Managing differential performance of polygenic risk scores across groups: Real-world experience of the eMERGE Network.

The differential performance of polygenic risk scores (PRSs) by group is one of the major ethical barriers to their clinical use. It is also one of the main practical challenges for any implementation effort. The social repercussions of how people are grouped in PRS research must be considered in communications with research participants, including return of results. Here, we outline the decisions faced and choices made by a large multi-site clinical implementation study returning PRSs to diverse participants in handling this issue of differential performance. Our approach to managing the complexities associated with the differential performance of PRSs serves as a case study that can help future implementers of PRSs to plot an anticipatory course in response to this issue.

Prospective, multi-site study of healthcare utilization after actionable monogenic findings from clinical sequencing.

As large-scale genomic screening becomes increasingly prevalent, understanding the influence of actionable results on healthcare utilization is key to estimating the potential long-term clinical impact. The eMERGE network sequenced individuals for actionable genes in multiple genetic conditions and returned results to individuals, providers, and the electronic health record. Differences in recommended health services (laboratory, imaging, and procedural testing) delivered within 12 months of return were compared among individuals with pathogenic or likely pathogenic (P/LP) findings to matched individuals with negative findings before and after return of results. Of 16,218 adults, 477 unselected individuals were found to have a monogenic risk for arrhythmia (n = 95), breast cancer (n = 96), cardiomyopathy (n = 95), colorectal cancer (n = 105), or familial hypercholesterolemia (n = 86). Individuals with P/LP results more frequently received services after return (43.8%) compared to before return (25.6%) of results and compared to individuals with negative findings (24.9%; p < 0.0001). The annual cost of qualifying healthcare services increased from an average of $162 before return to $343 after return of results among the P/LP group (p < 0.0001); differences in the negative group were non-significant. The mean difference-in-differences was $149 (p < 0.0001), which describes the increased cost within the P/LP group corrected for cost changes in the negative group. When stratified by individual conditions, significant cost differences were observed for arrhythmia, breast cancer, and cardiomyopathy. In conclusion, less than half of individuals received billed health services after monogenic return, which modestly increased healthcare costs for payors in the year following return.

Returning integrated genomic risk and clinical recommendations: The eMERGE study.

PURPOSE: Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk. METHODS: To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores, monogenic risks, family history, and clinical risk assessments via a genome-informed risk assessment (GIRA) report and will assess uptake of care recommendations after return of results. RESULTS: GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022. CONCLUSION: Return of a novel report for communicating monogenic, polygenic, and family history-based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.

Missense Genetic Variation of ICAM1 and Incident Heart Failure.

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) is a cell surface protein that participates in endothelial activation and is hypothesized to play a central role in heart failure (HF). We evaluated associations of ICAM1 missense genetic variants with circulating ICAM-1 levels and with incident HF. METHODS AND RESULTS: We identified 3 missense variants within ICAM1 (rs5491, rs5498 and rs1799969) and evaluated their associations with ICAM-1 levels in the Coronary Artery Risk Development in Young Adults Study and the Multi-Ethnic Study of Atherosclerosis (MESA). We determined the association among these 3 variants and incident HF in MESA. We separately evaluated significant associations in the Atherosclerosis Risk in Communities (ARIC) study. Of the 3 missense variants, rs5491 was common in Black participants (minor allele frequency [MAF] > 20%) and rare in other race/ethnic groups (MAF < 5%). In Black participants, the presence of rs5491 was associated with higher levels of circulating ICAM-1 at 2 timepoints separated by 8 years. Among Black participants in MESA (n = 1600), the presence of rs5491 was associated with an increased risk of incident HF with preserved ejection fraction (HFpEF; HR = 2.30; [95% CI 1.25-4.21; P = 0.007]). The other ICAM1 missense variants (rs5498 and rs1799969) were associated with ICAM-1 levels, but there were no associations with HF. In ARIC, rs5491 was significantly associated with incident HF (HR = 1.24 [95% CI 1.02 - 1.51]; P = 0.03), with a similar direction of effect for HFpEF that was not statistically significant. CONCLUSIONS: A common ICAM1 missense variant among Black individuals may be associated with increased risk of HF, which may be HFpEF-specific.

Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.

Multi-ethnic GWAS and fine-mapping of glycaemic traits identify novel loci in the PAGE Study.

AIMS/HYPOTHESIS: Type 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA1c, that serve as early markers of type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits. However, most of these findings were based only on populations of European ancestry. To address this research gap, we examined the genetic basis of fasting glucose, fasting insulin and HbA1c in participants of the diverse Population Architecture using Genomics and Epidemiology (PAGE) Study. METHODS: We conducted a GWAS of fasting glucose (n = 52,267), fasting insulin (n = 48,395) and HbA1c (n = 23,357) in participants without diabetes from the diverse PAGE Study (23% self-reported African American, 46% Hispanic/Latino, 40% European, 4% Asian, 3% Native Hawaiian, 0.8% Native American), performing transethnic and population-specific GWAS meta-analyses, followed by fine-mapping to identify and characterise novel loci and independent secondary signals in known loci. RESULTS: Four novel associations were identified (p < 5 × 10-9), including three loci associated with fasting insulin, and a novel, low-frequency African American-specific locus associated with fasting glucose. Additionally, seven secondary signals were identified, including novel independent secondary signals for fasting glucose at the known GCK locus and for fasting insulin at the known PPP1R3B locus in transethnic meta-analysis. CONCLUSIONS/INTERPRETATION: Our findings provide new insights into the genetic architecture of glycaemic traits and highlight the continued importance of conducting genetic studies in diverse populations. DATA AVAILABILITY: Full summary statistics from each of the population-specific and transethnic results are available at NHGRI-EBI GWAS catalog ( https://www.ebi.ac.uk/gwas/downloads/summary-statistics ).

Integrating clinical genetics in cardiology: Current practices and recommendations for education.

PURPOSE: Recent advances in genetics can facilitate the identification of at-risk individuals and diagnosis of cardiovascular disorders. As a nascent field, more research is needed to optimize the clinical practice of cardiovascular genetics, including the assessment of educational needs to promote appropriate use of genetic testing. METHODS: Qualitative interviews conducted with cardiovascular specialists (N = 43) were audiotaped. Thematic analysis was conducted on professional transcripts. RESULTS: Participants recognized the value of genetics in identifying and diagnosing at-risk individuals. However, organizational systems, cost, and feeling of unpreparedness were identified as barriers. Participants felt that the rapid pace of genetic science resulted in further challenges to maintaining an adequate knowledge base and highlighted genetics experts' importance. Even when a genetics expert was available, participants wanted to know more about which patients benefit most from genetic testing and expressed a desire to better understand management recommendations associated with a positive test result. CONCLUSION: Participants recognized the benefit but felt underprepared to provide recommendations for genetic testing and, in some cases, lacked organizational resources to refer patients to a genetics expert. Additional training in genetics for cardiology practitioners and ensuring availability of a genetics expert can improve the use of genetics in cardiology settings.

The eMERGE genotype set of 83,717 subjects imputed to ~40 million variants genome wide and association with the herpes zoster medical record phenotype.

The Electronic Medical Records and Genomics (eMERGE) network is a network of medical centers with electronic medical records linked to existing biorepository samples for genomic discovery and genomic medicine research. The network sought to unify the genetic results from 78 Illumina and Affymetrix genotype array batches from 12 contributing medical centers for joint association analysis of 83,717 human participants. In this report, we describe the imputation of eMERGE results and methods to create the unified imputed merged set of genome-wide variant genotype data. We imputed the data using the Michigan Imputation Server, which provides a missing single-nucleotide variant genotype imputation service using the minimac3 imputation algorithm with the Haplotype Reference Consortium genotype reference set. We describe the quality control and filtering steps used in the generation of this data set and suggest generalizable quality thresholds for imputation and phenotype association studies. To test the merged imputed genotype set, we replicated a previously reported chromosome 6 HLA-B herpes zoster (shingles) association and discovered a novel zoster-associated loci in an epigenetic binding site near the terminus of chromosome 3 (3p29).

Network Engagement in Action: Stakeholder Engagement Activities to Enhance Patient-centeredness of Research.

BACKGROUND: Stakeholders (ie, patients, policymakers, clinicians, advocacy groups, health system leaders, payers, and others) offer critical input at various stages in the research continuum, and their contributions are increasingly recognized as an important component of effective translational research. Natural experiments, in particular, may benefit from stakeholder feedback in addressing real-world issues and providing insight into future policy decisions, though best practices for the engagement of stakeholders in observational studies are limited in the literature. METHODS: The Natural Experiments for Translation in Diabetes 2.0 (NEXT-D2) network utilizes rigorous methods to evaluate natural experiments in health policy and program delivery with a focus on diabetes-related outcomes. Each of the 8 partnering institutions incorporates stakeholder engagement throughout multiple study phases to enhance the patient-centeredness of results. NEXT-D2 dedicates a committee to Engagement for resource sharing, enhancing engagement approaches, and advancing network-wide engagement activities. Key stakeholder engagement activities include Study Meetings, Proposal Development, Trainings & Educational Opportunities, Data Analysis, and Results Dissemination. Network-wide patient-centered resources and multimedia have also been developed through the broad expertise of each site's stakeholder group. CONCLUSIONS: This collaboration has created a continuous feedback loop wherein site-level engagement approaches are informed via the network and network-level engagement efforts are shaped by individual sites. Emerging best practices include: incorporating stakeholders in multiple ways throughout the research, building on previous relationships with stakeholders, enhancing capacity through stakeholder and investigator training, involving stakeholders in refining outcome choices and understanding the meaning of variables, and recognizing the power of stakeholders in maximizing dissemination.

Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans.

BACKGROUND: End-stage kidney disease (ESKD) is a significant public health concern disproportionately affecting African Americans (AAs). Type 2 diabetes (T2D) is the leading cause of ESKD in the USA, and efforts to uncover genetic susceptibility to diabetic kidney disease (DKD) have had limited success. A prior genome-wide association study (GWAS) in AAs with T2D-ESKD was expanded with additional AA cases and controls and genotypes imputed to the higher density 1000 Genomes reference panel. The discovery analysis included 3432 T2D-ESKD cases and 6977 non-diabetic non-nephropathy controls (N = 10,409), followed by a discrimination analysis in 2756 T2D non-nephropathy controls to exclude T2D-associated variants. RESULTS: Six independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1 achieved genome-wide significant association (P < 5 × 10-8) with T2D-ESKD. Following extension analyses in 1910 non-diabetic ESKD cases and 908 non-diabetic non-nephropathy controls, a meta-analysis of 5342 AA all-cause ESKD cases and 6977 AA non-diabetic non-nephropathy controls revealed an additional novel all-cause ESKD locus at EFNB2 (rs77113398; P = 9.84 × 10-9; OR = 1.94). Exclusion of APOL1 renal-risk genotype carriers identified two additional genome-wide significant T2D-ESKD-associated loci at GRAMD3 and MGAT4C. A second variant at GNG7 (rs373971520; P = 2.17 × 10-8, OR = 1.46) remained associated with all-cause ESKD in the APOL1-negative analysis. CONCLUSIONS: Findings provide further evidence for genetic factors associated with advanced kidney disease in AAs with T2D.

Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans.

Although type 2 diabetes (T2D) results from metabolic defects in insulin secretion and insulin sensitivity, most of the genetic risk loci identified to date relates to insulin secretion. We reported that T2D loci influencing insulin sensitivity may be identified through interactions with insulin secretion loci, thereby leading to T2D. Here, we hypothesize that joint testing of variant main effects and interaction effects with an insulin secretion locus increases power to identify genetic interactions leading to T2D. We tested this hypothesis with an intronic MTNR1B SNP, rs10830963, which is associated with acute insulin response to glucose, a dynamic measure of insulin secretion. rs10830963 was tested for interaction and joint (main + interaction) effects with genome-wide data in African Americans (2,452 cases and 3,772 controls) from five cohorts. Genome-wide genotype data (Affymetrix Human Genome 6.0 array) was imputed to a 1000 Genomes Project reference panel. T2D risk was modeled using logistic regression with rs10830963 dosage, age, sex, and principal component as predictors. Joint effects were captured using the Kraft two degrees of freedom test. Genome-wide significant (P < 5 × 10-8 ) interaction with MTNR1B and joint effects were detected for CMIP intronic SNP rs17197883 (Pinteraction  = 1.43 × 10-8 ; Pjoint  = 4.70 × 10-8 ). CMIP variants have been nominally associated with T2D, fasting glucose, and adiponectin in individuals of East Asian ancestry, with high-density lipoprotein, and with waist-to-hip ratio adjusted for body mass index in Europeans. These data support the hypothesis that additional genetic factors contributing to T2D risk, including insulin sensitivity loci, can be identified through interactions with insulin secretion loci.

LPA Variants Are Associated With Residual Cardiovascular Risk in Patients Receiving Statins.

BACKGROUND: Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. METHODS: We performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus. RESULTS: The meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35-1.86; P=2.6×10-10). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14-2.57; P=0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17-2.24; P=0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18-4.75; P=0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes. CONCLUSIONS: Genetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.

Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci.

RATIONALE: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE: To identify additional AAA risk loci using data from all available genome-wide association studies. METHODS AND RESULTS: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. CONCLUSIONS: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

Osmotic Shifts, Cerebral Edema, and Neurologic Deterioration in Severe Hepatic Encephalopathy.

OBJECTIVES: We sought to determine the effect of acute electrolyte and osmolar shifts on brain volume and neurologic function in patients with liver failure and severe hepatic encephalopathy. DESIGN: Retrospective analysis of brain CT scans and clinical data. SETTING: Tertiary care hospital ICUs. PATIENTS: Patients with acute or acute-on-chronic liver failure and severe hepatic encephalopathy. INTERVENTIONS: Clinically indicated CT scans and serum laboratory studies. MEASUREMENTS AND MAIN RESULTS: Change in intracranial cerebrospinal fluid volume between sequential CT scans was measured as a biomarker of acute brain volume change. Corresponding changes in serum osmolality, chemistry measurements, and Glasgow Coma Scale were determined. Associations with cerebrospinal fluid volume change and Glasgow Coma Scale change for initial volume change assessments were identified by Spearman's correlations (rs) and regression models. Consistency of associations with repeated assessments was evaluated using generalized estimating equations. Forty patients were included. Median baseline osmolality was elevated (310 mOsm/Kg [296-321 mOsm/Kg]) whereas sodium was normal (137 mEq/L [134-142 mEq/L]). Median initial osmolality change was 9 mOsm/kg (5-17 mOsm/kg). Neuroimaging consistent with increased brain volume occurred in 27 initial assessments (68%). Cerebrospinal fluid volume change was more strongly correlated with osmolality (r = 0.70; p = 4 × 10) than sodium (r = 0.28; p = 0.08) change. Osmolality change was independently associated with Glasgow Coma Scale change (p = 1 × 10) and cerebrospinal fluid volume change (p = 2.7 × 10) in initial assessments and in generalized estimating equations using all 103 available assessments. CONCLUSIONS: Acute decline in osmolality was associated with brain swelling and neurologic deterioration in severe hepatic encephalopathy. Minimizing osmolality decline may avoid neurologic deterioration.

Association of Bariatric Surgery Using Laparoscopic Banding, Roux-en-Y Gastric Bypass, or Laparoscopic Sleeve Gastrectomy vs Usual Care Obesity Management With All-Cause Mortality.

Importance: Bariatric surgery is an effective and safe approach for weight loss and short-term improvement in metabolic disorders such as diabetes. However, studies have been limited in most settings by lack of a nonsurgical group, losses to follow-up, missing data, and small sample sizes in clinical trials and observational studies. Objective: To assess the association of 3 common types of bariatric surgery compared with nonsurgical treatment with mortality and other clinical outcomes among obese patients. Design, Setting, and Participants: Retrospective cohort study in a large Israeli integrated health fund covering 54% of Israeli citizens with less than 1% turnover of members annually. Obese adult patients who underwent bariatric surgery between January 1, 2005, and December 31, 2014, were selected and compared with obese nonsurgical patients matched on age, sex, body mass index (BMI), and diabetes, with a final follow-up date of December 31, 2015. A total of 33 540 patients were included in this study. Exposures: Bariatric surgery (laparoscopic banding, Roux-en-Y gastric bypass, or laparoscopic sleeve gastrectomy) or usual care obesity management only (provided by a primary care physician and which may include dietary counseling and behavior modification). Main Outcomes and Measures: The primary outcome, all-cause mortality, matched and adjusted for BMI prior to surgery, age, sex, socioeconomic status, diabetes, hyperlipidemia, hypertension, cardiovascular disease, and smoking. Results: The study population included 8385 patients who underwent bariatric surgery (median age, 46 [IQR, 37-54] years; 5490 [65.5%] women; baseline median BMI, 40.6 [IQR, 38.5-43.7]; laparoscopic banding [n = 3635], gastric bypass [n = 1388], laparoscopic sleeve gastrectomy [n = 3362], and 25 155 nonsurgical matched patients (median age, 46 [IQR, 37-54] years; 16 470 [65.5%] women; baseline median BMI, 40.5 [IQR, 37.0-43.5]). The availability of follow-up data was 100% for all-cause mortality. There were 105 deaths (1.3%) among surgical patients during a median follow-up of 4.3 (IQR, 2.8-6.6) years (including 61 [1.7%] who underwent laparoscopic banding, 18 [1.3%] gastric bypass, and 26 [0.8%] sleeve gastrectomy), and 583 deaths (2.3%) among nonsurgical patients during a median follow-up of 4.0 (IQR, 2.6-6.2) years. The absolute difference was 2.51 (95% CI, 1.86-3.15) fewer deaths/1000 person-years in the surgical vs nonsurgical group. Adjusted hazard ratios (HRs) for mortality among nonsurgical vs surgical patients were 2.02 (95% CI, 1.63-2.52) for the entire study population; by surgical type, HRs were 2.01 (95% CI, 1.50-2.69) for laparoscopic banding, 2.65 (95% CI, 1.55-4.52) for gastric bypass, and 1.60 (95% CI, 1.02-2.51) for laparoscopic sleeve gastrectomy. Conclusions and Relevance: Among obese patients in a large integrated health fund in Israel, bariatric surgery using laparoscopic banding, gastric bypass, or laparoscopic sleeve gastrectomy, compared with usual care nonsurgical obesity management, was associated with lower all-cause mortality over a median follow-up of approximately 4.5 years. The evidence of this association adds to the limited literature describing beneficial outcomes of these 3 types of bariatric surgery compared with usual care obesity management alone.

Prevalence and Predictors of Diastolic Dysfunction According to Different Classification Criteria: The Coronary Artery Risk Development in Young in Adults Study.

Heart failure with preserved ejection fraction is often preceded by diastolic dysfunction (DD). Of several published DD criteria, it is unclear which, if any, are applicable to data obtained in epidemiologic cohorts. We evaluated the prevalence of DD using previously published definitions in a population-based study, the Coronary Artery Risk Development in Young Adults (CARDIA) Study, using data gathered in 2010-2011. Echocardiography was performed on 3,474 individuals (mean age = 50.2 years) at the CARDIA year 25 examination. Four published definitions of DD were studied. We calculated DD prevalence for each definition and determined the overlap between definitions. We used logistic regression to assess the strength of associations between demographic and clinical factors and the definitions of DD. Prevalence of DD ranged from 2% to 32% across the 4 definitions, with a minority of cases identified by more than 1 definition. Two definitions classified 38%-39% of the study sample as indeterminate for DD. Associations of risk factors with DD varied considerably, with male sex being associated positively with DD for one definition (odds ratio = 1.4, 95% confidence interval: 1.2, 1.6) and inversely for another (odds ratio = 0.7, 95% confidence interval: 0.6, 0.8). Prevalence of DD varies markedly in CARDIA by the definition applied. A uniform, reliable, and accurate definition of DD for epidemiologic studies is needed.

Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)

Genetic loci associated with ideal cardiovascular health: A meta-analysis of genome-wide association studies.

BACKGROUND: Multiple genetic loci are associated with clinical cardiovascular (CV) disease and individual CV risk factors. Individuals with ideal levels of all major CV risk factors have very low risk for CV disease morbidity or mortality. Ideal levels of risk factors can be attained by lifestyle modifications; however, little is known about gene variants associated with ideal CV health. Our objective was to carry out a genome-wide association study on the trait. METHODS AND RESULTS: We examined 2 dichotomous phenotypes of ideal CV health-clinical (untreated cholesterol <200 mg/dL, untreated blood pressure <120/<80, not diabetic) and clinical+behavioral (clinical plus: not a current smoker, body mass index <25 kg/m(2))-among white participants aged 50±5 years. We performed a meta-analysis of 4 genome-wide association studies (total n=11,708) from the MESA, CARDIA, ARIC, and Framingham Heart Study cohorts. We identified a single-nucleotide polymorphism (rs445925) in the APOC1/APOE region that was associated with clinical ideal CV health at genome-wide level of significance (P<2.0 × 10(-9)). The significance of this region was validated using exome chip genotyping. The association with ideal CV health was attenuated after adjusting for low-density lipoprotein cholesterol. CONCLUSION: A common single-nucleotide polymorphism in the APOC1/APOE region, previously found to be associated with protective levels of cholesterol and lower CV risk, may be associated with ideal health. In future replication studies, larger sample sizes may be needed to detect loci with more modest effects on ideal CV health. In addition to the important impact of lifestyle modifications, we have identified evidence for gene variation that plays a role in ideal CV health.

Description and initial evaluation of incorporating electronic follow-up of study participants in a longstanding multisite cohort study.

BACKGROUND: The objective of this study was to evaluate a pilot program that allowed Chicago field center participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study to submit follow-up information electronically (eCARDIA). METHODS: Chicago field center participants who provided email addresses were invited to complete contact information and follow-up questionnaires on medical conditions electronically in 2012-2013. Sociodemographic characteristics were compared between those who did and did not complete follow-up electronically. The number of participant contacts by CARDIA staff needed before follow-up was completed was also evaluated. RESULTS: Blacks and low socioeconomic position individuals were less likely to complete follow-up using the electronic questionnaire. Participants who used the electronic questionnaire for follow-up needed fewer contacts (e.g., median 1 contact compared with 3for contact information follow-up), but they also needed fewer contacts prior to eCARDIA (median 1 before and after eCARDIA). CONCLUSIONS: Findings suggest other approaches will be needed to maintain contact and elicit follow-up information from harder-to-reach individuals.