The Influence of Obesity-Related Single Nucleotide Polymorphisms on BMI Across the Life Course: The PAGE Study

Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18–100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18–25 years), adulthood (ages 26–49 years), middle-age adulthood (ages 50–69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m2, respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data

Blood DNA methylation sites predict death risk in a longitudinal study of 12,300 individuals

This is the final version. Available on open access from Impact Journals via the DOI in this recordDNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to SERINC2, CHST12, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care

Whole blood DNA methylation signatures of diet are associated with cardiovascular disease risk factors and all-cause mortality

Background: DNA methylation patterns associated with habitual diet have not been well studied. Methods: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality. Results: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni correctedP&lt;1.6x10(-3)). Hypermethylation of cg18181703 (SOCS3) was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (P=5.7x10(-15)). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (P&lt;0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MRP&lt;4.5x10(-4)). For example, hypermethylation of cg11250194 (FADS2) was associated with lower triglyceride concentrations (MR,P=1.5x10(-14)).and hypermethylation of cg02079413 (SNORA54;NAP1L4) was associated with body mass index (corrected MR,P=1x10(-6)). Conclusions: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment

Genome-Wide Detection of Allele Specific Copy Number Variation Associated with Insulin Resistance in African Americans from the HyperGEN Study

African Americans have been understudied in genome wide association studies of diabetes and related traits. In the current study, we examined the joint association of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with fasting insulin and an index of insulin resistance (HOMA-IR) in the HyperGEN study, a family based study with proband ascertainment for hypertension. This analysis is restricted to 1,040 African Americans without diabetes. We generated allele specific CNV genotypes at 872,243 autosomal loci using Birdsuite, a freely available multi-stage program. Joint tests of association for SNPs and CNVs were performed using linear mixed models adjusting for covariates and familial relationships. Our results highlight SNPs associated with fasting insulin and HOMA-IR (rs6576507 and rs8026527, 3.7*10−7≤P≤1.1*10−5) near ATPase, class V, type 10A (ATP10A), and the L Type voltage dependent calcium channel (CACNA1D, rs1401492, P≤5.2*10−6). ATP10A belongs to a family of aminophospholipid-transporting ATPases and has been associated with type 2 diabetes in mice. CACNA1D has been linked to pancreatic beta cell generation in mice. The two most significant copy variable markers (rs10277702 and rs361367; P<2.0*10−4) were in the beta variable region of the T-cell receptor gene (TCRVB). Human and mouse TCR has been shown to mimic insulin and its receptor and could contribute to insulin resistance. Our findings differ from genome wide association studies of fasting insulin and other diabetes related traits in European populations, highlighting the continued need to investigate unique genetic influences for understudied populations such as African Americans

Triggering of Coronary Heart Disease by Infection Type: The Atherosclerosis Risk in Communities Study

Introduction: Acute infections are known triggers of coronary heart disease (CHD). It is unclear how the strength of the association varies by infection type. Hypothesis: We hypothesized that all acute infections increase CHD risk but the level of increased risk varies by infection type. Methods: Incident CHD (myocardial infarction and fatal CHD) cases were identified and adjudicated in the ARIC cohort. ARIC participants were linked to Medicare claims data. We used ICD-9 codes to identify 4 infection types based on infection frequency: cellulitis, pneumonia, urinary tract infections (UTI), and bloodstream infections. We used a case-crossover design and conditional logistic regression to compare infections among CHD cases 90 days before the event with two corresponding control periods 1 year and 2 years prior. The Wald test was used to assess differences between infection types. Results:A total of 1,312 CHD cases were identified. Among cases, 43 had cellulitis, 102 had pneumonia, 116 had a UTI, and 28 had a bloodstream infection within 90 days of the CHD event. All infection types were associated with higher CHD risk within 90 days of the infection; (odds ratios and 95% Cis) (cellulitis = 1.41 (0.93, 2.15), pneumonia = 5.60 (3.72, 8.43), UTI = 2.62 (1.92, 3.57), bloodstream infections = 4.77 (2.34, 9.71)) although cellulitis was not statistically significant (Figure). The association between infection and CHD was significantly stronger for pneumonia, UTI, and bloodstream infections compared to cellulitis (p Conclusions: Patients with pneumonia or bloodstream infections may be at particularly elevated CHD risk. Clinical trials of CHD preventive therapies during and immediately following infection to reduce the otherwise elevated CHD risk are needed. Healthcare providers should consider CHD risk during and immediately after infection and optimize preventive therapies

Periodontal Disease and Incident Venous Thromboembolism: The Atherosclerosis Risk in the Community (ARIC) Study

Background and Purpose: Previous research has identified an association between periodontal disease (PD) and atherosclerotic cardiovascular disease, but the relationship between PD and venous thromboembolism (VTE) has not been studied. PD may trigger VTE through activating inflammatory, coagulation, and fibrinolysis processes associated with thrombosis. We hypothesize an independent association between PD and increased risk of VTE. Methods: PD was assessed among ARIC participants at visit 4 (1996-1998) using self-reported tooth loss due to gum disease and clinical PD definitions based on ARIC dental exams. PD case definitions from the CDC Periodontal Disease Surveillance workgroup in collaboration with the American Academy of Periodontology (CDC/AAP) and the biofilm-gingival interface (BGI) index were used. The outcome of interest was validated VTE, including all cases of deep vein thrombosis occurring in the leg and pulmonary embolism. Follow- up time was from visit 4 to the first VTE hospitalization, dropping out of the study, death, or else, December 31, 2011. Multivariate-adjusted Cox proportional hazards regression models were used. Results: There were a total of 424 VTE events among the 10,651 ARIC participants who provided baseline self-reported PD data and 314 VTE events among the 8,119 participants who were edentulous at visit 4 or who completed the dental exam from which baseline clinical PD data were obtained. Compared to those without periodontal disease, self-reported history of tooth loss due to gum disease was associated with higher VTE risk (HR = 1.42 (1.11, 1.82)), as was being edentulous at exam 4 [1.51 (1.07, 2.14)] using the CDC/AAP PD definition. No other statistically significant associations were observed between clinical levels of PD and VTE risk. Conclusions: These results suggest that individuals who are edentulous or have experienced tooth loss due to PD may be at higher VTE risk

First low-frequency Einstein@Home all-sky search for continuous gravitational waves in Advanced LIGO data

International audienceWe report results of a deep all-sky search for periodic gravitational waves from isolated neutron stars in data from the first Advanced LIGO observing run. This search investigates the low frequency range of Advanced LIGO data, between 20 and 100 Hz, much of which was not explored in initial LIGO. The search was made possible by the computing power provided by the volunteers of the Einstein@Home project. We find no significant signal candidate and set the most stringent upper limits to date on the amplitude of gravitational wave signals from the target population, corresponding to a sensitivity depth of 48.7  [1/Hz]. At the frequency of best strain sensitivity, near 100 Hz, we set 90% confidence upper limits of 1.8×10-25. At the low end of our frequency range, 20 Hz, we achieve upper limits of 3.9×10-24. At 55 Hz we can exclude sources with ellipticities greater than 10-5 within 100 pc of Earth with fiducial value of the principal moment of inertia of 1038  kg m2