Interaction between XRCC2 gene polymorphism and abdominal obesity on risk of endometrial carcinoma.

AIMS: The aim of this study was to investigate the impact of three single nucleotide polymorphisms (SNPs) within X-Ray Repair Cross Complementary Group 2 (XRCC2) gene and additional gene- abdominal obesity (AO) interaction with endometrial carcinoma (EC) risk. METHODS: Hardy-Weinberg equilibrium was tested for all participants by using SNPstats (online software: http://bioinfo.iconcologia.net/SNPstats). The best SNP-SNP and gene-AO interaction combination among three SNPs within XRCC2 gene and AO was screened using generalized multifactor dimensionality reduction (GMDR). RESULTS: We employed the logistic regression analysis showed that rs718282-T allele is associated with increased EC risk, adjusted ORs (95%CI) were 1.67 (1.23-2.04). However, we did not find statistical association between rs3218536, and rs3218384 and EC susceptibility. GMDR analysis was used for SNP-SNP- and gene-abdominal obesity analysis. The cross-validation consistency and the testing accuracy for the interaction were calculated. The two-locus model between rs718282 and AO had a testing accuracy of 60.11%, which was significant at the p < .001 level, and this two- locus model was considered as the best model. It provided statistical evidence for rs718282 gene-AO interaction effects. The results indicated that AO influenced the EC risk depending on the rs718282 genotypes. Compared with non- AO subjects with rs718282-CC genotype, AO subjects with rs718282-CT or TT genotype had the highest EC risk, OR (95%CI) was 2.83 (1.67 - 4.02), after covariates adjustment. CONCLUSIONS: Both the rs718282- T allele, and its interaction with AO were associated with increased EC risk.

Estimating causality between smoking and abdominal obesity by Mendelian randomization.

BACKGROUND AND AIMS: Smokers tend to have a lower body weight than non-smokers, but also more abdominal fat. It remains unclear whether or not the relationship between smoking and abdominal obesity is causal. Previous Mendelian randomization (MR) studies have investigated this relationship by relying upon a single genetic variant for smoking heaviness. This approach is sensitive to pleiotropic effects and may produce imprecise causal estimates. We aimed to estimate causality between smoking and abdominal obesity using multiple genetic instruments. DESIGN: MR study using causal analysis using summary effect estimates (CAUSE) and latent heritable confounder MR (LHC-MR) methods that instrument smoking using genome-wide data, and also two-sample MR (2SMR) methods. SETTING: Genome-wide association studies (GWAS) summary statistics from participants of European ancestry, obtained from the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN), Genetic Investigation of Anthropometric Traits (GIANT) Consortium and the UK Biobank. PARTICIPANTS: We used GWAS results for smoking initiation (n = 1 232 091), life-time smoking (n = 462 690) and smoking heaviness (n = 337 334) as exposure traits, and waist-hip ratio (WHR) and waist and hip circumferences (WC and HC) (n up to 697 734), with and without adjustment for body mass index (adjBMI), as outcome traits. MEASUREMENTS: Smoking initiation, life-time smoking, smoking heaviness, WHR, WC, HC, WHRadjBMI, WCadjBMI and HCadjBMI. FINDINGS: Both CAUSE and LHC-MR indicated a positive causal effect of smoking initiation on WHR (0.13 [95% confidence interval (CI) = 0.10, 0.16 and 0.49 (0.41, 0.57), respectively] and WHRadjBMI (0.07 (0.03, 0.10) and 0.31 (0.26, 0.37). Similarly, they indicated a positive causal effect of life-time smoking on WHR [0.35 (0.29, 0.41) and 0.44 (0.38, 0.51)] and WHRadjBMI [0.18 (0.13, 0.24) and 0.26 (0.20, 0.31)]. In follow-up analyses, smoking particularly increased visceral fat. There was no evidence of a mediating role by cortisol or sex hormones. CONCLUSIONS: Smoking initiation and higher life-time smoking may lead to increased abdominal fat distribution. The increase in abdominal fat due to smoking is characterized by an increase in visceral fat. Thus, efforts to prevent and cease smoking can have the added benefit of reducing abdominal fat.

Adherence to a healthy lifestyle, genetic susceptibility to abdominal obesity, cardiometabolic risk markers, and risk of coronary heart disease.

BACKGROUND: Little is known about whether the association between genetic susceptibility to high waist-to-hip ratio (WHR), a measure of abdominal obesity, and incident coronary heart disease (CHD) is modified by adherence to a healthy lifestyle. OBJECTIVES: To explore the interplay of genetic susceptibility to high WHR and adherence to a healthy lifestyle on incident CHD. METHODS: This study included 282,316 white British individuals from the UK Biobank study. Genetic risk for high WHR was estimated in the form of weighted polygenic risk scores (PRSs), calculated based on 156 single-nucleotide polymorphisms. Lifestyle scores were calculated based on 5 healthy lifestyle factors: regular physical activity, no current smoking, a healthy diet, <3 times/wk of alcohol consumption and 7-9 h/d of sleep. Incident CHD (n = 11,635) was accrued over a median 13.8 y of follow-up, and 12 individual cardiovascular disease risk markers assessed at baseline. RESULTS: Adhering to a favorable lifestyle (4-5 healthy factors) was associated with a 25% (hazard ratio: 0.75, 95% confidence interval: 0.70, 0.81) lower hazard of CHD compared with an unfavorable lifestyle (0-1 factor), independent of PRS for high WHR. Estimated 12-y absolute risk of CHD was lower for a favorable lifestyle at high genetic risk (1.73%) and medium genetic risk (1.67%) than for an unfavorable lifestyle at low genetic risk (2.08%). Adhering to a favorable lifestyle was associated with healthier levels of cardiovascular disease risk markers (except random glucose and high-density lipoprotein), independent of PRS for high WHR. CONCLUSIONS: Individuals who have high or medium genetic risk of abdominal obesity but adhere to a healthy lifestyle may have a lower risk of developing CHD, compared with those who have low genetic risk and an unhealthy lifestyle. Future clinical trials of lifestyle modification could be implemented for individuals at high genetic risk of abdominal obesity for the primary prevention of CHD events.

Abdominal obesity and alcohol use modify the impact of genetic risk for incident advanced liver disease in the general population.

BACKGROUND & AIMS: Genetic variants, abdominal obesity and alcohol use are risk factors for incident liver disease (ILD). We aimed to study whether variants either alone or when aggregated into genetic risk scores (GRSs) associate with ILD, and whether waist-hip ratio (WHR) or alcohol use interacts with this risk. METHODS: Our study included 33 770 persons (mean age 50 years, 47% men) who participated in health-examination surveys (FINRISK 1992-2012 or Health 2000) with data on alcohol use, WHR and 63 genotypes associated with liver disease. Data were linked with national health registers for liver-related outcomes (hospitalizations, malignancies and death). Exclusions were baseline clinical liver disease. Mean follow-up time was 12.2 years. Cox regression analyses between variants and ILD were adjusted for age, sex and BMI. RESULTS: Variants in PNPLA3, IFNL4, TM6SF2, FDFT1, PPP1R3B, SERPINA1 and HSD17B13 were associated with ILD. GRSs calculated from these variants were not associated with WHR or alcohol use, but were exponentially associated with ILD (up to 25-fold higher risk in high versus low score). The risk of ILD in individuals with high GRS and high WHR or alcohol use compared with those with none of these risk factors was increased by up to 90-fold. GRSs provided new prognostic information particularly in individuals with high WHR. CONCLUSIONS: The effect of multiple genetic variants on the risk of ILD is potentiated by abdominal obesity and alcohol use. Simple GRSs may help to identify individuals with adverse lifestyle who are at a particularly high risk of ILD.

Reassessing the causal role of obesity in breast cancer susceptibility: a comprehensive multivariable Mendelian randomization investigating the distribution and timing of exposure.

BACKGROUND: Previous Mendelian randomization (MR) studies on obesity and risk of breast cancer adopted a small number of instrumental variables and focused mainly on the crude total effect. We aim to investigate the independent causal effect of obesity on breast cancer susceptibility, considering the distribution of fat, covering both early and late life. METHODS: Using an enlarged set of female-specific genetic variants associated with adult general [body mass index (BMI)] and abdominal obesity [waist-to-hip ratio (WHR) with and without adjustment for BMI, WHR and WHRadjBMI] as well as using sex-combined genetic variants of childhood obesity (childhood BMI), we performed a two-sample univariable MR to re-evaluate the total effect of each obesity-related exposure on overall breast cancer (Ncase = 133 384, Ncontrol = 113 789). We further looked into its oestrogen receptor (ER)-defined subtypes (NER+ = 69 501, NER- = 21 468, Ncontrol = 105 974). Multivariable MR was applied to estimate the independent causal effect of each obesity-related exposure on breast cancer taking into account confounders as well as to investigate the independent effect of adult and childhood obesity considering their inter-correlation. RESULTS: In univariable MR, the protective effects of both adult BMI [odds ratio (OR) = 0.89, 95% CI = 0.83-0.96, P = 2.06 × 10-3] and childhood BMI (OR = 0.78, 95% CI = 0.70-0.87, P = 4.58 × 10-6) were observed for breast cancer overall. Comparable effects were found in ER+ and ER- subtypes. Similarly, genetically predicted adult WHR was also associated with a decreased risk of breast cancer overall (OR = 0.87, 95% CI = 0.80-0.96, P = 3.77 × 10-3), restricting to ER+ subtype (OR = 0.88, 95% CI = 0.80-0.98, P = 1.84 × 10-2). Conditional on childhood BMI, the effect of adult general obesity on breast cancer overall attenuated to null (BMI: OR = 1.00, 95% CI = 0.90-1.10, P = 0.96), whereas the effect of adult abdominal obesity attenuated to some extent (WHR: OR = 0.90, 95% CI = 0.82-0.98, P = 1.49 × 10-2; WHRadjBMI: OR = 0.92, 95% CI = 0.86-0.99, P = 1.98 × 10-2). On the contrary, an independent protective effect of childhood BMI was observed in breast cancer overall, irrespective of adult measures (adjusted for adult BMI: OR = 0.84, 95% CI = 0.77-0.93, P = 3.93 × 10-4; adjusted for adult WHR: OR = 0.84, 95% CI = 0.76-0.91, P = 6.57 × 10-5; adjusted for adult WHRadjBMI: OR = 0.80, 95% CI = 0.74-0.87, P = 1.24 × 10-7). CONCLUSION: Although successfully replicating the inverse causal relationship between adult obesity-related exposures and risk of breast cancer, our study demonstrated such effects to be largely (adult BMI) or partly (adult WHR or WHRadjBMI) attributed to childhood obesity. Our findings highlighted an independent role of childhood obesity in affecting the risk of breast cancer as well as the importance of taking into account the complex interplay underlying correlated exposures.

Rare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity.

Identifying genetic variants associated with lower waist-to-hip ratio can reveal new therapeutic targets for abdominal obesity. We use exome sequences from 362,679 individuals to identify genes associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI), a surrogate for abdominal fat that is causally linked to type 2 diabetes and coronary heart disease. Predicted loss of function (pLOF) variants in INHBE associate with lower WHRadjBMI and this association replicates in data from AMP-T2D-GENES. INHBE encodes a secreted protein, the hepatokine activin E. In vitro characterization of the most common INHBE pLOF variant in our study, indicates an in-frame deletion resulting in a 90% reduction in secreted protein levels. We detect associations with lower WHRadjBMI for variants in ACVR1C, encoding an activin receptor, further highlighting the involvement of activins in regulating fat distribution. These findings highlight activin E as a potential therapeutic target for abdominal obesity, a phenotype linked to cardiometabolic disease.

Identification of the interactions between specific genetic polymorphisms and nutrient intake associated with general and abdominal obesity in middle-aged adults.

BACKGROUND & AIMS: Comprehensive understanding of gene-diet interactions is necessary to establish proper dietary guidelines to prevent and manage general and abdominal obesity. We investigated the role of genetic variants and their interactions with general and abdominal obesity-associated nutrients using a largescale genome-wide association study of Korean adults. METHODS: A total of 50,808 participants from a Korean genome and epidemiology study were included. Dietary intake was assessed using a food frequency questionnaire. Obesity was defined as a body mass index ≥25 kg/m2. Abdominal obesity (AO) was defined as waist circumference ≥90 cm and 80 cm in males and females, respectively. Dietary nutrient intake was classified based on Korean Dietary Reference Intakes (DRIs). Odds ratios and 95% confidence intervals were calculated after adjusting for age, sex, exercise, smoking, alcohol drinking, total energy consumption, PC1, and PC2. RESULTS: Among the individuals consuming fat (%) above DRI, carriers of Ca binding protein 39 (CAB39)- rs6722579 minor allele (A) have a higher risk of AO than those not carrying the SNP (odds ration [OR] = 3.73, p-value = 2.05e-07; interaction p-value = 1.80e-07). Among the individuals consuming vitamin C above DRI, carriers of carboxypeptidase Q (CPQ)- rs59465035 minor allele (T) have a lower risk of AO than those without that SNP (OR = 0.89, p-value = 1.44e-08; interaction p-value = 9.50e-06). The genetic association with obesity was stronger among individuals with a genetic variant rs4130113 near GHR gene region in those consume folate above DRI and with a genetic variant rs5760920 near CRYBB2 gene region in those consume vitamin B2 above DRI. CONCLUSION: Our study results suggested that interactions of specific polymorphisms at loci and certain nutrients may influence obesity and abdominal obesity.

Glucocorticoid-induced Fingerprints on Visceral Adipose Tissue Transcriptome and Epigenome.

CONTEXT: Chronic glucocorticoid (GC) overexposure, resulting from endogenous Cushing's syndrome (CS) or exogenous GC therapy, causes several adverse outcomes, including persistent central fat accumulation associated with a low-grade inflammation. However, no previous multiomics studies in visceral adipose tissue (VAT) from patients exposed to high levels of unsuppressed GC during active CS or after remission are available yet. OBJECTIVE: To determine the persistent VAT transcriptomic alterations and epigenetic fingerprints induced by chronic hypercortisolism. METHODS: We employed a translational approach combining high-throughput data on endogenous CS patients and a reversible CS mouse model. We performed RNA sequencing and chromatin immunoprecipitation sequencing on histone modifications (H3K4me3, H3K27ac, and H3K27me3) to identify persistent transcriptional and epigenetic signatures in VAT produced during active CS and maintained after remission. RESULTS: VAT dysfunction was associated with low-grade proinflammatory status, macrophage infiltration, and extracellular matrix remodeling. Most notably, chronic hypercortisolism caused a persistent circadian rhythm disruption in VAT through core clock genes modulation. Importantly, changes in the levels of 2 histone modifications associated to gene transcriptional activation (H3K4me3 and H3K27ac) correlated with the observed differences in gene expression during active CS and after CS remission. CONCLUSION: We identified for the first time the persistent transcriptional and epigenetic signatures induced by hypercortisolism in VAT, providing a novel integrated view of molecular components driving the long-term VAT impairment associated with CS.

Aldosterone-producing adenoma-harbouring KCNJ5 mutations is associated with lower prevalence of metabolic disorders and abdominal obesity.

OBJECTIVE: Aldosterone overproduction and lipid metabolic disturbances between idiopathic hyperaldosteronism (IHA) and unilateral aldosterone-producing adenoma (APA) have been inconsistently linked in patients with primary aldosteronism. Moreover, KCNJ5 mutations are prevalent among APAs and enhance aldosterone synthesis in adrenal cortex. We aimed to investigate the prevalence of metabolic syndrome (MetS) in each primary aldosteronism subtype and observe the role of KCNJ5 mutations among APAs on the distribution of abdominal adipose tissues quantified using computed tomography (CT), including their changes postadrenalectomy. DESIGN AND METHODS: We retrospectively collected 244 and 177 patients with IHA and APA at baseline. Patients with APA had undergone adrenalectomy, and gene sequencing revealed the absence (n = 75) and presence (n = 102) of KCNJ5 mutations. We also recruited 31 patients with APA who had undergone CT-scan 1-year postadrenalectomy. RESULTS: The patients with APA harbouring KCNJ5 mutations had significantly lower prevalence of MetS and smaller distribution in waist circumference, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) than the other groups. Logistic regression analysis indicated that the VAT area correlated significantly with KCNJ5 mutations among the APAs. Only participants with KCNJ5 mutations had significant increases in triglycerides, cholesterol, SAT, and VAT after 1-year postadrenalectomy. CONCLUSION: This study is the first to demonstrate that MetS and abdominal obesity were less prevalent in the patients with APA harbouring KCNJ5 mutations compared with the IHA group and the non-KCNJ5-mutated APA group. Increasing prevalence of dyslipidaemia and abdominal obesity was observed in patients with KCNJ5 mutations 1-year postadrenalectomy.

An Intronic Risk SNP rs12454712 for Central Obesity Acts As an Allele-Specific Enhancer To Regulate BCL2 Expression.

Genome-wide association studies (GWAS) have reproducibly associated the single nucleotide polymorphism (SNP) rs12454712 with waist-to-hip ratio adjusted for BMI (WHRadjBMI), but the functional role underlying this intronic variant is unknown. Integrative genomic and epigenomic analyses supported rs12454712 as a functional independent variant. We further demonstrated that rs12454712 acted as an allele-specific enhancer regulating expression of its located gene BCL2 by using dual-luciferase reporter assays and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9. Specifically, the rs12454712-C allele can bind transcription factor ZNF329, which efficiently elevates the enhancer activity and increases BCL2 expression. Knocking down Bcl2 in 3T3-L1 cells led to the downregulation of adipogenic differentiation marker genes and increased cell apoptosis. A significant negative correlation between BCL2 expression in subcutaneous adipose tissues and obesity was observed. Our findings illustrate the molecular mechanisms behind the intronic SNP rs12454712 for central obesity, which would be a potential and promising target for developing appropriate therapies.

Genetic markers of abdominal obesity and weight loss after gastric bypass surgery.

BACKGROUND: Weight loss after bariatric surgery varies widely between individuals, partly due to genetic differences. In addition, genetic determinants of abdominal obesity have been shown to attenuate weight loss after dietary intervention with special attention paid to the rs1358980-T risk allele in the VEGFA locus. Here we aimed to test if updated genetic risk scores (GRSs) for adiposity measures and the rs1358980-T risk allele are linked with weight loss following gastric bypass surgery. METHODS: Five hundred seventy six patients with morbid obesity underwent Roux-en-Y gastric bypass. A GRS for BMI and a GRS for waist-hip-ratio adjusted for BMI (proxy for abdominal obesity), respectively, were constructed. All patients were genotyped for the rs1358980-T risk allele. Associations between the genetic determinants and weight loss after bariatric surgery were evaluated. RESULTS: The GRS for BMI was not associated with weight loss (ß = -2.0 kg/100 risk alleles, 95% CI -7.5 to 3.3, p = 0.45). Even though the GRS for abdominal obesity was associated with an attenuated weight loss response adjusted for age, sex and center (ß = -14.6 kg/100 risk alleles, 95% CI -25.4 to -3.8, p = 0.008), it was not significantly associated with weight loss after adjustment for baseline BMI (ß = -7.9 kg/100 risk alleles, 95% CI -17.5 to 1.6, p = 0.11). Similarly, the rs1358980-T risk allele was not significantly associated with weight loss (ß = -0.8 kg/risk allele, 95% CI -2.2 to 0.6, p = 0.25). DISCUSSION: GRSs for adiposity derived from large meta-analyses and the rs1358980-T risk allele in the VEGFA locus did not predict weight loss after gastric bypass surgery. The association between a GRS for abdominal obesity and the response to bariatric surgery may be dependent on the association between the GRS and baseline BMI.

Identification of a TMEM182 rs141764639 polymorphism associated with central obesity by regulating tumor necrosis factor-α in a Korean population.

AIMS: To investigate the effect of a single nucleotide polymorphism (SNP) in transmembrane protein 182 (TMEM182) on the risk of having central obesity and the related phenotype. METHODS: In total, 2141 subjects with central obesity (n = 827) and normal controls (n = 1314) were included. The most strongly associated SNPs were related to waist circumference, and one SNP, rs141764639, was identified in TMEM182 (p = 7.30E-06, q = 0.0326). RESULTS: The TC genotype was associated with more central obesity; higher levels of blood pressure, glucose-related parameters, and inflammatory markers; abnormal lipid profiles; and smaller LDL particle sizes than the major allele homozygotes in the total population. TNF-α in the TC genotype showed extremely high levels compared to the TT genotype. There were significant interactions between the genotypes and waist circumference in relation to LDL particle size, TNF-α level, and IL-6 level. Compared with the reference group, the odds ratio for central obesity in C allele carriers was significantly increased by 2-fold. CONCLUSIONS: The polymorphism of TMEM182 rs141764639 might have an effect on the incidence of central obesity in the Korean population by interacting with the upregulation of TNF-α, a proinflammatory cytokine. Moreover, LDL particle size, which is an atherogenic lipid profile trait, was associated with the TMEM182 rs141764639 genotype.

Genetic evidence that higher central adiposity causes gastro-oesophageal reflux disease: a Mendelian randomization study.

BACKGROUND: Gastro-oesophageal reflux disease (GORD) is associated with multiple risk factors but determining causality is difficult. We used a genetic approach [Mendelian randomization (MR)] to identify potential causal modifiable risk factors for GORD. METHODS: We used data from 451 097 European participants in the UK Biobank and defined GORD using hospital-defined ICD10 and OPCS4 codes and self-report data (N = 41 024 GORD cases). We tested observational and MR-based associations between GORD and four adiposity measures [body mass index (BMI), waist-hip ratio (WHR), a metabolically favourable higher body-fat percentage and waist circumference], smoking status, smoking frequency and caffeine consumption. RESULTS: Observationally, all adiposity measures were associated with higher odds of GORD. Ever and current smoking were associated with higher odds of GORD. Coffee consumption was associated with lower odds of GORD but, among coffee drinkers, more caffeinated-coffee consumption was associated with higher odds of GORD. Using MR, we provide strong evidence that higher WHR and higher WHR adjusted for BMI lead to GORD. There was weak evidence that higher BMI, body-fat percentage, coffee drinking or smoking caused GORD, but only the observational effects for BMI and body-fat percentage could be excluded. This MR estimated effect for WHR equates to a 1.23-fold higher odds of GORD per 5-cm increase in waist circumference. CONCLUSIONS: These results provide strong evidence that a higher waist-hip ratio leads to GORD. Our study suggests that central fat distribution is crucial in causing GORD rather than overall weight.

Association of FTO rs1421085 with obesity, diet, physical activity, and socioeconomic status: A longitudinal birth cohort study.

BACKGROUND AND AIMS: Fat mass and obesity-associated protein (FTO) variants are among genetic variants frequently associated with obesity. We analyzed the association between FTO rs1421085 polymorphism and obesity, dietary intake, cardiorespiratory fitness (CRF), physical activity, and socioeconomic status (SES) from the age of 9-25 years. METHODS AND RESULTS: The sample included both birth cohorts (originally n = 1176) of the Estonian Children Personality Behaviour and Health Study. The association between FTO rs1421085 and obesity, dietary intake, CRF, physical activity, and SES from the age of 15-25 years was assessed using linear mixed-effects regression models. Associations at ages 9 (younger cohort only), 15, 18, and 25 years were assessed by one-way ANOVA. Male C-allele carriers had significantly (p < 0.05) higher body mass index (BMI), sum of 5 skinfolds, body fat percentage, and hip circumference from the age of 15-25 years. Findings were similar at the age of 9 years. In female subjects, waist-to-hip ratio was significantly greater in CC homozygotes. Interestingly, female CC homozygotes had a greater decrease in the rate of change in daily energy intake and lipid intake per year and higher physical activity score at every fixed time point. Moreover, in females, an effect of FTO × SES interaction on measures of obesity was observed. CONCLUSION: The FTO rs1421085 polymorphism was associated with obesity and abdominal obesity from childhood to young adulthood in males, and with abdominal obesity from adolescence to young adulthood in females. This association is rather related to differences in adipocyte energy metabolism than lifestyle.

The Effect of Habitual Fat Intake, IL6 Polymorphism, and Different Diet Strategies on Inflammation in Postmenopausal Women with Central Obesity.

The hypothesis that habitual fat intake, the IL6 genotype, the Mediterranean diet or the central European diet for 16 weeks affect biomarkers of inflammation in centrally obese postmenopausal women, was tested in a randomized controlled trial. Dietary intake was assessed using a three-day food diary. Lipid parameters were measured using a Beckman Coulter AU analyzer. Transcription of TNF and IL6 genes was analyzed in peripheral blood mononuclear cells using real-time PCR. Concentrations of tumor necrosis factor alpha (TNFα) and interleukin 6 (IL6) were measured with ELISA. rs1800795 polymorphism of IL6 was analyzed using hydrolyzing probes. Higher energy intake from fat was associated with higher IL6 levels (p < 0.05). Significantly (p < 0.01) lower total cholesterol (T-C) and low-density lipoprotein cholesterol (LDL-C) concentrations were observed in the GG IL6 rs1800795 genotype group. Both diets significantly (p < 0.001) decreased TNFα concentrations. Neither IL6 gene transcription levels nor blood IL6 concentrations were affected by them. Our findings confirm that habitual fat intake may affect inflammation. The rs1800795 IL6 polymorphism alone did not significantly affect body weight or body composition in aimed group, but C-allele carriers had higher levels of T-C and LDL-C. This polymorphism did not affect inflammation. Both diets may lead to a decrease in TNFα concentration.

Visceral Adipose Tissue Modulates Radiosensitivity in Oesophageal Adenocarcinoma.

Oesophageal adenocarcinoma (OAC) is an exemplar model of obesity-associated cancer. Response to neoadjuvant chemoradiotherapy (NA CRT) is a clinical challenge. We examined if visceral adipose tissue and obesity status alter radiosensitivity in OAC. The radioresistant (OE33R) and radioresponsive (OE33P) OAC isogenic model was cultured with adipose tissue conditioned media from three patient cohorts: non-cancer patients, surgery only OAC patients and NA CRT OAC patients. Cell survival was characterised by clonogenic assay, metabolomic profiling by nuclear magnetic resonance spectroscopy and adipokine receptor gene expression by qPCR. A retrospective in vivo study compared tumour response to NA CRT in normal weight (n=53) versus overweight/obese patients (n=148). Adipose conditioned media (ACM) from all patient cohorts significantly increased radiosensitivity in radioresistant OE33R cells. ACM from the NA CRT OAC cohort increased radiosensitivity in OE33P cells. Metabolomic profiling demonstrated separation of the non-cancer and surgery only OAC cohorts and between the non-cancer and NA CRT OAC cohorts. Gene expression profiling of OE33P versus OE33R cells demonstrated differential expression of the adiponectin receptor-1 (AR1), adiponectin receptor-2 (AR2), leptin receptor (LepR) and neuropilin receptor-1 (NRP1) genes. In vivo overweight/obese OAC patients achieved an enhanced tumour response following NA CRT compared to normal weight patients. This study demonstrates that visceral adipose tissue modulates the cellular response to radiation in OAC.

Melanocortin-4 Receptor and Lipocalin 2 Gene Variants in Spanish Children with Abdominal Obesity: Effects on BMI-SDS After a Lifestyle Intervention.

Mutations leading to a reduced function of the melanocortin-4 receptor (MC4R) exert a major gene effect on extreme obesity. Recently it was shown that the bone derived hormone lipocalin 2 (LCN2) binds to the MC4R and activates a MC4R dependent anorexigenic pathway. We identified mutations in both genes and screened the effects of MC4R and LCN2 mutations on eating behavior and weight change after a lifestyle intervention. One hundred and twelve children (11.24 ± 2.6 years, BMI-SDS 2.91 ± 1.07) with abdominal obesity participated in a lifestyle intervention. MC4R and LCN2 coding regions were screened by Sanger sequencing. Eating behavior was assessed at baseline with the Children Eating Behavior Questionnaire (CEBQ). We detected three previously described non-synonymous MC4R variants (Glu42Lys, Thr150Ile, and Arg305Gln) and one non-synonymous polymorphism (Ile251Leu). Regarding LCN2, one known non-synonymous variant (Thr124Met) was detected. Eating behavior was described in carriers of the MC4R and LCN2 mutation and in non-carriers. MC4R and LCN2 mutations were detected in 2.42% and 0.84%, respectively, of Spanish children with abdominal obesity. A number of subjects with functional mutation variants in MC4R and LCN2 were able to achieve a reduction in BMI-SDS after a lifestyle intervention.

Identification of a 1p21 independent functional variant for abdominal obesity.

OBJECTIVES: Aiming to uncover the genetic basis of abdominal obesity, we performed a genome-wide association study (GWAS) meta-analysis of trunk fat mass adjusted by trunk lean mass (TFMadj) and followed by a series of functional investigations. SUBJECTS: A total of 11,569 subjects from six samples were included into the GWAS meta-analysis. METHODS: Meta-analysis was performed by a weighted fixed-effects model. In silico replication analysis was performed in the UK-Biobank (UKB) sample (N = 331,093) and in the GIANT study (N up to 110,204). Cis-expression QTL (cis-eQTL) analysis, dual-luciferase reporter assay and electrophoresis mobility shift assay (EMSA) were conducted to examine the functional relevance of the identified SNPs. At last, differential gene expression analysis (DGEA) was performed. RESULTS: We identified an independent SNP rs12409479 at 1p21 (MAF = 0.07, p = 7.26 × 10-10), whose association was replicated by the analysis of TFM in the UKB sample (one-sided p = 3.39 × 10-3), and was cross-validated by the analyses of BMI (one-sided p = 0.03) and WHRadj (one-sided p = 0.04) in the GIANT study. Cis-eQTL analysis demonstrated that allele A at rs12409479 was positively associated with PTBP2 expression level in subcutaneous adipose tissue (N = 385, p = 4.15 × 10-3). Dual-luciferase reporter assay showed that the region repressed PTBP2 gene expression by downregulating PTBP2 promoter activity (p < 0.001), and allele A at rs12409479 induced higher luciferase activity than allele G did (p = 4.15 × 10-3). EMSA experiment implied that allele A was more capable of binding to unknown transcription factors than allele G. Lastly, DGEA showed that the level of PTBP2 expression was higher in individuals with obesity than in individuals without obesity (N = 20 and 11, p = 0.04 and 9.22 × 10-3), suggesting a regulatory role in obesity development. CONCLUSIONS: Taken together, we hypothesize a regulating path from rs12409479 to trunk fat mass development through its allelic specific regulation of PTBP2 gene expression, thus providing some novel insight into the genetic basis of abdominal obesity.

Pentraxin 3 deficiency protects from the metabolic inflammation associated to diet-induced obesity.

AIMS: Low-grade chronic inflammation characterizes obesity and metabolic syndrome. Here, we aim at investigating the impact of the acute-phase protein long pentraxin 3 (PTX3) on the immune-inflammatory response occurring during diet-induced obesity. METHODS AND RESULTS: PTX3 deficiency in mice fed a high-fat diet for 20 weeks protects from weight gain and adipose tissue deposition in visceral and subcutaneous depots. This effect is not related to changes in glucose homeostasis and lipid metabolism but is associated with an improved immune cell phenotype in the adipose tissue of Ptx3 deficient animals, which is characterized by M2-macrophages polarization and increased angiogenesis. These findings are recapitulated in humans where carriers of a PTX3 haplotype (PTX3 h2/h2 haplotype), resulting in lower PTX3 plasma levels, presented with a reduced prevalence of obesity and decreased abdominal adiposity compared with non-carriers. CONCLUSION: Our results support a critical role for PTX3 in the onset of obesity by promoting inflammation and limiting adipose tissue vascularization and delineate PTX3 targeting as a valuable strategy for the treatment of adipose tissue-associated inflammatory response.

The Combination of Whey Protein and Dietary Fiber Does Not Alter Low-Grade Inflammation or Adipose Tissue Gene Expression in Adults with Abdominal Obesity.

BACKGROUND: Abdominal obesity is characterized by low-grade inflammation and plays a central role in the development of type 2 diabetes and cardiovascular diseases. Dietary factors can influence low-grade inflammation and affect adipose tissue function. AIM: To investigate the separate and combined effects of whey protein and cereal fiber on inflammatory markers and adipose tissue gene expression in abdominal obesity. METHODS: We performed a 12-week, double-blind, randomized controlled dietary intervention in 65 adults with abdominal obesity. The participants were randomized to 4 groups using a 2 × 2 factorial design; they received either 60 g/day of whey protein or maltodextrin in combination with high-fiber wheat bran products (30 g fiber/day) or low-fiber refined wheat products (10 g fiber/day). Plasma concentrations of tumor necrosis factor α (TNF-α), high-sensitivity C-reactive protein (hs-CRP), monocyte chemoattractant protein-1 (MCP-1), interleukin 1 receptor antagonist (IL-1Ra), and adiponectin were measured before and after intervention. Changes in gene expression related to inflammation, insulin signaling, and lipid metabolism were measured in abdominal subcutaneous adipose tissue. RESULTS: After intervention, TNF-α was reduced for both high-fiber groups compared with baseline, but did not significantly differ from the low-fiber groups. There were no differences in fasting or postprandial inflammatory markers between the groups. The relative gene expression of ribosomal protein S6 kinase B1 (S6K1) was increased after whey protein compared with maltodextrin consumption. CONCLUSION: Intake of whey protein in combination with high cereal fiber content did not differentially affect low-grade inflammation or adipose tissue gene expression compared with maltodextrin and low fiber content in individuals with abdominal obesity.