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

McCaffery, Jeanne M.; Papandonatos, George D.; Huggins, Gordon S.; Peter, Inga; Erar, Bahar; Kahn, Steven E.; Knowler, William C.; Lipkin, Edward W.; Kitabchi, Abbas E.; Wagenknecht, Lynne E.; Wing, Rena R.

doi:10.1159/000353181

Cited by 23 publications

(24 citation statements)

References 64 publications

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“…The rs1402837 T allele (gene G6PC2 of chr 2) is known to be associated with blood sugar levels (glycated hemoglobin levels). McCaffery et al [2013] reported that SNPs in ABCB11 (like rs484066) of chr 2 are associated with weight loss and regain. Meta-analysis of several GWAS found rs17271305 (gene VPS13C of chr 15) to be associated with glucose levels 2 hours after an oral glucose challenge [Saxena et al, 2010].…”

Section: Resultsmentioning

confidence: 99%

USAT: A Unified Score‐Based Association Test for Multiple Phenotype‐Genotype Analysis

Ray

Pankow

Basu

2015

Genetic Epidemiology

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Genome-wide Association Studies (GWASs) for complex diseases often collect data on multiple correlated endo-phenotypes. Multivariate analysis of these correlated phenotypes can improve the power to detect genetic variants. Multivariate analysis of variance (MANOVA) can perform such association analysis at a GWAS level, but the behavior of MANOVA under different trait models has not been carefully investigated. In this paper, we show that MANOVA is generally very powerful for detecting association but there are situations, such as when a genetic variant is associated with all the traits, where MANOVA may not have any detection power. In these situations, marginal model based methods, however, perform much better than multivariate methods. We investigate the behavior of MANOVA, both theoretically and using simulations, and derive the conditions where MANOVA loses power. Based on our findings, we propose a unified score-based test statistic USAT that can perform better than MANOVA in such situations and nearly as well as MANOVA elsewhere. Our proposed test reports an approximate asymptotic p-value for association and is computationally very efficient to implement at a GWAS level. We have studied through extensive simulations the performance of USAT, MANOVA and other existing approaches and demonstrated the advantage of using the USAT approach to detect association between a genetic variant and multivariate phenotypes. We applied USAT to data from three correlated traits collected on 5, 816 Caucasian individuals from the Atherosclerosis Risk in Communities (ARIC, The ARIC Investigators [1989]) Study and detected some interesting associations.

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Section: Resultsmentioning

confidence: 99%

USAT: A Unified Score‐Based Association Test for Multiple Phenotype‐Genotype Analysis

Ray

Pankow

Basu

2015

Genetic Epidemiology

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“…We also genotyped 35 unrelated samples from the International HapMap Project ( n =15 for CEPH [Utah residents with ancestry from northern and western Europe; CEU]; n =4 for Han Chinese in Beijing, China [CHB]; n =4 for Japanese in Tokyo, Japan [JPT]; n =3 for Mexican ancestry in Los Angeles, California [MEX] and n =9 for Yoruba in Ibadan, Nigeria [YRI]) to serve as anchors in analyses of genetic ancestry. We removed samples that failed genotyping (>5% missing data), blind duplicate samples, samples displaying sex inconsistencies, and samples displaying a high degree of discordance with genotyping available from the Institute of Translational Medicine and Therapeutics (ITMAT)-Broad-CARe (IBC) CVD array [19]. This reduced the available sample size to 4,258.…”

Section: Methodsmentioning

confidence: 99%

Prospective association of a genetic risk score and lifestyle intervention with cardiovascular morbidity and mortality among individuals with type 2 diabetes: the Look AHEAD randomised controlled trial

2015

Diabetologia

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Aims/hypothesis Both obesity and genetics contribute to cardiovascular disease (CVD). We examined whether a genetic risk score (GRS) prospectively predicted cardiovascular morbidity and mortality among overweight/obese individuals with type 2 diabetes and whether behavioural weight loss could diminish this association. Methods Look AHEAD (Action for Health in Diabetes) is a randomised 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 among overweight/obese individuals with type 2 diabetes. Of the participants, 4,016 provided consent for genetic analyses and had DNA samples passing quality control procedures. These secondary data analyses focused on whether a GRS derived from 153 single nucleotide polymorphisms (SNPs) associated with coronary artery disease in the most recent genome-wide association study predicted cardiovascular morbidity and mortality over a median of 9.6 years of follow-up, and whether ILI would diminish this association. Results The GRS significantly predicted the primary composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for angina in the full sample (HR, 95% CI per 1 SD increase in GRS: 1.19 [1.10, 1.28]) and among individuals with no known history of CVD at baseline (HR 1.18 [95% CI 1.07, 1.30]). In no case did ILI significantly alter this association. Conclusions/interpretation A GRS comprised of SNPs significantly predicts cardiovascular morbidity and mortality over 9.6 years of follow-up in Look AHEAD. Lifestyle intervention did not alter the genetic association.

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“…After excluding SNPs in linkage disequilibrium (LD, r 2 > 0.3), EIGENSTRAT was used to compute principal components (PCs) for use as covariates to control for population admixture in the regression analyses (26). …”

Section: Methodsmentioning

confidence: 99%

Genetic Modifiers of Cardiorespiratory Fitness Response to Lifestyle Intervention

Peter

Papandonatos

Belalcazar³

et al. 2014

Medicine &Amp; Science in Sports &Amp; Exercise

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Purpose Numerous prospective studies indicate that improved cardiorespiratory fitness reduces type 2 diabetes (T2D) 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 T2D compared to 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 metabolic equivalent (MET) level, estimated using a treadmill test, in response to a one-year intervention in 3,899 participants. Results We identified a significant signal in previously reported fitness-related gene RUNX1 that was associated with one-year 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 chip-wide 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=5.3×10−7), and genotype-treatment interaction (P=5.3×10−5). GRAIL 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.

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

Cited by 23 publications

References 64 publications

USAT: A Unified Score‐Based Association Test for Multiple Phenotype‐Genotype Analysis

USAT: A Unified Score‐Based Association Test for Multiple Phenotype‐Genotype Analysis

Prospective association of a genetic risk score and lifestyle intervention with cardiovascular morbidity and mortality among individuals with type 2 diabetes: the Look AHEAD randomised controlled trial

Genetic Modifiers of Cardiorespiratory Fitness Response to Lifestyle Intervention

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