Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach

Background The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. Methods and Findings We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. Conclusions We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

Association of body mass index with DNA methylation and gene expression in blood cells and relations to cardiometabolic disease: A Mendelian randomization approach

Background The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. Methods and Findings We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. Conclusions We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases

Sources of Error in Chilled and Hot Water Metering at Shared Sites: Differential Pressure Transmitters and Flowmeter Installation

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Includes bibliographical references: p.55Issued also on microfiche from Lange Micrographics.The Energy Systems Lab at Texas A&M University monitors energy consumption through shared signals in twenty-two campus buildings under a contract with the University. A major part of this monitoring includes measuring chilled and hot water usage. In many of the buildings, the ESL opted to use existing flowmeters and differential pressure transmitters installed by contractors for the University. The purpose of this study is to determine measurement error associated with the differential pressure transmitters and to verify flowmeter installation meets manufacturer specifications. Calibration tests were performed on thirty-one transmitters. The results fell into one of three categories. Category I transmitters performed within an average error of 0.5%. Category 2 transmitters exhibited calibration problems in the form of span and offset errors. Category 3 transmitters showed large errors due to hysteresis or unknown sources. Eleven of forty-four flowmeter installations met manufacturer requirements. The remaining flowmeters were installed too close to piping elements such as elbows and valves. Specific site problems were discovered including non-removable flowmeters, non-working isolation valves, and potentially hazardous transmitter locations. Improper flowmeter installation was determined to be the largest source of measurement error

Mobilization and Translocation of Subsurface Lead by Tithonia rotundifolia

Phytoremediation is a cost-effective and relatively cleaner method for remediating contaminated areas using plants. Certain plants, including some sunflower species, have already been identified as potential phytoremediation candidates because of their ability to accumulate heavy metals. This study investigated the ability of Tithonia rotundifolia (red sunflower) to accumulate lead from lab-contaminated soils. T. rotundifolia was assessed as a candidate for phytoremediation of lead soils. The study also assessed whether the form (species) of lead as the source of contamination or whether arbuscular mycorrhizal fungi had effects on plant uptake of the metal. Results showed that T. rotundifolia was able to accumulate up to 33% of the lead from the contaminated soils making it a promising candidate for phytoremediation. The amount of lead taken up by the plant ranged from 0.1 to 1.2 mg/kg of plant biomass. The source of the contamination, either lead nitrate or lead carbonate, had a significant impact on the amount of lead that accumulated in the plant. The sunflowers grown in the lead nitrate treatment were able to accumulate significantly more lead than the sunflowers grown in the lead carbonate treatment

Molecular evidence for paraphyly in Nyctomys sumichrasti : support for a new genus of vesper mice? /

no.306 (2011

Behavioral disinhibition and sexual risk behavior among adolescents and young adults in Malawi.

While behavioral factors such as early age of sexual debut, inconsistent use of condoms and multiple sexual partners have been studied in Africa, less is known about how characteristics such as impulsivity and externalizing behaviors relate to HIV-related sexual risk-taking in that region. The purpose of this study was to develop a culturally adapted behavioral disinhibition index in a sample of adolescents and young adults in Malawi. We then sought to examine the relationship between the index and sexual risk behavior as measured by multiple sexual partners and number of lifetime sexual partners.Cross-sectional data were collected from 2342 participants in rural Malawi aged 15 to 29 years. We constructed a disinhibitory behavior score (DBS) using questions assessing disinhibitory behaviors. Bivariate analyses were conducted to assess the relationships among the individual DBS component behaviors. We utilized multivariable logistic regression to determine the association of the DBS with multiple sexual partners, and negative binomial regression to model the relationship between the DBS and number of lifetime sexual partners.Nearly all the DBS component behaviors were significantly associated in the bivariate analyses. The DBS was associated with having multiple sexual partners (OR 1.97; 95% CI 1.57-2.48) in the multivariable logistic regression analysis. Further, negative binomial regression results demonstrated that the DBS was associated with an increased number of lifetime sexual partners (OR 1.11; 95% CI 1.07-1.16).HIV preventive programs in Africa should take into consideration disinhibitory behaviors that may be associated with sexual risk-taking. The DBS can be used as a simple tool to identify those who may be more likely to engage in these behaviors and provide useful information regarding which groups of individuals particularly need to be targeted for behavior change interventions