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Background: Individual differences in susceptibility to developing asthma, a heterogeneous chronic inflammatory lung disease, are poorly understood. Whether genetics can predict asthma risk and how genetic variants modulate the complex pathophysiology of asthma are still debated., Aim: To build polygenic risk scores for asthma risk prediction and epigenomically link predictive genetic variants to pathophysiological mechanisms., Methods: Restricted polygenic risk scores were constructed using single nucleotide variants derived from genome-wide association studies and validated using data generated in the Rotterdam Study, a Dutch prospective cohort of 14 926 individuals. Outcomes used were asthma, childhood-onset asthma, adulthood-onset asthma, eosinophilic asthma and asthma exacerbations. Genome-wide chromatin analysis data from 19 disease-relevant cell types were used for epigenomic polygenic risk score partitioning., Results: The polygenic risk scores obtained predicted asthma and related outcomes, with the strongest associations observed for childhood-onset asthma (2.55 odds ratios per polygenic risk score standard deviation, area under the curve of 0.760). Polygenic risk scores allowed for the classification of individuals into high-risk and low-risk groups. Polygenic risk score partitioning using epigenomic profiles identified five clusters of variants within putative gene regulatory regions linked to specific asthma-relevant cells, genes and biological pathways., Conclusions: Polygenic risk scores were associated with asthma(-related traits) in a Dutch prospective cohort, with substantially higher predictive power observed for childhood-onset than adult-onset asthma. Importantly, polygenic risk score variants could be epigenomically partitioned into clusters of regulatory variants with different pathophysiological association patterns and effect estimates, which likely represent distinct genetically driven disease pathways. Our findings have potential implications for personalised risk mitigation and treatment strategies., Competing Interests: Conflict of interest: G. Brusselle has received fees for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Sanofi Regeneron; and honoraria for participating on advisory boards from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck Sharp & Dohme, Novartis and Sanofi Regeneron. The remaining authors declare no conflicts of interest., (Copyright ©The authors 2024.)

Metabolic syndrome (MetS) is one of the most important risk factors for cardiovascular disease. The 11p23.3 chromosomal region plays a potential role in the pathogenesis of MetS. The present study aimed to assess the association between 18 single nucleotide polymorphisms (SNPs) located at the BUD13, ZPR1, and APOA5 genes with MetS in the Tehran Cardio-metabolic Genetics Study (TCGS). In 5421 MetS affected and non-affected participants, we analyzed the data using two models. The first model (MetS model) examined SNPs' association with MetS. The second model (HTg-MetS Model) examined the association of SNPs with MetS affection participants who had a high plasma triglyceride (TG). The four-gamete rules were used to make SNP sets from correlated nearby SNPs. The kernel machine regression models and single SNP regression evaluated the association between SNP sets and MetS. The kernel machine results showed two sets over three sets of correlated SNPs have a significant joint effect on both models (p < 0.0001). Also, single SNP regression results showed that the odds ratios (ORs) for both models are almost similar; however, the p-values had slightly higher significance levels in the HTg-MetS model. The strongest ORs in the HTg-MetS model belonged to the G allele in rs2266788 (MetS: OR = 1.3, p = 3.6 × 10 -7 ; HTg-MetS: OR = 1.4, p = 2.3 × 10 -11 ) and the T allele in rs651821 (MetS: OR = 1.3, p = 2.8 × 10 -7 ; HTg-MetS: OR = 1.4, p = 3.6 × 10 -11 ). In the present study, the kernel machine regression models could help assess the association between the BUD13, ZPR1, and APOA5 gene variants (11p23.3 region) with lipid-related traits in MetS and MetS affected with high TG.

Background: Morbid obesity could last for a long period of life and increase the risk of morbidity as well as premature mortality. Although bariatric surgery benefits patients by quick weight loss, not all bariatric patients lose the same percentage of weight after a long time from surgery, which may be the result of diet, physical activity, and genetic components., Objectives: In this study, we evaluated the association between the MC4R gene and both excess weight loss percentage (EWL%) and excess BMI loss percentage (EBMIL%) in a cohort of bariatric surgery patients after 6 and 12 months from surgery., Methods: A total of 424 bariatric surgery patients who had participated in the Tehran Obesity Treatment Study and had weight measurements after 6 and 12 months from surgery were included in the study. Four SNPs in the MC4R gene were selected for evaluating the associations., Results: We found that rs17773430 had a significant effect on both EWL% and EBMIL%, especially after 12 months of bariatric surgery. Furthermore, three other SNPs, rs17782313, rs476828, and rs11152213, did not show any significant association with EWL% and EBMIL%., Conclusion: This study was the first to report on the association of rs17773430 with both EWL% and EBMIL% in a cohort of patients after bariatric surgery. We found that weight loss after surgery is influenced by genetic factors, and there were significant differences between the distribution of EWL% and EBMIL% in morbid obese bariatric patients who have two minor alleles of the rs17773430 and other SNPs.

Background: Obesity is currently an international epidemic and metabolic derangements pose these individuals at greater risk for future morbidity and mortality. Genetics and environmental factors have undeniable effects and among genetic risk factors, FTO/CETP genes are important. The current study examines the interaction between obesity phenotypes and FTO/CETP SNPs and their effects on lipid profile changes., Materials and Methods: We selected 954 adult subjects from TCGS (47.9% male). Participants were stratified according to their BMI and presence of metabolic syndrome according to the Joint Interim Statement (JIS) definition. Nine selected polymorphisms from FTO/CETP genes were genotyped using Tetra ARMS-PCR method. After age and sex adjustment the interaction of 9 markers with lipid profiles among phenotypes were tested by PASW., Results: In three main groups, HDL&#95;C level had a strong significant association with CETP markers: (rs3764261, β(95% CI) - 0.48(- 0.61 to - 0.35), P = 1.0 × 10 -11 ), (rs1800775, β(95% CI) 0.5(0.36;0.65), P = 1.0 × 10 -6 ) and (rs1864163, β(95% CI) 0.3(0.16;0.43), P = 9.1 × 10 -5 ). This association was also seen in rs7202116 within the total population. In only unhealthy metabolic obese (MUHO) subgroups four new FTO markers (rs1421085, rs1121980, rs1558902 and rs8050136) (P value < 0.01) demonstrated significant association, even after lipid profile adjustment., Conclusion: In the present study, we investigated the association between obesity phenotypes and some variations in FTO/CETP genes for the first time. Our study showed that four markers in the first intron of the FTO gene should be the risk marker in MUHO participants., Level of Evidence: Level III, case-control study.

Background and Aims: The results of studies on the effect of trans-fatty acids (TFAs) and added sugars on obesity are not consistent. This study aimed to investigate whether the association of changes in general and central obesity with added sugar and TFA intakes is modified by common fat mass and obesity-associated gene (FTO) polymorphisms, in isolation or in a combined-form genetic risk score (GRS)., Methods and Results: Subjects of this cohort study were selected from among adult participants of the Tehran Lipid and Glucose Study (n = 4292, 43.2% male). Dietary data were collected using a valid and reliable food frequency questionnaire. The genotypes of selected polymorphisms (rs1421085, rs1121980, and rs8050136) were determined. Genetic risk score (GRS) was calculated using the dominant weighted method. The mean age of participants was 42.6 ± 14 and 40.4 ± 13 years in men and women, respectively. FTO rs8050136 polymorphisms and TFAs have a significant interaction in changing body mass index (BMI) (P interaction = 0.01). There were no changes in waist circumference (WC) and BMI among FTO risk allele carriers, across quartiles of added sugar intake. GRS and TFA intakes significantly interacted in altering the BMI and WC; thus, a higher intake of TFAs was associated with higher changes of BMI and WC in subjects with high GRS (P trend<0.05) compared to individuals with low GRS., Conclusion: Our findings suggest that TFA intake can increase the genetic susceptibility of FTO SNPs to BMI or WC change., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

The relationship of CCND2 gene variation, rs11063069 with metabolic syndrome (MetS) modulates by dietary factors but enough data are not available on this issue. So, the hypothesis, which assumes that dietary factors modulate the relationship of CCND2 polymorphisms with the risk of MetS was investigated in our study. Subjects of this nested case-control study were selected from participants of the Tehran Lipid and Glucose Study. Each case (n=974) was pair-matched individually with a control by age, sex and the follow-up duration. Dietary patterns were determined using factor analysis. CCND2 rs11063069 was genotyped by the ARMS-polymerase chain reaction analysis. Two dietary patterns were extracted: the healthy dietary pattern (HDP) and the Western dietary pattern; among G allele carriers, being in the highest quartiles of HDP score decreased risk of MetS (OR, Q1:3.01 [1.95-6.15], Q4:0.88 [0.39-1.78], P trend=.001), compared with those in the lowest quartile. In addition, the consumption of some vegetables, red-yellow vegetable (tomatoes, squash and carrots) and fruits by G allele carriers could decrease the risk of high fasting plasma glucose (P interaction=.003), low HDL-C (P interaction=.03) and high blood pressure (P interaction=.01) respectively. No significant interaction was observed in this study between nutrients (macronutrients, zinc, magnesium and iron) and CCND2 rs11063069 in relation to MetS or its components in this study. Our findings showed that by promoting adherence to HDP and increasing intake of some vegetables and fruits, the risk of MetS or its components reduced in G allele carriers; these associations were not observed in the AA genotype group., (Copyright © 2017. Published by Elsevier Inc.)

Controversies surrounding the effectiveness of fiber intake for prevention of obesity can be attributed to differences in the genetic makeup of individuals. This study aims to examining the interaction between dietary fiber intake and common fat mass and obesity-associated (FTO) single-nucleotide polymorphisms (SNPs), in relation to obesity. Subjects of this nested case-control study were selected from among adult participants of the Tehran Lipid and Glucose Study. Cases (n = 627) were individually matched with controls, who had normal weight. Six selected SNPs (rs1421085, rs1121980, rs17817449, rs8050136, rs9939973, and rs3751812) were genotyped by tetra-refractory mutation system-polymerase chain reaction analysis. Genetic risk scores (GRS) were calculated using the weighted method. A significant interaction was observed between total fiber intake and the GRS in relation to obesity (Pinteraction = 0.01); the difference in the risk for obesity was more pronounced in individuals with GRS ≥ 6 who consumed ≥ 14 grams of fiber a day (OR: 2.74, CI: 2.40-3.35 vs Ref.; P trend = 0.0005) than in individuals with GRS < 6 (P trend = 0.34). Dietary fiber intakes modified the association of FTO SNPs and the GRS with general obesity, an effect which was more pronounced in those who consumed high levels of dietary fiber and had a high number of risk alleles.

There is increasing interest of which dietary patterns can modify the association of fat mass and obesity associated (FTO) variants with obesity. This study was aimed at investigating the interaction of the Mediterranean dietary pattern (Med Diet) with FTO polymorphisms in relation to obesity phenotypes. Subjects of this nested case-control study were selected from the Tehran Lipid and Glucose Study participants. Each case was individually matched with a normal weight control ( n = 1254). Selected polymorphisms (rs1421085, rs1121980, rs17817449, rs8050136, rs9939973, and rs3751812) were genotyped. Genetic risk score (GRS) were calculated using the weighted method. The Mediterranean dietary score (MDS) was computed. Individuals with minor allele carriers of rs9939973, rs8050136, rs1781749, and rs3751812 had lower risk of obesity when they had higher MDS, compared to wild-type homozygote genotype carriers. The obesity risk was decreased across quartiles of MDS in participants with high GRS (OR: 1, 0.8, 0.79, 0.67) compared to individuals with low GRS (OR: 1.33, 1.06, 0.97, 1.12) (Pinteraction < 0.05). No significant interaction between the GRS and MDS on abdominal obesity was found. A higher Med Diet adherence was associated with lower obesity risk in subjects with more genetic predisposition to obesity, compared to those with lower adherence to the Med Diet and lower GRS., Competing Interests: The authors declare no conflict of interest.