimate the annual mean concentrations of fine particulate matter. Liver attenuation was measured by computed tomography, and liver-to-phantom ratio (LPR) was calculated. Lower values of LPR represent more liver fat. We estimated differences in continuous LPR using linear regression models and prevalence ratios for presence of hepatic steatosis (LPR ≤ 0.33) using generalized linear models, adjusting for demographics, individual and area-level measures of socioeconomic position, and clinical and lifestyle factors. Participants who lived 58 m (25th percentile) from major roadways had lower LPR (ß = -0.003, 95% confidence interval: -0.006, -0.001) and higher prevalence of hepatic steatosis (prevalence ratio = 1.16, 95% confidence interval: 1.05, 1.28) than those who lived 416 m (75th percentile) away. The 2003 annual average fine particulate matter concentration was not associated with liver-fat measurements. Our findings suggest that living closer to major roadways was associated with more liver fat.

Urinary metabolites along with common and rare genetic variations are associated with incident chronic kidney disease.

We assessed the association between urinary metabolites, genetic variants, and incident chronic kidney disease (CKD) in the Framingham Offspring cohort. Among the participants, 193 individuals developed CKD (estimated glomerular filtration rate under 60 ml/min/1.73m2) between cohort examinations 6 (1995-1998) and 8 (2005-2008, mean follow-up 9.7 years). They were age- and sex-matched to 193 control individuals free of CKD. A total of 154 urinary metabolites were measured using mass spectrometry, and the association between metabolites and CKD was examined using logistic regression. Next, we tested the genetic associations of each metabolite with an Illumina exome chip. Urinary glycine and histidine were associated with a lower risk of incident CKD with an odds ratio of 0.59 (95% confidence interval [CI] 0.43-0.80) and 0.65 (0.50-0.85) respectively, per one standard deviation increase in metabolite concentration. Follow-up in the Atherosclerosis Risk in Communities cohort confirmed the association of urinary glycine with CKD. In exome chip analyses, 36 single nucleotide polymorphisms at 30 loci were significantly associated with 31 metabolites. We surveyed exome chip findings for associations with known renal function loci such as rs8101881 in SLC7A9 coding for an amino acid transporter, which has been associated with a lower risk of CKD. We found this polymorphism was significantly associated with higher levels of lysine and NG-monomethyl-L-arginine (NMMA). Increased urinary lysine and NMMA were associated with a lower risk of CKD (0.73 [0.50-0.90] and 0.66 [0.53-0.83], respectively) in the univariate model. Thus, low urinary glycine and histidine are associated with incident CKD. Furthermore, genomic association of urinary metabolomics identified lysine and NMMA as being linked with CKD and provided additional evidence for the association of SLC7A9 with kidney disease.

Bi-directional analysis between fatty liver and cardiovascular disease risk factors.

BACKGROUND & AIMS: The relations of non-alcoholic fatty liver disease to cardiovascular disease (CVD) risk factors are not fully understood. The objective of our study is to explore the bi-directional relationships of fatty liver to CVD risk factors. METHODS: We prospectively evaluated whether liver fat predicted the development of CVD risk factors and whether CVD risk factors predicted new onset fatty liver during 6years of follow-up in middle- to older-aged Framingham Heart Study participants. We estimated liver fat using multi-detector computed tomography. RESULTS: We included 1051 participants (mean age 45±6years, 46% women). The prevalence of fatty liver was 18% at baseline. In participants without fatty liver at baseline, 101 participants developed incident fatty liver over approximately 6years. Baseline liver fat (per standard deviation increase) was associated with increased odds of incident hypertension (OR 1.42; 95% CI 1.15-1.76; p=0.001) and incident type 2 diabetes (OR 1.43; 95% CI 1.09-1.88, p<0.001). In a parallel analysis, individuals with hypertension (OR 3.34; 95% CI 2.04-5.49), hypertriglyceridemia (OR 3.04; 95% CI: 1.84-5.02), impaired fasting glucose (OR 2.92; 95% CI 1.76-4.82), or type 2 diabetes (OR 4.15; 95% CI 1.19-14.46) at baseline had higher odds of incident fatty liver compared to individuals without those conditions (all p<0.03). In both analyses, the observed associations remained similar after additional adjustments for measures of adiposity. CONCLUSIONS: The present study demonstrated bi-directional relationships between fatty liver and CVD risk factors among middle- to older-aged Framingham Heart Study participants. LAY SUMMARY: It is not fully understood whether non-alcoholic fatty liver (NAFLD) disease precedes or develops after increased cardiovascular disease (CVD) risk factors. The findings of our study suggest a bi-directional relationship between NAFLD and CVD risk factors.

Loss-of-function mutations in APOC3, triglycerides, and coronary disease.

BACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)). CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).

Residual lifetime risk of chronic kidney disease.

BACKGROUND: An accurate estimation of the lifetime risk of chronic kidney disease (CKD) can aid in patient education while also informing the development of public health screening programs and educational campaigns. METHODS: Framingham Offspring Study participants were included if they were free of CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2) at age 50 years and had at least two serum creatinine measures during follow-up (mean 16 years, 49 506 person-years). We estimated the lifetime risk of CKD to age 90 years adjusting for the competing risk of death in the overall cohort and in population subgroups with known CKD risk factors including hypertension, obesity and diabetes. RESULTS: Overall 3362 individuals (52% women) were included in the study. Mean age at study baseline was 54 years. By the end of the study, 729 individuals (21.7%) developed CKD and 618 (18.4%) died. At age 50 years, the cumulative lifetime risk of CKD was 41.3% [95% confidence interval (CI) 38.5-44.0]. The risk was increased in those with risk factors at baseline including diabetes (52.6%, 95% CI 44.8-60.4), hypertension (50.2%, 95% CI 46.1-54.3) and obesity (46.5%, 95% CI 41.1-52.0). For those individuals without any risk factors at baseline, the lifetime risk of CKD was lower (34.2%, 95% CI 29.4-39.0) relative to those with 1, 2 or 3 risk factors (45.0, 51.5 and 56.1% respectively, P < 0.01 for all compared with those with no risk factors). CONCLUSIONS: Four out of 10 individuals without CKD at age 50 years will eventually develop CKD. This risk is modified by the presence of hypertension, diabetes and obesity at baseline. This demonstrates the importance of early identification of CKD risk factors, to aid in patient education, and potentially to reduce the future risk of disease.

Clinical associations of total kidney volume: the Framingham Heart Study.

BACKGROUND: Total kidney volume (TKV) is an imaging biomarker that may have diagnostic and prognostic utility. The relationships between kidney volume, renal function and cardiovascular disease (CVD) have not been characterized in a large community-dwelling population. This information is needed to advance the clinical application of TKV. METHODS: We measured TKV in 1852 Framingham Heart Study participants (mean age 64.1 ± 9.2 years, 53% women) using magnetic resonance imaging. A healthy sample was used to define reference values. The associations between TKV, renal function and CVD risk factors were determined using multivariable logistic regression analysis. RESULTS: Overall, mean TKV was 278 ± 54 cm3 for women and 365 ± 66 cm3 for men. Risk factors for high TKV (>90% healthy referent size) were body surface area (BSA), diabetes, smoking and albuminuria, while age, female and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 were protective. Participants with high TKV had higher odds of diabetes [odds ratio (OR) 2.15, P < 0.001] and lower odds of eGFR <60 mL/min/1.73 m2 (OR 0.32, P = 0.007). Risk factors for low TKV (<10% healthy referent size) were age, female and eGFR <60 mL/min/1.73 m2, while BSA and diabetes were protective. Participants with low TKV had higher odds of eGFR <60 mL/min/1.73 m2 (OR 6.12, P < 0.001) and albuminuria (OR 1.56, P = 0.03). CONCLUSIONS: Low TKV is associated with markers of kidney damage including albuminuria and eGFR <60 mL/min/1.73 m2, while high TKV is associated with diabetes and decreased odds of eGFR <60 mL/min/1.73 m2. Prospective studies are needed to characterize the natural progression and clinical consequences of TKV.

Genetic risk score and risk of stage 3 chronic kidney disease.

BACKGROUND: We developed a genetic risk score (GRS) and examined whether the GRS may predict incident stage 3 chronic kidney disease (CKD) independent of common clinical risk factors. METHOD: The present study included 2,698 individuals who attended the 15th (1977 to 1979) and the 24th exams (1995 to 1998) in the Framingham Original cohort or the 6th (1995 to 1998) and the 8th exams (2005 to 2008) in the Framingham Offspring cohort. A weighted GRS was constructed combining 53 single nucleotide polymorphisms (SNPs) associated with lower creatinine-based estimated glomerular filtration rate (eGFR). Stage 3 CKD was defined as eGFR <60 mL/min/1.73 m2, and incident cases were identified at follow-up after excluding prevalent cases at baseline. RESULTS: A total of 292 incident cases and 2,406 non-cases were identified over, on average, 11 years of follow-up. After adjustment for sex, age, cohort, baseline eGFR, hypertension, diabetes, and dipstick proteinuria, the odds ratio of incident stage 3 CKD was 1.37 (95%CI: 1.02-1.83) per 10 alleles of the GRS (P = 0.04). There was no statistically significant difference between the C-statistic without and with inclusion of the GRS (0.783 and 0.785, respectively; P = 0.39). CONCLUSIONS: A GRS developed based on 53 SNPs associated with reduced eGFR was prospectively associated with incident stage 3 CKD. However, this score did not substantially improve discrimination of stage 3 CKD beyond the common clinical risk factors.

Past Decline Versus Current eGFR and Subsequent Mortality Risk.

A single determination of eGFR associates with subsequent mortality risk. Prior decline in eGFR indicates loss of kidney function, but the relationship to mortality risk is uncertain. We conducted an individual-level meta-analysis of the risk of mortality associated with antecedent eGFR slope, adjusting for established risk factors, including last eGFR, among 1.2 million subjects from 12 CKD and 22 other cohorts within the CKD Prognosis Consortium. Over a 3-year antecedent period, 12% of participants in the CKD cohorts and 11% in the other cohorts had an eGFR slope <-5 ml/min per 1.73 m(2) per year, whereas 7% and 4% had a slope >5 ml/min per 1.73 m(2) per year, respectively. Compared with a slope of 0 ml/min per 1.73 m(2) per year, a slope of -6 ml/min per 1.73 m(2) per year associated with adjusted hazard ratios for all-cause mortality of 1.25 (95% confidence interval [95% CI], 1.09 to 1.44) among CKD cohorts and 1.15 (95% CI, 1.01 to 1.31) among other cohorts during a follow-up of 3.2 years. A slope of +6 ml/min per 1.73 m(2) per year also associated with higher all-cause mortality risk, with adjusted hazard ratios of 1.58 (95% CI, 1.29 to 1.95) among CKD cohorts and 1.43 (95% CI, 1.11 to 1.84) among other cohorts. Results were similar for cardiovascular and noncardiovascular causes of death and stronger for longer antecedent periods (3 versus <3 years). We conclude that prior decline or rise in eGFR associates with an increased risk of mortality, independent of current eGFR.

Association between visceral and subcutaneous adipose depots and incident cardiovascular disease risk factors.

BACKGROUND: Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) vary in volume and quality. We evaluated whether fat volume or attenuation (indirect measure of quality) predicts metabolic risk factor changes. METHODS AND RESULTS: Framingham Heart Study Multi-detector Computed Tomography Substudy participants (n=1730, 45% women) were followed up over a mean of 6.2 years. Baseline VAT and SAT volume (in cm(3)) and attenuation (in Hounsfield units) were assessed. Outcomes included blood pressure, lipids, and glucose. We constructed multivariable regression models predicting change from baseline to follow-up. Baseline VAT was associated with metabolic risk factors at follow-up. Per 500-cm(3) increase in baseline VAT, glucose was 2.34 mg/dL higher (95% confidence interval, 1.71-2.97) and high-density lipoprotein was 1.62 mg/dL lower (95% confidence interval, 0.97-2.28) in women (P<0.0001 for both). These findings remained significant after adjustment for body mass index. Results for SAT were similar although less striking. Lower (more negative) fat attenuation was associated with more adverse metabolic profiles at follow-up. For example, per 5-unit decrease in baseline VAT Hounsfield units, log triglycerides increased by 0.08 mg/dL (95% confidence interval, 0.05-0.12; P=0.005), which remained significant after adjustment for baseline VAT. Among men, VAT and SAT Hounsfield units were associated with changes in cardiovascular disease risk factors but were mostly attenuated after baseline volume adjustment. CONCLUSIONS: VAT volume and SAT volume are associated with incident metabolic risk factors beyond overall adiposity. Decreases in fat attenuation are also associated with incident risk factors. These findings suggest that both volume and quality of VAT and SAT contribute to metabolic risk.

A randomized trial of social media from Circulation.

BACKGROUND: Medical journals use social media to distribute the findings of published articles. Whether social media exposure to original articles improves article impact metrics is uncertain. METHODS AND RESULTS: Articles were randomized to receive targeted social media exposure from Circulation, including postings on the journal's Facebook and Twitter feeds. The primary end point was 30-day article page views. We conducted an intention-to-treat analysis comparing article page views by the Wilcoxon Rank sum test between articles randomized to social media as compared with those in the control group, which received no social media from Circulation. Prespecified subgroups included article type (population/clinical/basic), US versus non-US corresponding author, and whether the article received an editorial. Overall, 243 articles were randomized: 121 in the social media arm and 122 in the control arm. There was no difference in median 30-day page views (409 [social media] versus 392 [control], P=0.80). No differences were observed by article type (clinical, population, or basic science; P=0.19), whether an article had an editorial (P=0.87), or whether the corresponding author was from the United States (P=0.73). CONCLUSIONS: A social media strategy for a cardiovascular journal did not increase the number of times an article was viewed. Further research is necessary to understand and quantify the ways in which social media can increase the impact of published cardiovascular research.

Integromic analysis of genetic variation and gene expression identifies networks for cardiovascular disease phenotypes.

BACKGROUND: Cardiovascular disease (CVD) reflects a highly coordinated complex of traits. Although genome-wide association studies have reported numerous single nucleotide polymorphisms (SNPs) to be associated with CVD, the role of most of these variants in disease processes remains unknown. METHODS AND RESULTS: We built a CVD network using 1512 SNPs associated with 21 CVD traits in genome-wide association studies (at P≤5×10(-8)) and cross-linked different traits by virtue of their shared SNP associations. We then explored whole blood gene expression in relation to these SNPs in 5257 participants in the Framingham Heart Study. At a false discovery rate <0.05, we identified 370 cis-expression quantitative trait loci (eQTLs; SNPs associated with altered expression of nearby genes) and 44 trans-eQTLs (SNPs associated with altered expression of remote genes). The eQTL network revealed 13 CVD-related modules. Searching for association of eQTL genes with CVD risk factors (lipids, blood pressure, fasting blood glucose, and body mass index) in the same individuals, we found examples in which the expression of eQTL genes was significantly associated with these CVD phenotypes. In addition, mediation tests suggested that a subset of SNPs previously associated with CVD phenotypes in genome-wide association studies may exert their function by altering expression of eQTL genes (eg, LDLR and PCSK7), which in turn may promote interindividual variation in phenotypes. CONCLUSIONS: Using a network approach to analyze CVD traits, we identified complex networks of SNP-phenotype and SNP-transcript connections. Integrating the CVD network with phenotypic data, we identified biological pathways that may provide insights into potential drug targets for treatment or prevention of CVD.

Update on Prevention of Cardiovascular Disease in Adults With Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement From the American Heart Association and the American Diabetes Association.

Cardiovascular disease risk factor control as primary prevention in patients with type 2 diabetes mellitus has changed substantially in the past few years. The purpose of this scientific statement is to review the current literature and key clinical trials pertaining to blood pressure and blood glucose control, cholesterol management, aspirin therapy, and lifestyle modification. We present a synthesis of the recent literature, new guidelines, and clinical targets, including screening for kidney and subclinical cardiovascular disease for the contemporary management of patients with type 2 diabetes mellitus.