Bahar Erar

FTO genotype and weight loss: systematic review and meta-analysis of 9563 individual participant data from eight randomised controlled trials

Objective To assess the effect of the FTO genotype on weight loss after dietary, physical activity, or drug based interventions in randomised controlled trials. Design Systematic review and random effects meta-analysis of individual participant data from randomised controlled trials. Data sources Ovid Medline, Scopus, Embase, and Cochrane from inception to November 2015. Eligibility criteria for study selection Randomised controlled trials in overweight or obese adults reporting reduction in body mass index, body weight, or waist circumference by FTO genotype (rs9939609 or a proxy) after dietary, physical activity, or drug based interventions. Gene by treatment interaction models were fitted to individual participant data from all studies included in this review, using allele dose coding for genetic effects and a common set of covariates. Study level interactions were combined using random effect models. Metaregression and subgroup analysis were used to assess sources of study heterogeneity. Results We identified eight eligible randomised controlled trials for the systematic review and meta-analysis (n=9563). Overall, differential changes in body mass index, body weight, and waist circumference in response to weight loss intervention were not significantly different between FTO genotypes. Sensitivity analyses indicated that differential changes in body mass index, body weight, and waist circumference by FTO genotype did not differ by intervention type, intervention length, ethnicity, sample size, sex, and baseline body mass index and age category. Conclusions We have observed that carriage of the FTO minor allele was not associated with differential change in adiposity after weight loss interventions. These findings show that individuals carrying the minor allele respond equally well to dietary, physical activity, or drug based weight loss interventions and thus genetic predisposition to obesity associated with the FTO minor allele can be at least partly counteracted through such interventions. Systematic review registration PROSPERO CRD42015015969.

Genetic Predisposition to Weight Loss and Regain With Lifestyle Intervention: Analyses From the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials

Clinically relevant weight loss is achievable through lifestyle modification, but unintentional weight regain is common. We investigated whether recently discovered genetic variants affect weight loss and/or weight regain during behavioral intervention. Participants at high-risk of type 2 diabetes (Diabetes Prevention Program [DPP]; N = 917/907 intervention/comparison) or with type 2 diabetes (Look AHEAD [Action for Health in Diabetes]; N = 2,014/1,892 intervention/comparison) were from two parallel arm (lifestyle vs. comparison) randomized controlled trials. The associations of 91 established obesity-predisposing loci with weight loss across 4 years and with weight regain across years 2–4 after a minimum of 3% weight loss were tested. Each copy of the minor G allele of MTIF3 rs1885988 was consistently associated with greater weight loss following lifestyle intervention over 4 years across the DPP and Look AHEAD. No such effect was observed across comparison arms, leading to a nominally significant single nucleotide polymorphism×treatment interaction (P = 4.3 × 10−3). However, this effect was not significant at a study-wise significance level (Bonferroni threshold P < 5.8 × 10−4). Most obesity-predisposing gene variants were not associated with weight loss or regain within the DPP and Look AHEAD trials, directly or via interactions with lifestyle.

Genetic modifiers of cardiorespiratory fitness response to lifestyle intervention.

PURPOSE Numerous prospective studies indicate that improved cardiorespiratory fitness reduces type 2 diabetes risk and delays disease progression. We hypothesized that genetic variants modify fitness response to an intensive lifestyle intervention (ILI) in the Action for Health in Diabetes (Look AHEAD) randomized clinical trial, aimed to detect whether ILI will reduce cardiovascular events in overweight/obese subjects with type 2 diabetes compared with a standard of care. METHODS Polymorphisms in established fitness genes and in all loci assayed on the Illumina CARe iSelect chip were examined as predictors of change in MET level, estimated using a treadmill test, in response to a 1-yr intervention in 3899 participants. RESULTS We identified a significant signal in previously reported fitness-related gene RUNX1 that was associated with 1-yr METs response in ILI (0.19 ± 0.04 MET less improvement per minor allele copy; P = 1.9 × 10(-5)) and genotype-intervention interaction (P = 4.8 × 10(-3)). In the chipwide analysis, FKBP7 rs17225700 showed a significant association with ILI response among subjects not receiving beta-blocker medications (0.47 ± 0.09 METs less improvement; P = 5.3 × 10(-5)) and genotype-treatment interaction (P = 5.3 × 10(-7)). The Gene Relationships Among Implicated Loci pathway-based analysis identified connections between associated genes, including those influencing vascular tone, muscle contraction, cardiac energy substrate dynamics, and muscle protein synthesis. CONCLUSIONS This is the first study to identify genetic variants associated with fitness responses to a randomized lifestyle intervention in overweight/obese diabetic individuals. RUNX1 and FKBP7, involved in erythropoesis and muscle protein synthesis, respectively, are related to change in cardiorespiratory fitness in response to exercise.

Do Genetic Modifiers of High-Density Lipoprotein Cholesterol and Triglyceride Levels Also Modify Their Response to a Lifestyle Intervention in the Setting of Obesity and Type-2 Diabetes Mellitus? The Action for Health in Diabetes (Look AHEAD) Study

Background—High-density lipoprotein cholesterol (HDL-C) and triglycerides are cardiovascular risk factors susceptible to lifestyle behavior modification and genetics. We hypothesized that genetic variants identified by genome-wide association studies as associated with HDL-C or triglyceride levels modify 1-year treatment response to an intensive lifestyle intervention, relative to a usual care of diabetes mellitus support and education. Methods and Results—We evaluated 82 single-nucleotide polymorphisms, which represent 31 loci demonstrated by genome-wide association studies to be associated with HDL-C and triglycerides, in 3561 participants who consented for genetic studies and met eligibility criteria. Variants associated with higher baseline HDL-C levels, cholesterol ester transfer protein (CETP) rs3764261 and hepatic lipase (LIPC) rs8034802, were found to be associated with HDL-C increases with intensive lifestyle intervention (P=0.0038 and 0.013, respectively) and had nominally significant treatment interactions (P=0.047 and 0.046, respectively). The fatty acid desaturase-2 rs1535 variant, associated with low baseline HDL-C (P=0.017), was associated with HDL-C increases with intensive lifestyle intervention (0.0037) and had a nominal treatment interaction (P=0.035). Apolipoprotein B (rs693) and LIPC (rs8034802) single-nucleotide polymorphisms showed nominally significant associations with HDL-C and triglyceride changes with intensive lifestyle intervention and a treatment interaction (P<0.05). Phosphatidylglycerophosphate synthase-1 single-nucleotide polymorphisms (rs4082919) showed the most significant triglyceride treatment interaction in the full cohort (P=0.0009). Conclusions—This is the first study to identify genetic variants modifying lipid responses to a randomized lifestyle behavior intervention in overweight or obese individuals with diabetes mellitus. The effects of genetic factors on lipid changes may differ from the effects on baseline lipids and are modifiable by behavioral intervention.

Human Cardiovascular Disease IBC Chip-Wide Association with Weight Loss and Weight Regain in the Look AHEAD Trial

Background/Aims: The present study identified genetic predictors of weight change during behavioral weight loss treatment. Methods: Participants were 3,899 overweight/obese individuals with type 2 diabetes from Look AHEAD, a randomized controlled trial to determine the effects of intensive lifestyle intervention (ILI), including weight loss and physical activity, relative to diabetes support and education, on cardiovascular outcomes. Analyses focused on associations of single nucleotide polymorphisms (SNPs) on the Illumina CARe iSelect (IBC) chip (minor allele frequency >5%; n = 31,959) with weight change at year 1 and year 4, and weight regain at year 4, among individuals who lost ≥3% at year 1. Results: Two novel regions of significant chip-wide association with year-1 weight loss in ILI were identified (p < 2.96E-06). ABCB11 rs484066 was associated with 1.16 kg higher weight per minor allele at year 1, whereas TNFRSF11A, or RANK, rs17069904 was associated with 1.70 kg lower weight per allele at year 1. Conclusions: This study, the largest to date on genetic predictors of weight loss and regain, indicates that SNPs within ABCB11, related to bile salt transfer, and TNFRSF11A, implicated in adipose tissue physiology, predict the magnitude of weight loss during behavioral intervention. These results provide new insights into potential biological mechanisms and may ultimately inform weight loss treatment.

Improving Adherence to Smoking Cessation Treatment: Intervention Effects in a Web-Based Randomized Trial

Background Web-based smoking cessation interventions can deliver evidence-based treatments to a wide swath of the population, but effectiveness is often limited by insufficient adherence to proven treatment components. This study evaluated the impact of a social network (SN) intervention and free nicotine replacement therapy (NRT) on adherence to evidence-based components of smoking cessation treatment in the context of a Web-based intervention. Methods A sample of adult U.S. smokers (N = 5290) was recruited via BecomeAnEX.org, a free smoking cessation Web site. Smokers were randomized to one of four arms: (1) an interactive, evidence-based smoking cessation Web site (WEB) alone; (2) WEB in conjunction with an SN intervention designed to integrate participants into the online community (WEB+SN); (3) WEB plus free NRT (WEB+NRT); and (4) the combination of all treatments (WEB+SN+NRT). Adherence outcomes assessed at 3-month follow-up were as follows: Web site utilization metrics, use of skills training components, intratreatment social support, and pharmacotherapy use. Results WEB+SN+NRT outperformed all others on Web site utilization metrics, use of practical counseling tools, intratreatment social support, and NRT use. It was the only intervention to promote the sending of private messages and the viewing of community pages over WEB alone. Both social network arms outperformed WEB on most metrics of online community engagement. Both NRT arms showed higher medication use compared to WEB alone. Conclusions This study demonstrated the effectiveness of two approaches for improving adherence to evidence-based components of smoking cessation treatment. Integrated approaches to medication provision and social network engagement can enhance adherence to components known to improve cessation. Implications This study demonstrated that an integrated approach to medication provision and social network integration, when delivered through an online program, can enhance adherence across all three recommended components of an evidence-based smoking cessation program (skills training, social support, and pharmacotherapy use). Nicotine replacement therapy-when provided as part of an integrated program-increases adherence to other program elements, which in turn augment its own therapeutic effects. An explicit focus on approaches to improve treatment adherence is an important first step to identifying leverage points for optimizing intervention effectiveness.

Prenatal environmental chemical exposures and longitudinal patterns of child neurobehavior

Background: Prenatal chemical exposures may adversely affect neurodevelopment, but few studies have examined the persistence of these associations. We examined whether associations between prenatal bisphenol A (BPA) or polybrominated diphenyl ether (PBDE) exposures persist or resolve as children age. Methods: We followed 346 mother‐child pairs (enrolled 2003–2006) from Cincinnati, OH from pregnancy until children were 8 years old. We measured BPA in urine collected at 16 and 26 weeks gestation and PBDE‐47 in serum collected at 16 weeks gestation. We administered repeated measures of childrens behavior, mental/psychomotor development, and IQ from ages 1–8 years. We determined if associations of BPA or PBDE‐47 with child neurobehavior persisted or resolved as children aged using linear mixed models and estimated neurobehavioral measure reproducibility using intraclass correlation coefficients (ICCs). Results: Higher BPA in girls and higher PBDE‐47 in both boys and girls were associated with more externalizing behaviors; these associations persisted from ages 2–8 years (exposure × age interaction p‐values ≥ 0.36). Higher PBDE‐47 concentrations were associated with decreases in MDI from ages 1–3 years (PBDE–47 x age interaction p‐value = 0.03) and persistently lower IQ at ages 5 and 8 years (PBDE–47 × age interaction p‐value = 0.56). Mental/psychomotor abilities had fair reproducibility from ages 1–3 years (ICCs ˜ 0.4), cognitive abilities from ages 5 to 8 years had excellent reproducibility (ICCs = 0.7–0.8), and parent‐reported behaviors from ages 2–8 years had poor to good reproducibility (ICCs = 0.38–0.59). Conclusions: Prenatal BPA and PBDE‐47 concentrations were persistently associated with more externalizing behaviors. PBDE‐47 concentrations were inversely associated with cognitive abilities that strengthened over time. HIGHLIGHTSPrenatal BPA and PBDE exposures were associated with more externalizing behaviors.Prenatal PBDE exposure was associated with poorer cognitive abilities.The association between PBDE and cognitive abilities strengthened as children aged.Reproducibility of neurobehavioral measures from age 1–8 years varied by domain.

Online community use predicts abstinence in combined Internet/phone intervention for smoking cessation.

OBJECTIVE To estimate the causal effects of online community use on 30-day point prevalence abstinence at 3 months among smokers that received a combined Internet/phone intervention for smoking cessation. METHOD Participants were 399 adult smokers selected from the combined Internet/phone arm of The iQUITT Study (Graham et al., 2011), a randomized trial of Internet and proactive telephone counseling for smoking cessation. All selected participants had accessed a web-based smoking-cessation program with an established online community and received at least one telephone counseling call. Automated tracking metrics of passive (e.g., reading posts, viewing profiles) and active (e.g., writing posts, sending messages) community use were extracted at 3 months. Self-selected community use defined the groups of interest as None, Passive, and Both (passive and active). Inverse probability of treatment weighting corrected for baseline imbalances on demographic, smoking, and psychosocial variables. Propensity weights estimated via generalized boosted models were used to calculate average treatment effects (ATE) and average treatment effects on the treated (ATT). RESULTS Patterns of community use were None = 145 (36.3%), Passive = 82 (20.6%), and Both = 172 (43.1%). ATE-weighted abstinence rates were None = 12.2% (95% CI = 6.7-17.7), Passive = 25.2% (95% CI = 15.1-35.2), and Both = 35.5% (95% CI = 28.1-42.9). ATT-weighted abstinence rates indicated even greater benefits of passive community use by nonusers. CONCLUSIONS More than 1/3 of the participants who used the community both passively and actively achieved abstinence. Participation in an established online community as part of a combined Internet/phone intervention has the potential to promote short-term abstinence. Results also demonstrated that information and support that originate in the community can serve as a resource for all users. (PsycINFO Database Record

Lifestyle Intervention for Weight Loss and Cardiometabolic Changes in the Setting of Glucokinase Regulatory Protein Inhibition Glucokinase Regulatory Protein-Leu446Pro Variant in Look AHEAD

Background—Glucokinase regulatory protein (GCKR) inhibitors offer a novel treatment approach for glucose control in diabetes mellitus; however, their cardiometabolic effects, particularly in relation to increased triglycerides and C-reactive protein (CRP) levels, are of concern. GCKR Leu446Pro is a common variant associated with reduced GCKR function, increased triglycerides, and CRP. Methods and Results—We investigated whether a 1-year intensive lifestyle intervention (ILI) for weight loss would avert the unfavorable cardiometabolic effects associated with GCKR Leu446Pro when compared with a diabetes mellitus support and education arm in overweight/obese individuals with type 2 diabetes mellitus with triglyceride (n=3214) and CRP (n=1411) data participating in a randomized lifestyle intervention study for weight loss, Action for Health in Diabetes Mellitus (Look AHEAD). Once demographics, medication use and baseline adiposity, and fitness were accounted for, ILI did not modify the baseline association of GCKR-Leu446Pro with elevated triglycerides (&bgr;±SE=0.067±0.013, P=1.5×10−7 and &bgr;±SE=0.052±0.015, P=5×10−4) or with elevated CRP (&bgr;±SE=0.136±0.034, P=5.1×10−5and &bgr;±SE=0.903±0.038, P=0.015) in the overall sample and Non-Hispanic Whites, respectively. The lack of a protective effect from ILI at 1 year when compared with diabetes mellitus support and education (ILI versus diabetes mellitus support and education interaction for triglyceride and CRP change, respectively: P=0.64 and 0.37 in the overall sample; P=0.27 and 0.05 in Non-Hispanic Whites) persisted after additional adjustment for changes in adiposity and fitness. Conclusions—Moderate improvements in adiposity and fitness with ILI did not mitigate the adverse cardiometabolic effects of GCKR inhibition in overweight/obese individuals with diabetes mellitus.

Improving Adherence to Smoking Cessation Treatment: Smoking Outcomes in a Web-based Randomized Trial

Background Partial adherence in Internet smoking cessation interventions presents treatment and evaluation challenges. Increasing adherence may improve outcomes. Purpose To present smoking outcomes from an Internet randomized trial of two strategies to encourage adherence to tobacco dependence treatment components: (i) a social network (SN) strategy to integrate smokers into an online community and (ii) free nicotine replacement therapy (NRT). In addition to intent-to-treat analyses, we used novel statistical methods to distinguish the impact of treatment assignment from treatment utilization. Methods A total of 5,290 current smokers on a cessation website (WEB) were randomized to WEB, WEB + SN, WEB + NRT, or WEB + SN + NRT. The main outcome was 30-day point prevalence abstinence at 3 and 9 months post-randomization. Adherence measures included self-reported medication use (meds), and website metrics of skills training (sk) and community use (comm). Inverse Probability of Retention Weighting and Inverse Probability of Treatment Weighting jointly addressed dropout and treatment selection. Propensity weights were used to calculate Average Treatment effects on the Treated. Results Treatment assignment analyses showed no effects on abstinence for either adherence strategy. Abstinence rates were 25.7%-32.2% among participants that used all three treatment components (sk+comm +meds).Treatment utilization analyses revealed that among such participants, sk+comm+meds yielded large percentage point increases in 3-month abstinence rates over sk alone across arms: WEB = 20.6 (95% CI = 10.8, 30.4), WEB + SN = 19.2 (95% CI = 11.1, 27.3), WEB + NRT = 13.1 (95% CI = 4.1, 22.0), and WEB + SN + NRT = 20.0 (95% CI = 12.2, 27.7). Conclusions Novel propensity weighting approaches can serve as a model for establishing efficacy of Internet interventions and yield important insights about mechanisms. Clinical Trials.gov NCT01544153.