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Background: Individuals differ in the response to regular exercise. Whether there are people who experience adverse changes in cardiovascular and diabetes risk factors has never been addressed., Methodology/principal Findings: An adverse response is defined as an exercise-induced change that worsens a risk factor beyond measurement error and expected day-to-day variation. Sixty subjects were measured three times over a period of three weeks, and variation in resting systolic blood pressure (SBP) and in fasting plasma HDL-cholesterol (HDL-C), triglycerides (TG), and insulin (FI) was quantified. The technical error (TE) defined as the within-subject standard deviation derived from these measurements was computed. An adverse response for a given risk factor was defined as a change that was at least two TEs away from no change but in an adverse direction. Thus an adverse response was recorded if an increase reached 10 mm Hg or more for SBP, 0.42 mmol/L or more for TG, or 24 pmol/L or more for FI or if a decrease reached 0.12 mmol/L or more for HDL-C. Completers from six exercise studies were used in the present analysis: Whites (N = 473) and Blacks (N = 250) from the HERITAGE Family Study; Whites and Blacks from DREW (N = 326), from INFLAME (N = 70), and from STRRIDE (N = 303); and Whites from a University of Maryland cohort (N = 160) and from a University of Jyvaskyla study (N = 105), for a total of 1,687 men and women. Using the above definitions, 126 subjects (8.4%) had an adverse change in FI. Numbers of adverse responders reached 12.2% for SBP, 10.4% for TG, and 13.3% for HDL-C. About 7% of participants experienced adverse responses in two or more risk factors., Conclusions/significance: Adverse responses to regular exercise in cardiovascular and diabetes risk factors occur. Identifying the predictors of such unwarranted responses and how to prevent them will provide the foundation for personalized exercise prescription.

The association of single nucleotide polymorphisms (SNPs) from seven candidate genes, including genotype-by-baseline fitness and genotype-by-baseline body mass index (BMI) interactions, with incident hypertension over 20 years was investigated in 2663 participants (1301 blacks, 1362 whites) of the Coronary Artery Risk Development in Young Adults Study (CARDIA). Baseline cardiorespiratory fitness was determined from duration of a modified Balke treadmill test. A total of 98 SNPs in blacks and 89 SNPs in whites from seven candidate genes were genotyped. Participants that became hypertensive (295 blacks and 146 whites) had significantly higher blood pressure and BMI (both races), and lower fitness (blacks only) at baseline than those who remained normotensive. Markers at the peroxisome proliferative activated receptor gamma coactivator 1α (PPARGC1A) and bradykinin β2 receptor (BDKRB2) genes were nominally associated with greater risk of hypertension, although one marker each at the BDKRB2 and endothelial nitric oxide synthase-3 (NOS3) genes were nominally associated with lower risk. The association of baseline fitness with risk of hypertension was nominally modified by genotype at markers within the angiotensin converting enzyme, angiotensinogen, BDKRB2 and NOS3 genes in blacks and the BDKRB2, endothelin-1 and PPARGC1A genes in whites. BDKRB2 rs4900318 showed nominal interactions with baseline fitness on the risk of hypertension in both races. The association of baseline BMI with risk of hypertension was nominally modified by GNB3 rs2301339 genotype in whites. None of the above associations were statistically significant after correcting for multiple testing. We found that SNPs in these candidate genes did not modify the association between baseline fitness or BMI and risk of hypertension in CARDIA participants.

Context and Objective: The magnitude of weight loss-induced high-density lipoprotein cholesterol (HDL-C) changes may depend on genetic factors. We examined the associations of eight candidate genes, identified by genome-wide association studies, with HDL-C at baseline and 10 yr after bariatric surgery in the Swedish Obese Subjects study., Methods: Single-nucleotide polymorphisms (SNP) (n = 60) in the following gene loci were genotyped: ABCA1, APOA5, CETP, GALNT2, LIPC, LIPG, LPL, and MMAB/MVK. Cross-sectional associations were tested before (n = 1771) and 2 yr (n = 1583) and 10 yr (n = 1196) after surgery. Changes in HDL-C were tested between baseline and yr 2 (n = 1518) and yr 2 and 10 (n = 1149). A multiple testing corrected threshold of P = 0.00125 was used for statistical significance., Results: In adjusted multivariate models, CETP SNP rs3764261 explained from 3.2-4.2% (P < 10(-14)) of the variation in HDL-C at all three time points, whereas CETP SNP rs9939224 contributed an additional 0.6 and 0.9% at baseline and yr 2, respectively. LIPC SNP rs1077834 showed consistent associations across all time points (R(2) = 0.4-1.1%; 3.8 × 10(-6) < P < 3 × 10(-3)), whereas LPL SNP rs6993414 contributed approximately 0.5% (5 × 10(-4) < P < 0.0012) at yr 2 and 10. In aggregate, four SNP in three genes explained 4.2, 6.8, and 5.6% of the HDL-C variance at baseline, yr 2, and yr 10, respectively. None of the SNP was significantly associated with weight loss-related changes in HDL-C., Conclusions: SNP in the CETP, LIPC, and LPL loci contribute significantly to plasma HDL-C levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, they are not associated with surgery-induced changes in HDL-C levels.

Low cardiorespiratory fitness is a powerful predictor of morbidity and cardiovascular mortality. In 473 sedentary adults, all whites, from 99 families of the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study, the heritability of gains in maximal O(2) uptake (VO(2max)) after exposure to a standardized 20-wk exercise program was estimated at 47%. A genome-wide association study based on 324,611 single-nucleotide polymorphisms (SNPs) was undertaken to identify SNPs associated with improvements in VO(2max) Based on single-SNP analysis, 39 SNPs were associated with the gains with P < 1.5 × 10(-4). Stepwise multiple regression analysis of the 39 SNPs identified a panel of 21 SNPs that accounted for 49% of the variance in VO(2max) trainability. Subjects who carried ≤9 favorable alleles at these 21 SNPs improved their VO(2max) by 221 ml/min, whereas those who carried ≥19 of these alleles gained, on average, 604 ml/min. The strongest association was with rs6552828, located in the acyl-CoA synthase long-chain member 1 (ACSL1) gene, which accounted by itself for ~6% of the training response of VO(2max). The genes nearest to the SNPs that were the strongest predictors were PR domain-containing 1 with ZNF domain (PRDM1); glutamate receptor, ionotropic, N-methyl-D-aspartate 3A (GRIN3A); K(+) channel, voltage gated, subfamily H, member 8 (KCNH8); and zinc finger protein of the cerebellum 4 (ZIC4). The association with the SNP nearest to ZIC4 was replicated in 40- to 65-yr-old, sedentary, overweight, and dyslipidemic subjects trained in Studies of a Targeted Risk Reduction Intervention Through Defined Exercise (STRRIDE; n = 183). Two SNPs were replicated in sedentary obese white women exercise trained in the Dose Response to Exercise (DREW) study (n = 112): rs1956197 near dishevelled associated activator of morphogenesis 1 (DAAM1) and rs17117533 in the vicinity of necdin (NDN). The association of SNPs rs884736 in the calmodulin-binding transcription activator 1 (CAMTA1) locus and rs17581162 ~68 kb upstream from regulator of G protein signaling 18 (RGS18) with the gains in VO(2max) in HERITAGE whites were replicated in HERITAGE blacks (n = 247). These genomic predictors of the response of Vo(2max) to regular exercise provide new targets for the study of the biology of fitness and its adaptation to regular exercise. Large-scale replication studies are warranted.

Purpose: To test whether DNA sequence variation in 11 obesity genes is associated with maximum weight loss and weight regain over 6 years of follow-up in bariatric surgery patients of the Swedish obese subjects (SOS) intervention study., Methods: A total of 1443 subjects were available for analysis (vertical banded gastroplasty: n = 966, banding: n = 293 and gastric bypass: n = 184). Single-nucleotide polymorphisms (SNPs) from the following 11 genes were included: ADIPOQ, BDNF, FTO, GNB3, LEP, LEPR, MC4R, NR3C1, PPARG, PPARGC1A and TNF. General linear models were used to analyze associations between the SNPs and maximum weight loss and weight regain., Results: The average maximum weight loss was 33.7 kg (s.d. 13.3; min -95.5 kg, max +2.0 kg), which was reached 2.2 (s.d. 1.6) years after the surgery. Subjects regained approximately 12 kg (range 0.0-51.4 kg) by year 6. After correcting for multiple testing, the FTO SNP rs16945088 remained significantly associated with maximum weight loss (P = 0.0002), as minor allele carriers lost approximately 3 kg less compared with common allele homozygotes. This association was particularly evident in the banding surgery patients (P < 0.0001), whereas no significant association was found in the gastric bypass subjects. No other SNPs were associated with maximum weight loss. Furthermore, no SNPs were significantly associated with weight regain., Conclusion: The FTO SNP rs16945088 was associated with maximum weight loss after banding surgery. We found no evidence that obesity-risk SNPs in FTO or other obesity candidate genes derived from genome-wide association studies are associated with maximum weight loss or weight regain over 6 years of follow-up in bariatric surgery patients. The potential role of other obesity genes remains to be investigated.

Background: It is not known whether the genes involved with endurance performance during young adulthood are also involved with changes in performance. We examined the associations of gene variants with symptom-limited exercise test duration at baseline and decrease in duration over 20 years., Methods and Results: A total of 3783 (1835 black, 1948 white) and 2335 (1035 black, 1300 white) participants from the Coronary Artery Risk Development in Young Adults study were included in the baseline and 20-year models, respectively. Two hundred seventeen single-nucleotide polymorphisms (SNPs) in black participants and 171 in white participants from 17 genes were genotyped. In blacks, 5 SNPs in the ATP1A2, HIF1A, NOS3, and PPARGC1A loci tended to be associated (P<0.05) with baseline duration in a multivariate regression model. Blacks (n=99) with at least 4 of the most-favorable genotypes at these loci had an ≈2-minute longer baseline duration than those with only 2 such genotypes (P<0.0001). In whites, the HIF1A rs1957757 and PPARGC1A rs3774909 markers tended to be associated with baseline duration, but the association of a multimarker construct of the most-favorable genotypes at both SNPs with baseline duration was not statistically significant. In whites, 4 SNPs in the AGT, AMPD1, ANG, and PPARGC1A loci tended to be associated with decrease in exercise duration over 20 years, and those with all 4 favorable genotypes (n=40) had a 0.8-minute less decline in duration compared with those with none or 1 (n=232) (P<0.0001)., Conclusions: In multimarker constructs, alleles at genes related to skeletal muscle Na(+)/K(+) transport, hypoxia, and mitochondrial metabolism are associated with symptom-limited exercise test duration over time in adults.

The purpose of this study was to examine if offspring physical activity may affect the relationship between maternal overweight and offspring fatness and blood pressure (BP). Subjects included 144 maternal-child pairs (n = 74 boys and 70 girls, mean age = 7.3 yrs). Maternal prepregnancy BMI was determined by self-report. Offspring characteristics included resting systolic and diastolic BP, body fatness by dual energy x-ray absorbtiometry, and moderate-to-vigorous physical activity (MVPA) using the Actigraph accelerometer. Children whose mothers were overweight or obese prepregnancy (Prepreg OW) were significantly larger and fatter than children from mothers with a normal prepregnancy BMI (Prepreg NORM). Prepreg OW children also had higher mean arterial pressure than Prepreg NORM children. BP values were not different across maternal Prepreg BMI/ MVPA groups. Percent fat was significantly different across Prepreg BMI/MVPA groups. Prepreg OW children that did not meet the daily recommended value of MVPA were the fattest. Prepreg OW children that attained (3)60 min of MVPA/ day had a mean percent body fat that was similar to Prepreg NORM children of either MVPA group.

The present study examined the association between the angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism, physical activity, and resting blood pressure (BP) in a sample of 132 children (48.4% female). Children attaining 60 min/day of moderate-to-vigorous physical activity (MVPA) possessed lower % body fat (29% vs 24%, p < .05). Resting BP did not significantly differ between genotypes. Furthermore, partial correlations between MVPA and BP were low and did not vary by ACE genotype. Thus, the ACE I/D genotype is not associated with BP and does not modify the relationship between physical activity and BP in this sample of children.

Background: Angiotensin converting enzyme (ACE) is a possible candidate gene that may influence both body fatness and blood pressure. Although several genetic studies have been conducted in adults, relatively few studies have examined the contribution of potential candidate genes, and specifically ACE I/D, on adiposity and BP phenotypes in childhood. Such studies may prove insightful for the development of the obesity-hypertension phenotype early in life. The purpose of this study was to examine differences in body fatness and resting blood pressure (BP) by ACE I/D genotype, and determine if the association between adiposity and BP varies by ACE I/D genotype in children., Methods: 152 children (75 girls, 77 boys) were assessed for body composition (% body fat) using dual energy x-ray absorbtiometry and resting BP according to American Heart Association recommendations. Buccal cell samples were genotyped using newly developed PCR-RFLP tests for two SNPs (rs4341 and rs4343) in complete linkage disequilibrium with the ACE I/D polymorphism. Partial correlations were computed to assess the ociations between % body fat and BP in the total sample and by genotype. ANCOVA was used to examine differences in resting BP by ACE I/D genotype and fatness groups., Results: Approximately 39% of youth were overfat based on % body fat (>30% fat in girls, 25% fat in boys). Body mass, body mass index, and fat-free mass were significantly higher in the ACE D-carriers compared to the II group (p < 0.05). BP was not significantly different by ACE I/D genotypes. In the total sample, correlations between adiposity and BP ranged from 0.30 to 0.46, and were not significantly different between genotypes. When grouped by genotype and body fat category, the overfat D-carrier subjects had significantly higher SBP and MAP compared to the normal fat D-carrier and normal fat II groups (p < 0.05)., Conclusion: ACE D-carriers are heavier than ACE II children; however, BP did not differ by ACE I/D genotype but was adversely influenced in the overfat D-carriers. Further studies are warranted to investigate the genetics of fatness and BP phenotypes in children.