Dataset Information

A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes.

ABSTRACT: Overweight/obese individuals with Type 2 diabetes have low adiponectin levels, which may improve with lifestyle changes. We investigated whether genetic variants associated with adiponectin levels in genome-wide association studies (GWAS) would also be related with adiponectin changes in response to an intensive lifestyle intervention (ILI), potentially through mechanisms altering the adipose microenvironment via weight loss and/or improved cardiorespiratory fitness. Look AHEAD was a randomized trial comparing the cardiovascular benefits of ILI-induced weight loss and physical activity compared with diabetes support and education among overweight/obese individuals with Type 2 diabetes. In a subsample of Look AHEAD with adiponectin data and genetic consent (n=1,351), we evaluated the effects of 24 genetic variants, demonstrated by GWAS to be cross-sectionally associated with adiponectin, on adiponectin change 1-yr postintervention. We explored via mediational analyses whether any differential effects by treatment arm were occurring through weight loss and/or improved fitness. A variant, rs222857, in the CLDN7 locus, potentially associated with epithelial barrier integrity and tight junction physiology, and a putative cis expression quantitative trail locus for elongator acetyltransferase complex subunit 5 (ELP5), predicted adiponectin increases within ILI (log-adiponectin in overall sample per copy: ?±SE=0.05±0.02, P=0.008; in non-Hispanic whites: 0.06±0.02, P=0.009). The favorable effects of rs222857 (minor allele frequency 45.5%) appeared to be mediated by mechanisms associated with improved fitness, and not weight loss. This is the first study to identify a genetic variant that modifies adiponectin response to lifestyle intervention in overweight/obese diabetic individuals.

SUBMITTER: Belalcazar LM

PROVIDER: S-EPMC4451387 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes.

Belalcazar L Maria LM Papandonatos George D GD McCaffery Jeanne M JM Peter Inga I Pajewski Nicholas M NM Erar Bahar B Allred Nicholette D ND Balasubramanyam Ashok A Bowden Donald W DW Brautbar Ariel A Pi-Sunyer F Xavier FX Ballantyne Christie M CM Huggins Gordon S GS

Physiological genomics 20150310 6

Overweight/obese individuals with Type 2 diabetes have low adiponectin levels, which may improve with lifestyle changes. We investigated whether genetic variants associated with adiponectin levels in genome-wide association studies (GWAS) would also be related with adiponectin changes in response to an intensive lifestyle intervention (ILI), potentially through mechanisms altering the adipose microenvironment via weight loss and/or improved cardiorespiratory fitness. Look AHEAD was a randomized ...[more]

PMID: 25759378

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Project description:ObjectiveSevere obesity (body mass index [BMI] ≥40 kg/m(2)) is a serious public health concern. Although bariatric surgery is an efficacious treatment approach, it is limited in reach; thus, nonsurgical treatment alternatives are needed. We examined the 4-year effects of an intensive lifestyle intervention on body weight and cardiovascular disease risk factors among severely obese, compared with overweight (25 ≤BMI <30), class I (30 ≤BMI <35), and class II obese (35 ≤BMI <40) participants.MethodsThere were 5145 individuals with type 2 diabetes (45-76 years, BMI ≥25 kg/m(2)) randomized to an intensive lifestyle intervention or diabetes support and education. The lifestyle intervention group received a behavioral weight loss program that included group and individual meetings, a ≥10% weight loss goal, calorie restriction, and increased physical activity. Diabetes support and education received a less intense educational intervention. Four-year changes in body weight and cardiovascular disease risk factors were assessed.ResultsAcross BMI categories, 4-year changes in body weight were significantly greater in lifestyle participants compared with diabetes support and education (Ps <.05). At year 4, severely obese lifestyle participants lost 4.9%±8.5%, which was similar to class I (4.8%±7.2%) and class II obese participants (4.4%±7.6%), and significantly greater than overweight participants (3.4%±7.0%; P <.05). Four-year changes in low-density-lipoprotein cholesterol, triglycerides, diastolic blood pressure, HbA(1c), and blood glucose were similar across BMI categories in lifestyle participants; however, the severely obese had less favorable improvements in high-density-lipoprotein cholesterol (3.1±0.4 mg/dL) and systolic blood pressure (-1.4±0.7 mm Hg) compared with the less obese (Ps <.05).ConclusionLifestyle interventions can result in important long-term weight losses and improvements in cardiovascular disease risk factors among a significant proportion of severely obese individuals.

Project description:OBJECTIVE: The plasma adiponectin level, a potential upstream and internal facet of metabolic and cardiovascular diseases, has a reasonably high heritability. Whether other novel genes influence the variation in adiponectin level and the roles of these genetic variants on subsequent clinical outcomes has not been thoroughly investigated. Therefore, we aimed not only to identify genetic variants modulating plasma adiponectin levels but also to investigate whether these variants are associated with adiponectin-related metabolic traits and cardiovascular diseases. RESEARCH DESIGN AND METHODS: We conducted a genome-wide association study (GWAS) to identify quantitative trait loci (QTL) associated with high molecular weight forms of adiponectin levels by genotyping 382 young-onset hypertensive (YOH) subjects with Illumina HumanHap550 SNP chips. The culpable single nucleotide polymorphism (SNP) variants responsible for lowered adiponectin were then confirmed in another 559 YOH subjects, and the association of these SNP variants with the risk of metabolic syndrome (MS), type 2 diabetes mellitus (T2DM), and ischemic stroke was examined in an independent community-based prospective cohort, the CardioVascular Disease risk FACtors Two-township Study (CVDFACTS, n = 3,350). RESULTS: The SNP (rs4783244) most significantly associated with adiponectin levels was located in intron 1 of the T-cadherin (CDH13) gene in the first stage (P = 7.57 × 10(-9)). We replicated and confirmed the association between rs4783244 and plasma adiponectin levels in an additional 559 YOH subjects (P = 5.70 × 10(-17)). This SNP was further associated with the risk of MS (odds ratio [OR] = 1.42, P = 0.027), T2DM in men (OR = 3.25, P = 0.026), and ischemic stroke (OR = 2.13, P = 0.002) in the CVDFACTS. CONCLUSIONS: These findings indicated the role of T-cadherin in modulating adiponectin levels and the involvement of CDH13 or adiponectin in the development of cardiometabolic diseases.

Project description:BackgroundAlthough there are many effective lifestyle interventions for type 2 diabetes (T2DM) prevention, insight into effective intervention pathways, especially of long-term interventions, is often lacking. This study aims to provide insight into the effective intervention pathways of the SLIMMER diabetes prevention intervention using mediation analyses.MethodsIn total, 240 participants at increased risk of T2DM were included in the analyses over 18 months. The intervention was a combined lifestyle intervention with a dietary and a physical activity (PA) component. The primary and secondary outcomes were change in fasting insulin (pmol/L) and change in body weight (kg) after 18 months, respectively. Firstly, in a multiple mediator model, we investigated whether significant changes in these outcomes were mediated by changes in dietary and PA behavior. Secondly, in multiple single mediator models, we investigated whether changes in dietary and PA behavior were mediated by changes in behavioral determinants and the participants' psychological profile. The mediation analyses used linear regression models, where significance of indirect effects was calculated with bootstrapping.ResultsThe effect of the intervention on decreased fasting insulin was 40% mediated by change in dietary and PA behavior, where dietary behavior was an independent mediator of the association (34%). The effect of the intervention on decreased body weight was 20% mediated by change in dietary and PA behavior, where PA behavior was an independent mediator (17%). The intervention significantly changed intake of fruit, fat from bread spread, and fiber from bread. Change in fruit intake was mediated by change in action control (combination of consciousness, self-control, and effort), motivation, self-efficacy, intention, and skills. Change in fat intake was mediated by change in action control and psychological profile. No mediators could be identified for change in fiber intake. The change in PA behavior was mediated by change in action control, motivation, and psychological profile.ConclusionThe effect of the SLIMMER intervention on fasting insulin and body weight was mediated by changes in dietary and PA behavior, in distinct ways. These results indicate that changing dietary as well as PA behavior is important in T2DM prevention.

Dataset Information

A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes.

Publications

A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes.

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