GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Clinical Factors Associated With Remission of Obesity-Related Comorbidities After Bariatric Surgery.

IMPORTANCE: Little is known about comorbidity remission after bariatric surgery during typical clinical care across diverse and geographically distributed populations. OBJECTIVE: To estimate the improvement in obesity-related comorbidities after bariatric surgery and to identify clinical factors associated with these responses using a large representative population of patients. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included all patients (N = 33,718) with a recorded Current Procedural Terminology code for Roux-en-Y gastric bypass (RYGB) or adjustable gastric banding (AGB) in the MarketScan Commercial Claims and Encounters Medicare Supplemental Databases from January 1, 2005, to June 30, 2010, and who had continuous enrollment from 6 months or more before to 12 months after surgery. MAIN OUTCOMES AND MEASURES: Comorbidities before and after surgery were identified using both diagnoses (from International Classification of Diseases, Ninth Revision [ICD-9] codes) and prescription drug fills. Remission was based on a record of the comorbidity within 6 months before surgery, without record of the condition 18 months after surgery, using both ICD-9 codes and medication fills, as applicable. Multivariable logistic regression models were developed to identify factors associated with remission of diabetes and hypertension. RESULTS: Among the 33,718 patients, 13 comorbidities with at least 1% prevalence before surgery were identified. Both RYGB and AGB led to statistically and clinically significant reductions in these comorbidities; remission rates for all comorbidities were higher after RYGB than AGB. For comorbidities that could be defined using both ICD-9 and prescription drug fill codes, prevalence was higher before and lower after surgery when measured by fill codes. Diagnoses using ICD-9 codes, but not prescription fill codes, increased in the 3 months before surgery. In multivariable logistic regression models for remission of diabetes mellitus after RYGB and AGB, age (RYGB: odds ratio [OR], 0.976; 95% CI, 0.965-0.988 and AGB: OR, 0.982; 95% CI, 0.971-0.933), procedure year (RYGB: OR, 1.11; 95% CI, 1.012-1.218 and AGB: OR, 1.185; 95% CI, 1.039-1.351), preoperative insulin use (RYGB: OR, 0.14; 95% CI, 0.114-0.171; AGB: OR, 0.174; 95% CI, 0.131-0.230), preoperative sulfonylurea use (RYGB: OR, 0.616; 95% CI, 0.505-0.752 and AGB: OR, 0.449; 95% CI, 0.357-0.566), and other antidiabetic medication use (RYGB: OR, 0.747; 95% CI, 0.568-0.981 and AGB: OR, 0.506; 95% CI, 0.359-0.715) were significantly associated with response after both procedures. For remission of hypertension, age (RYGB: OR, 0.964; 95% CI, 0.957-0.972 and AGB: OR, 0.968; 95% CI, 0.959-0.977), number of preoperative antihypertensive medications (RYGB: OR, 0.104; 95% CI, 0.067-0.161 and AGB: OR, 0.239; 95% CI, 0.140-0.408), and preoperative diuretic use (RYGB: OR, 1.729; 95% CI, 1.462-2.045 and AGB: OR, 1.648; 95% CI, 1.380-1.967) were significantly associated with response after both procedures. CONCLUSIONS AND RELEVANCE: Analysis of a large, representative administrative database confirmed established predictors and revealed novel variables associated with comorbidity remission after bariatric surgery. Incorporating these factors into clinical tools to assess an individual patient's risk-to-benefit profile for these procedures could enhance patient selection and the overall use of surgery for the treatment of obesity and metabolic disease.

Advantages of percent weight loss as a method of reporting weight loss after Roux-en-Y gastric bypass.

OBJECTIVE: Although Roux-en-Y gastric bypass (RYGB) is an effective treatment for severe obesity, weight loss (WL) after this operation is highly variable. Accurate predictors of outcome would thus be useful in identifying those patients who would most benefit from this invasive therapy. WL has been characterized using several different metrics, including the number of BMI units lost (ΔBMI), percent baseline WL (%WL), and percent excess body WL (%EBWL). To identify clinically relevant predictors most sensitively, it is necessary to avoid confounding by other factors, including preoperative BMI (pBMI), the strongest known predictor of RYGB-induced WL. DESIGN AND METHODS: To determine the WL measure least associated with pBMI, outcomes of 846 patients undergoing RYGB were analyzed. RESULTS: Patients in this cohort had an average pBMI of 50.0 kg/m(2) at baseline. At weight nadir, they lost an average 19.4 kg/m(2), 38.7% WL, and 81.2% EBWL. pBMI was strongly and positively associated with ΔBMI at both 1 year (r = 0.56, P = 4.7 × 10(-51)) and nadir (r = 0.58, P = 2.8 × 10(-77)) and strongly but negatively associated with %EBWL at 1 year (r = -0.52, P = 3.8 × 10(-44)) and nadir (r = -0.45, P = 7.2×10(-43)). In contrast, pBMI was not significantly associated with %WL at 1 year (r = 0.04, P = 0.33) and only weakly associated at nadir (r = 0.13, P = 0.0002). CONCLUSIONS: Of the metrics examined, %WL is the parameter describing WL after RYGB least influenced by pBMI. It thus improves comparison of WL outcomes across studies of patients undergoing surgery and facilitates the most sensitive identification of novel predictors of surgery-induced WL. We therefore is recommend that %WL be adopted more broadly in reporting weight loss after RYGB.

Weight loss after gastric bypass is associated with a variant at 15q26.1.

The amount of weight loss attained after Roux-en-Y gastric bypass (RYGB) surgery follows a wide and normal distribution, and recent evidence indicates that this weight loss is due to physiological, rather than mechanical, mechanisms. To identify potential genetic factors associated with weight loss after RYGB, we performed a genome-wide association study (GWAS) of 693 individuals undergoing RYGB and then replicated this analysis in an independent population of 327 individuals undergoing RYGB. We found that a 15q26.1 locus near ST8SIA2 and SLCO3A1 was significantly associated with weight loss after RYGB. Expression of ST8SIA2 in omental fat of these individuals at baseline was significantly associated with weight loss after RYGB. Gene expression analysis in RYGB and weight-matched, sham-operated (WMS) mice revealed that expression of St8sia2 and Slco3a1 was significantly altered in metabolically active tissues in RYGB-treated compared to WMS mice. These findings provide strong evidence for specific genetic influences on weight loss after RYGB and underscore the biological nature of the response to RYGB.

Melanocortin-4 receptor signaling is required for weight loss after gastric bypass surgery.

CONTEXT: Roux-en-Y gastric bypass (RYGB) is one of the most effective long-term therapies for the treatment of severe obesity. Recent evidence indicates that RYGB effects weight loss through multiple physiological mechanisms, including changes in energy expenditure, food intake, food preference, and reward pathways. OBJECTIVE: Because central melanocortin signaling plays an important role in the regulation of energy homeostasis, we investigated whether genetic disruption of the melanocortin-4 receptor (MC4R) in rodents and humans affects weight loss after RYGB. METHODS AND RESULTS: Here we report that MC4R(-/-) mice lost substantially less weight after surgery than wild-type animals, indicating that MC4R signaling is necessary for the weight loss effects of RYGB in this model. Mice heterozygous for MC4R remain fully responsive to gastric bypass. To determine whether mutations affect surgically induced weight loss in humans, we sequenced the MC4R gene in 972 patients undergoing RYGB. Patients heterozygous for MC4R mutations exhibited the same magnitude and distribution of postoperative weight loss as patients without such mutations, suggesting that although two normal copies of the MC4R gene are necessary for normal weight regulation, a single normal copy of the MC4R gene is sufficient to mediate the weight loss effects of RYGB. CONCLUSIONS: MC4R is the first gene identified that is required for the sustained effects of bariatric surgery. The need for MC4R signaling for the weight loss effects of RYGB in mice underscores the physiological mechanisms of action of this procedure and demonstrates that RYGB both influences and is dependent on the normal pathways that regulate energy balance.

Heritability of the weight loss response to gastric bypass surgery.

CONTEXT: The use of Roux-en-Y gastric bypass (RYGB) surgery to treat severe obesity has grown dramatically. RYGB is highly effective, but the response in individual patients varies widely, and clinical predictors have been able to explain only a fraction of this variation. OBJECTIVE: Our objective was to determine whether there is a significant genetic contribution to weight loss after RYGB. METHODS: We genotyped 848 patients undergoing RYGB. Using identity-by-descent methods, we identified 13 pairs of first-degree relatives. We identified an additional 10 pairs of individuals who were living together but are not genetically related and randomly paired the remaining 794 individuals. We then compared weight loss within and across pairs. RESULTS: First-degree relative pairs had a similar response to surgery, with a 9% mean difference in excess weight loss between members of each pair. This similarity was not seen with cohabitating individuals (26% mean difference; P = 0.005 vs. first-degree pairs) or unrelated individuals (25% mean difference; P = 0.001). Cohabitating individuals had within-pair differences in weight loss no more similar than randomly paired individuals (P = 0.60). The pair relationship explained a significant portion of the variation in weight loss in first-degree relatives [intraclass correlation coefficient (ICC) = 70.4%; P = 0.02] but not in random subjects (ICC = 0.9%; P = 0.48) or genetically unrelated cohabitating individuals (ICC = 14.3%; P = 0.67). CONCLUSIONS: Genetic factors strongly influence the effect of RYGB on body weight. Identification of the specific genes that mediate this effect will advance our understanding of the biological mechanisms of weight loss after RYGB and should help identify patients who will benefit the most from this intervention.

A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort.

To map the genetics of gene expression in metabolically relevant tissues and investigate the diversity of expression SNPs (eSNPs) in multiple tissues from the same individual, we collected four tissues from approximately 1000 patients undergoing Roux-en-Y gastric bypass (RYGB) and clinical traits associated with their weight loss and co-morbidities. We then performed high-throughput genotyping and gene expression profiling and carried out a genome-wide association analyses for more than 100,000 gene expression traits representing four metabolically relevant tissues: liver, omental adipose, subcutaneous adipose, and stomach. We successfully identified 24,531 eSNPs corresponding to about 10,000 distinct genes. This represents the greatest number of eSNPs identified to our knowledge by any study to date and the first study to identify eSNPs from stomach tissue. We then demonstrate how these eSNPs provide a high-quality disease map for each tissue in morbidly obese patients to not only inform genetic associations identified in this cohort, but in previously published genome-wide association studies as well. These data can aid in elucidating the key networks associated with morbid obesity, response to RYGB, and disease as a whole.

Lipoprotein-associated phospholipase A2 activity improves risk discrimination of incident coronary heart disease among women.

BACKGROUND: This study sought to determine the relation between and discriminative capability of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and coronary heart disease (CHD) in a large population of disease-free women. METHODS: Among participants of the Nurses' Health Study who provided a blood sample, there were 421 cases of incident myocardial infarction during 14 years of follow-up. Controls were matched to cases 2:1 using risk set sampling based on age, smoking, and blood draw date. RESULTS: After conditioning on the matching factors, Lp-PLA(2) activity was significantly associated with myocardial infarction (relative risk [RR] 2.86 for extreme quartiles, 95% CI 1.98-4.12). Upon additional adjustment for lipid, inflammatory, and clinical risk factors, the RR remained statistically significant (RR 1.75, 95% CI 1.09-2.84). The discriminative capability of Lp-PLA(2) was assessed by comparing the area below the receiver operating characteristic curves for models with and without Lp-PLA(2) and by calculating the net reclassification improvement index. The addition of Lp-PLA(2) activity to a multivariable-adjusted model increased the receiver operating characteristic curves from 0.720 to 0.733 and significantly improved the net reclassification improvement index (P = .004). CONCLUSIONS: Levels of Lp-PLA(2) activity were significantly associated with incident CHD among women. In addition, Lp-PLA(2) activity added significantly to CHD risk discrimination.

Lipoprotein-associated phospholipase A2 activity and incident coronary heart disease among men and women with type 2 diabetes.

OBJECTIVE: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been shown to be associated with increased risk of coronary heart disease (CHD) in general adult populations. Because men and women with type 2 diabetes are at particularly high risk for CHD, the aim of this study was to assess the association of Lp-PLA(2) with future coronary events among diabetic men and women. RESEARCH DESIGN AND METHODS: We measured Lp-PLA(2) activity among 740 men and 777 women with confirmed diabetes enrolled in the Health Professionals Follow-Up Study (HPFS) and Nurses' Health Study (NHS). Participants were free of all cardiovascular disease and cancer at baseline. RESULTS: During 10 years of follow-up among men and 14 years among women, we documented 178 and 146 cases of CHD, respectively. We defined CHD as coronary artery bypass graft, angioplasty, nonfatal myocardial infarction, and fatal CHD. After adjustment for age, smoking, medical history, and biomarkers including C-reactive protein, HDL, and LDL, the relative risk of total CHD comparing extreme tertiles of Lp-PLA(2) was 1.39 (95% CI 1.01-1.90; P trend = 0.03). When we restricted analyses to only nonfatal myocardial infarction and fatal CHD, the relative risk was 1.75 (95% CI 1.05-2.92; P for trend = 0.001). LDL, HDL, C-reactive protein, hormone replacement therapy use, and diabetes duration did not modify these relationships. CONCLUSIONS: Levels of Lp-PLA(2) activity were significantly associated with incident CHD among men and women with type 2 diabetes, independent of traditional and inflammatory risk factors. This positive association was strongest for more severe clinical end points.

Dietary, lifestyle, and clinical predictors of lipoprotein-associated phospholipase A2 activity in individuals without coronary artery disease.

BACKGROUND: Elevated lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) may be positively associated with risk of coronary artery disease, yet little is known about potentially modifiable factors related to Lp-PLA(2). OBJECTIVE: The aim of this study was to determine dietary, lifestyle, and clinical measures associated with Lp-PLA(2) activity. DESIGN: We measured Lp-PLA(2) activity in 853 female participants of the Nurses' Health Study and 878 male participants of the Health Professionals Follow-Up Study who were free of cancer and cardiovascular disease. Multivariable linear regression models were used to assess the relation between potentially modifiable factors and Lp-PLA(2). RESULTS: The replacement of 5% of energy from carbohydrates with energy from protein was associated with 2.2 nmol . min(-1) . mL(-1) lower levels of Lp-PLA(2) (95% CI: -3.1, -0.4) activity, and every 15-g/d increase in alcohol consumption was associated with 4.4 nmol . min(-1) . mL(-1) lower levels of Lp-PLA(2) activity (95% CI: -6.4, -2.4). Smoking (beta = 10.2; 95% CI: 4.8, 15.5), being overweight (beta = 7.5; 95% CI: 3.6, 11.3), aspirin use (beta = 6.0; 95% CI: 2.1, 10.0), hypercholesterolemia (beta = 15.0; 95% CI: 11.3, 18.8), and age (beta = 2.5; 95% CI: 1.34, 3.74) were associated with elevated Lp-PLA(2) activity, whereas postmenopausal hormone use (beta = -15.8; 95% CI: -19.4, -12.1) and cholesterol medication use (beta = -9.6; 95% CI: -18.2, -1.1) were inversely associated. CONCLUSION: We found that not smoking, use of postmenopausal hormones, having a body mass index (in kg/m(2)) < or =25, increased alcohol consumption, and increased protein consumption all represent potential modifiable factors that may favorably influence Lp-PLA(2) activity.

Common body mass index-associated variants confer risk of extreme obesity.

To investigate the genetic architecture of severe obesity, we performed a genome-wide association study of 775 cases and 3197 unascertained controls at approximately 550,000 markers across the autosomal genome. We found convincing association to the previously described locus including the FTO gene. We also found evidence of association at a further six of 12 other loci previously reported to influence body mass index (BMI) in the general population and one of three associations to severe childhood and adult obesity and that cases have a higher proportion of risk-conferring alleles than controls. We found no evidence of homozygosity at any locus due to identity-by-descent associating with phenotype which would be indicative of rare, penetrant alleles, nor was there excess genome-wide homozygosity in cases relative to controls. Our results suggest that variants influencing BMI also contribute to severe obesity, a condition at the extreme of the phenotypic spectrum rather than a distinct condition.

Capacity for physical activity predicts weight loss after Roux-en-Y gastric bypass.

Despite its overall excellent outcomes, weight loss after Roux-en-Y gastric bypass (RYGB) is highly variable. We conducted this study to identify clinical predictors of weight loss after RYGB. We reviewed charts from 300 consecutive patients who underwent RYGB from August 1999 to November 2002. Data collected included patient demographics, medical comorbidities, and diet history. Of the 20 variables selected for univariate analysis, 9 with univariate P values