Integrated epigenome, whole genome sequence and metabolome analyses identify novel multi-omics pathways in type 2 diabetes: a Middle Eastern study.

BACKGROUND: T2D is of high prevalence in the middle east and thus studying its mechanisms is of a significant importance. Using 1026 Qatar BioBank samples, epigenetics, whole genome sequencing and metabolomics were combined to further elucidate the biological mechanisms of T2D in a population with a high prevalence of T2D. METHODS: An epigenome-wide association study (EWAS) with T2D was performed using the Infinium 850K EPIC array, followed by whole genome-wide sequencing SNP-CpG association analysis (> 5.5 million SNPs) and a methylome-metabolome (CpG-metabolite) analysis of the identified T2D sites. RESULTS: A total of 66 T2D-CpG associations were identified, including 63 novel sites in pathways of fructose and mannose metabolism, insulin signaling, galactose, starch and sucrose metabolism, and carbohydrate absorption and digestion. Whole genome SNP associations with the 66 CpGs resulted in 688 significant CpG-SNP associations comprising 22 unique CpGs (33% of the 66 CPGs) and included 181 novel pairs or pairs in novel loci. Fourteen of the loci overlapped published GWAS loci for diabetes related traits and were used to identify causal associations of HK1 and PFKFB2 with HbA1c. Methylome-metabolome analysis identified 66 significant CpG-metabolite pairs among which 61 pairs were novel. Using the identified methylome-metabolome associations, methylation QTLs, and metabolic networks, a multi-omics network was constructed which suggested a number of metabolic mechanisms underlying T2D methylated genes. 1-palmitoyl-2-oleoyl-GPE (16:0/18:1) - a triglyceride-associated metabolite, shared a common network with 13 methylated CpGs, including TXNIP, PFKFB2, OCIAD1, and BLCAP. Mannonate - a food component/plant shared a common network with 6 methylated genes, including TXNIP, BLCAP, THBS4 and PEF1, pointing to a common possible cause of methylation in those genes. A subnetwork with alanine, glutamine, urea cycle (citrulline, arginine), and 1-carboxyethylvaline linked to PFKFB2 and TXNIP revealed associations with kidney function, hypertension and triglyceride metabolism. The pathway containing STYXL1-POR was associated with a sphingosine-ceramides subnetwork associated with HDL-C and LDL-C and point to steroid perturbations in T2D. CONCLUSIONS: This study revealed several novel methylated genes in T2D, with their genomic variants and associated metabolic pathways with several implications for future clinical use of multi-omics associations in disease and for studying therapeutic targets.

Genetics and geography of leukocyte telomere length in sub-Saharan Africans.

Leukocyte telomere length (LTL) might be causal in cardiovascular disease and major cancers. To elucidate the roles of genetics and geography in LTL variability across humans, we compared LTL measured in 1295 sub-Saharan Africans (SSAs) with 559 African-Americans (AAms) and 2464 European-Americans (EAms). LTL differed significantly across SSAs (P = 0.003), with the San from Botswana (with the oldest genomic ancestry) having the longest LTL and populations from Ethiopia having the shortest LTL. SSAs had significantly longer LTL than AAms [P = 6.5(e-16)] whose LTL was significantly longer than EAms [P = 2.5(e-7)]. Genetic variation in SSAs explained 52% of LTL variance versus 27% in AAms and 34% in EAms. Adjustment for genetic variation removed the LTL differences among SSAs. LTL genetic variation among SSAs, with the longest LTL in the San, supports the hypothesis that longer LTL was ancestral in humans. Identifying factors driving LTL variation in Africa may have important ramifications for LTL-associated diseases.

Donor-specific phenotypic variation in hiPSC cardiomyocyte-derived exosomes impacts endothelial cell function.

Exosomes are an important mechanism of cell-cell interaction in the cardiovascular system, both in maintaining homeostasis and in stress response. Interindividual differences that alter content in exosomes may play a role in cardiovascular disease pathology. To study the effect of interindividual cardiomyocyte (CM) variation, we characterized exosomal content in phenotypically diverse human induced pluripotent stem cell-derived CMs (hiPSC-CMs). Cell lines were generated from six participants in the HyperGEN cohort: three with left ventricular hypertrophy (LVH) and three with normal left ventricular mass (LVM). Sequence analysis of the intracellular and exosomal RNA populations showed distinct expression pattern differences between hiPSC-CM lines derived from individuals with LVH and those with normal LVM. Functional analysis of hiPSC-endothelial cells (hiPSC-ECs) treated with exosomes from both hiPSC-CM groups showed significant variation in response, including differences in tube formation, migration, and proliferation. Overall, treatment of hiPSC-ECs with exosomes resulted in significant expression changes associated with angiogenesis and endothelial cell vasculogenesis. However, the hiPSC-ECs treated with exosomes from the LVH-affected donors exhibited significantly increased proliferation but decreased tube formation and migration, suggesting angiogenic dysregulation.NEW & NOTEWORTHY The intracellular RNA and the miRNA content in exosomes are significantly different in hiPSC-CMs derived from LVH-affected individuals compared with those from unaffected individuals. Treatment of endothelial cells with these exosomes functionally affects cellular phenotypes in a donor-specific manner. These findings provide novel insight into underlying mechanisms of hypertrophic cell signaling between different cell types. With a growing interest in stem cells and exosomes for cardiovascular therapeutic use, this also provides information important for regenerative medicine.

The retinopathy-derived HbA1c threshold of 6.5% for type 2 diabetes also captures the risk of diabetic nephropathy in NHANES.

AIM: To determine if an HbA1c diagnostic threshold of less than 6.5% (<48 mmol/mol) could be identified based on a urinary albumin-creatinine ratio (UACR) of 30 mg/g or higher in subjects not known to have diabetes. METHODS: A UACR was measured for 20 158 participants in the 2011-2018 nationally representative cross-sectional National Health and Nutrition Examination Surveys (NHANES; cycles 7-10 inclusive). RESULTS: There was a significant trend for an increasing risk with a UACR of 30 mg/g or higher across increasing HbA1c categories (P < .0001). This trend was mainly attributable to the high prevalence of raised UACR in the 7.0% or higher HbA1c subgroup of subjects not previously diagnosed with diabetes. None of the odds ratios in the lower HbA1c subgroups versus the HbA1c subgroup of less than 5.0% reached significance. There were racial/ethnic differences in UACR risk (P < .0001), with White and Black subjects exhibiting little increased risk (vs. HbA1c <5.0%) until they reached an HbA1c of 7.0%, while Asian and Hispanic subjects showed some increased, but non-significant, risks at lower HbA1c levels. Maximizing the area under receiver operating characteristic curves from logistic regressions predicted an ideal HbA1c threshold of 5.8%, but there was little variation in area from 5.5% to 7.0%. CONCLUSION: A clinically useful diagnostic threshold below 6.5% for HbA1c for elevated UACR risk was not identified, with an increased risk only obvious at an HbA1c of 7.0% or higher. Thus, the retinopathy-derived HbA1c threshold of 6.5% also captures the risk of diabetic nephropathy in NHANES.

Weight and Metabolic Outcomes 12 Years after Gastric Bypass.

BACKGROUND: Few long-term or controlled studies of bariatric surgery have been conducted to date. We report the 12-year follow-up results of an observational, prospective study of Roux-en-Y gastric bypass that was conducted in the United States. METHODS: A total of 1156 patients with severe obesity comprised three groups: 418 patients who sought and underwent Roux-en-Y gastric bypass (surgery group), 417 patients who sought but did not undergo surgery (primarily for insurance reasons) (nonsurgery group 1), and 321 patients who did not seek surgery (nonsurgery group 2). We performed clinical examinations at baseline and at 2 years, 6 years, and 12 years to ascertain the presence of type 2 diabetes, hypertension, and dyslipidemia. RESULTS: The follow-up rate exceeded 90% at 12 years. The adjusted mean change from baseline in body weight in the surgery group was -45.0 kg (95% confidence interval [CI], -47.2 to -42.9; mean percent change, -35.0) at 2 years, -36.3 kg (95% CI, -39.0 to -33.5; mean percent change, -28.0) at 6 years, and -35.0 kg (95% CI, -38.4 to -31.7; mean percent change, -26.9) at 12 years; the mean change at 12 years in nonsurgery group 1 was -2.9 kg (95% CI, -6.9 to 1.0; mean percent change, -2.0), and the mean change at 12 years in nonsurgery group 2 was 0 kg (95% CI, -3.5 to 3.5; mean percent change, -0.9). Among the patients in the surgery group who had type 2 diabetes at baseline, type 2 diabetes remitted in 66 of 88 patients (75%) at 2 years, in 54 of 87 patients (62%) at 6 years, and in 43 of 84 patients (51%) at 12 years. The odds ratio for the incidence of type 2 diabetes at 12 years was 0.08 (95% CI, 0.03 to 0.24) for the surgery group versus nonsurgery group 1 and 0.09 (95% CI, 0.03 to 0.29) for the surgery group versus nonsurgery group 2 (P<0.001 for both comparisons). The surgery group had higher remission rates and lower incidence rates of hypertension and dyslipidemia than did nonsurgery group 1 (P<0.05 for all comparisons). CONCLUSIONS: This study showed long-term durability of weight loss and effective remission and prevention of type 2 diabetes, hypertension, and dyslipidemia after Roux-en-Y gastric bypass. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Shorter telomere length in Europeans than in Africans due to polygenetic adaptation.

Leukocyte telomere length (LTL), which reflects telomere length in other somatic tissues, is a complex genetic trait. Eleven SNPs have been shown in genome-wide association studies to be associated with LTL at a genome-wide level of significance within cohorts of European ancestry. It has been observed that LTL is longer in African Americans than in Europeans. The underlying reason for this difference is unknown. Here we show that LTL is significantly longer in sub-Saharan Africans than in both Europeans and African Americans. Based on the 11 LTL-associated alleles and genetic data in phase 3 of the 1000 Genomes Project, we show that the shifts in allele frequency within Europe and between Europe and Africa do not fit the pattern expected by neutral genetic drift. Our findings suggest that differences in LTL within Europeans and between Europeans and Africans is influenced by polygenic adaptation and that differences in LTL between Europeans and Africans might explain, in part, ethnic differences in risks for human diseases that have been linked to LTL.

A genome-wide association meta-analysis on apolipoprotein A-IV concentrations.

Apolipoprotein A-IV (apoA-IV) is a major component of HDL and chylomicron particles and is involved in reverse cholesterol transport. It is an early marker of impaired renal function. We aimed to identify genetic loci associated with apoA-IV concentrations and to investigate relationships with known susceptibility loci for kidney function and lipids. A genome-wide association meta-analysis on apoA-IV concentrations was conducted in five population-based cohorts (n = 13,813) followed by two additional replication studies (n = 2,267) including approximately 10 M SNPs. Three independent SNPs from two genomic regions were significantly associated with apoA-IV concentrations: rs1729407 near APOA4 (P = 6.77 × 10 - 44), rs5104 in APOA4 (P = 1.79 × 10-24) and rs4241819 in KLKB1 (P = 5.6 × 10-14). Additionally, a look-up of the replicated SNPs in downloadable GWAS meta-analysis results was performed on kidney function (defined by eGFR), HDL-cholesterol and triglycerides. From these three SNPs mentioned above, only rs1729407 showed an association with HDL-cholesterol (P = 7.1 × 10 - 07). Moreover, weighted SNP-scores were built involving known susceptibility loci for the aforementioned traits (53, 70 and 38 SNPs, respectively) and were associated with apoA-IV concentrations. This analysis revealed a significant and an inverse association for kidney function with apoA-IV concentrations (P = 5.5 × 10-05). Furthermore, an increase of triglyceride-increasing alleles was found to decrease apoA-IV concentrations (P = 0.0078). In summary, we identified two independent SNPs located in or next the APOA4 gene and one SNP in KLKB1 The association of KLKB1 with apoA-IV suggests an involvement of apoA-IV in renal metabolism and/or an interaction within HDL particles. Analyses of SNP-scores indicate potential causal effects of kidney function and by lesser extent triglycerides on apoA-IV concentrations.

A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms.

High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10-30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be significantly associated with Lp(a) concentrations (P = 3.47 × 10-10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the population's mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the TLR2 gene with Lp(a) (P = 3.4 × 10-4). In summary, we identified a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be significantly associated with Lp(a) concentrations.

Walking and Calcified Atherosclerotic Plaque in the Coronary Arteries: The National Heart, Lung, and Blood Institute Family Heart Study.

OBJECTIVE: Studies have reported mixed findings on the association between physical activity and subclinical atherosclerosis. We sought to examine whether walking is associated with prevalent coronary artery calcification (CAC) and aortic calcification. APPROACH AND RESULTS: In a cross-sectional design, we studied 2971 participants of the National Heart, Lung, and Blood Institute Family Heart Study without a history of myocardial infarction, coronary artery bypass grafting, or percutaneous transluminal angioplasty. A standardized questionnaire was used to ascertain the number of blocks walked daily to compute walking metabolic equivalent hours. CAC was measured by cardiac computed tomography. We defined prevalent CAC and aortic calcification using an Agatston score of at least 100 and used generalized estimating equations to calculate adjusted prevalence ratios. Mean age was 55 years, and 60% of participants were women. Compared with the ≤3.75-Met-h/wk group, prevalence ratios for CAC after adjusting for age, sex, race, smoking, alcohol use, total physical activity (excluding walking), and familial clustering were 0.53 (95% confidence interval, 0.35-0.79) for >3.75 to 7.5 Met-h/wk, 0.72 (95% confidence interval, 0.52-0.99) for >7.5 to 15 Met-h/wk, and 0.54 (95% confidence interval, 0.36-0.81) for >15 to 22.5 Met-h/wk, (P trend=0.01). The walking-CAC relationship remained significant for those with body mass index ≥25 (P trend=0.02) and persisted with CAC cutoffs of 300, 200, 150, and 50 but not 0. When examined as a continuous variable, a J-shaped association between walking and CAC was found. The walking-aortic calcification association was not significant. CONCLUSIONS: Our findings suggest that walking is associated with lower prevalent CAC (but not aortic calcification) in adults without known heart disease.

APOH interacts with FTO to predispose to healthy thinness.

We identified eight candidate thinness predisposition variants from the Illumina HumanExome chip genotyped on members of pedigrees selected for either healthy thinness or severe obesity. For validation, we tested the candidates for association with healthy thinness in additional pedigree members while accounting for effects of obesity-associated genes: NPFFR2, NPY2R, FTO, and MC4R. Significance was obtained for the interaction of FTO rs9939609 with APOH missense variant rs52797880 (minor allele frequency 0.054). The thinness odds ratio was estimated as 2.15 (p < 0.05) for the combination of APOH heterozygote with the homozygote for the non-obesity FTO allele. Significance was not obtained for any other combination of a candidate variant with an obesity gene or for any of the eight candidates tested independently.

DCAF4, a novel gene associated with leucocyte telomere length.

BACKGROUND: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR). RESULTS: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10(-3) and 2×10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97×10(-169) to 3.42×10(-24). CONCLUSIONS: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.

Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.

Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1 × 10(-4) in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.

The role of rare variants in systolic blood pressure: analysis of ExomeChip data in HyperGEN African Americans.

Cardiovascular diseases are among the most significant health problems in the United States today, with their major risk factor, hypertension, disproportionately affecting African Americans (AAs). Although GWAS have identified dozens of common variants associated with blood pressure (BP) and hypertension in European Americans, these variants collectively explain <2.5% of BP variance, and most of the genetic variants remain yet to be identified. Here, we report the results from rare-variant analysis of systolic BP using 94,595 rare and low-frequency variants (minor allele frequency, MAF, <5%) from the Illumina exome array genotyped in 2,045 HyperGEN AAs. In addition to single-variant analysis, 4 gene-level association tests were used for analysis: burden and family-based SKAT tests using MAF cutoffs of 1 and 5%. The gene-based methods often provided lower p values than the single-variant approach. Some consistency was observed across these 4 gene-based analysis options. While neither the gene-based analyses nor the single-variant analysis produced genome-wide significant results, the top signals, which had supporting evidence from multiple gene-based methods, were of borderline significance. Though additional molecular validations are required, 6 of the 16 most promising genes are biologically plausible with physiological connections to BP regulation.

An empirical comparison of meta-analysis and mega-analysis of individual participant data for identifying gene-environment interactions.

For analysis of the main effects of SNPs, meta-analysis of summary results from individual studies has been shown to provide comparable results as "mega-analysis" that jointly analyzes the pooled participant data from the available studies. This fact revolutionized the genetic analysis of complex traits through large GWAS consortia. Investigations of gene-environment (G×E) interactions are on the rise since they can potentially explain a part of the missing heritability and identify individuals at high risk for disease. However, for analysis of gene-environment interactions, it is not known whether these methods yield comparable results. In this empirical study, we report that the results from both methods were largely consistent for all four tests; the standard 1 degree of freedom (df) test of main effect only, the 1 df test of the main effect (in the presence of interaction effect), the 1 df test of the interaction effect, and the joint 2 df test of main and interaction effects. They provided similar effect size and standard error estimates, leading to comparable P-values. The genomic inflation factors and the number of SNPs with various thresholds were also comparable between the two approaches. Mega-analysis is not always feasible especially in very large and diverse consortia since pooling of raw data may be limited by the terms of the informed consent. Our study illustrates that meta-analysis can be an effective approach also for identifying interactions. To our knowledge, this is the first report investigating meta-versus mega-analyses for interactions.

Association of ideal cardiovascular health and calcified atherosclerotic plaque in the coronary arteries: the National Heart, Lung, and Blood Institute Family Heart Study.

BACKGROUND: The American Heart Association (AHA) established recommendations based on 7 ideal health behaviors and factors with the goal of improving cardiovascular health (CVH) and reducing both morbidity and mortality from cardiovascular disease by 20% by 2020. Few studies have investigated their association with subclinical coronary heart disease. We sought to examine whether the 7 AHA CVH metrics were associated with calcified atherosclerotic plaque in the coronary arteries. METHODS: In a cross-sectional design, we studied 1,731 predominantly white men and women from the National Heart, Lung, and Blood Institute Family Heart Study without prevalent coronary heart disease. Diet was assessed by a semiquantitative food frequency questionnaire. Coronary artery calcium (CAC) was measured by cardiac computed tomography. We defined prevalent CAC using an Agatston score of 100+ and fitted generalized estimating equations to calculate prevalence odds ratios of CAC. RESULTS: Mean age was 56.8 years, and 41% were male. The median number of ideal CVH metrics was 3, and no participant met all 7. There was a strong inverse relationship between number of ideal CVH metrics and prevalent CAC. Odds ratios (95% CI) for CAC of 100+ were 1.0 (reference), 0.37 (0.29-0.45), 0.35 (0.26-0.44), and 0.27 (0.20-0.36) among subjects with 0 to 1, 2, 3, and 4+ ideal CVH metrics, respectively (P = .0001), adjusting for sex, age, field center, alcohol, income, education, and energy consumption. CONCLUSIONS: These data demonstrate a strong and graded inverse relationship between AHA ideal CVH metrics and prevalent CAC in adult men and women.

Lack of association of apolipoprotein E (Apo E) polymorphism with the prevalence of metabolic syndrome: the National Heart, Lung and Blood Institute Family Heart Study.

OBJECTIVE: Metabolic syndrome (MetS), characterized by abdominal obesity, atherogenic dyslipidaemia, elevated blood pressure and insulin resistance, is a major public health concern in the United States. The effects of apolipoprotein E (Apo E) polymorphism on MetS are not well established. METHODS: We conducted a cross-sectional study consisting of 1551 participants from the National Heart, Lung and Blood Institute Family Heart Study to assess the relation of Apo E polymorphism with the prevalence of MetS. MetS was defined according to the American Heart Association-National Heart, Lung and Blood Institute-International Diabetes Federation-World Health Organization harmonized criteria. We used generalized estimating equations to estimate adjusted odds ratios (ORs) for prevalent MetS and the Bonferroni correction to account for multiple testing in the secondary analysis. RESULTS: Our study population had a mean age (standard deviation) of 56.5 (11.0) years, and 49.7% had MetS. There was no association between the Apo E genotypes and the MetS. The multivariable adjusted ORs (95% confidence interval) were 1.00 (reference), 1.26 (0.31-5.21), 0.89 (0.62-1.29), 1.13 (0.61-2.10), 1.13 (0.88-1.47) and 1.87 (0.91-3.85) for the Ɛ3/Ɛ3, Ɛ2/Ɛ2, Ɛ2/Ɛ3, Ɛ2/Ɛ4, Ɛ3/Ɛ4 and Ɛ4/Ɛ4 genotypes, respectively. In a secondary analysis, Ɛ2/Ɛ3 genotype was associated with 41% lower prevalence odds of low high-density lipoprotein [multivariable adjusted ORs (95% confidence interval) = 0.59 (0.36-0.95)] compared with Ɛ3/Ɛ3 genotype. CONCLUSIONS: Our findings do not support an association between Apo E polymorphism and MetS in a multicentre population-based study of predominantly White US men and women.

All-Cause and Cause-Specific Mortality Associated with Bariatric Surgery: A Review.

The question of whether or not nonsurgical intentional or voluntary weight loss results in reduced mortality has been equivocal, with long-term mortality following weight loss being reported as increased, decreased, and not changed. In part, inconsistent results have been attributed to the uncertainty of whether the intentionality of weight loss is accurately reported in large population studies and also that achieving significant and sustained voluntary weight loss in large intervention trials is extremely difficult. Bariatric surgery has generally been free of these conflicts. Patients voluntarily undergo surgery and the resulting weight is typically significant and sustained. These elements, combined with possible non-weight loss-related mechanisms, have resulted in improved comorbidities, which likely contribute to a reduction in long-term mortality. This paper reviews the association between bariatric surgery and long-term mortality. From these studies, the general consensus is that bariatric surgical patients have: 1) significantly reduced long-term all-cause mortality when compared to severely obese non-bariatric surgical control groups; 2) greater mortality when compared to the general population, with the exception of one study; 3) reduced cardiovascular-, stroke-, and cancer-caused mortality when compared to severely obese non-operated controls; and 4) increased risk for externally caused death such as suicide.

Effects of rare and common blood pressure gene variants on essential hypertension: results from the Family Blood Pressure Program, CLUE, and Atherosclerosis Risk in Communities studies.

RATIONALE: Hypertension affects ≈30% of adults in industrialized countries and is the major risk factor for cardiovascular disease. OBJECTIVE: We sought to study the genetic effect of coding and conserved noncoding variants in syndromic hypertension genes on systolic blood pressure (BP) and diastolic BP to assess their overall impact on essential hypertension. METHODS AND RESULTS: We resequenced 11 genes (AGT, CYP11B1, CYP17A1, HSD11B2, NR3C1, NR3C2, SCNN1A, SCNN1B, SCNN1G, WNK1, and WNK4) in 560 European American (EA) and African American ancestry GenNet participants with extreme systolic BP. We investigated genetic associations of 2535 variants with BP in 19997 EAs and in 6069 African Americans in 3 types of analyses. First, we studied the combined effects of all variants in GenNet. Second, we studied 1000 Genomes imputed polymorphic variants in 9747 EA and 3207 African American Atherosclerosis Risk in Communities subjects. Finally, we genotyped 37 missense and common noncoding variants in 6591 EAs and in 6521 individuals (3659 EA/2862 African American) from the CLUE and Family Blood Pressure Program studies, respectively. None of the variants individually reached significant false-discovery rates ≤0.05 for systolic BP and diastolic BP. However, on pooling all coding and noncoding variants, we identified at least 5 loci (AGT, CYP11B1, NR3C2, SCNN1G, and WNK1) with higher association at evolutionary conserved sites. CONCLUSIONS: Both rare and common variants at these genes affect BP in the general population with modest effects sizes (<0.05 standard deviation units), and much larger sample sizes are required to assess the impact of individual genes. Collectively, conserved noncoding variants affect BP to a greater extent than missense mutations.

Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans.

Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.