Rs9939609 Variant Research Articles

The rs2910164 variant is associated with reduced miR-146a expression but not cytokine levels in patients with type 2 diabetes.

Previous reports have demonstrated that genetic variations in microRNAs regulome could affect microRNAs-mediated regulation. Therefore, in the present study we were aimed at (1) comparison of microRNA 146-a (miR-146a) peripheral blood mononuclear cells (PBMCs) and plasma levels between diabetic patients and controls, and (2) investigating the possible association of rs2910164 with miR-146a and its related target genes expression and also serum cytokine levels. The study population consisted of 60 subjects including 30 type 2 diabetes (T2D) patients and 30 controls with determined genotypes for rs2910164. The RNA expression levels were determined by real-time PCR. Moreover, TNF-α, IL-6, IL-10 and IL-1β serum levels were measured using ELISA method. Our results showed that the miR-146a expression levels were significantly decreased in PBMCs (P=0.004) and plasma (P=0.008) samples of patients with T2D compared to healthy participants. In addition, we observed that IRAK1 mRNA expression-but not TLR4, TRAF6 and NFĸB-was significantly increased in patients with T2D compared to controls (P=0.028). The relative expression levels of miR-146a in plasma and PBMCs samples of diabetic patients with the rs2910164 GG genotypes were significantly higher than that in CC (P<0.05). Moreover, no significant differences were found in miR-146a targets and cytokine levels between the rs2910164 different genotypes. Our study demonstrated that miR-146a circulating levels were significantly elevated in controls compared with T2D patients. In addition, we identified that rs2910164-C allele is associated with reduced expression levels of the miR-146a but not its mRNAs targets and cytokine levels in diabetic patients.

Investigating the association of rs2910164 with cancer predisposition in an Irish cohort.

IntroductionMicroRNAs (miRNAs) are small noncoding RNA molecules that exert post-transcriptional effects on gene expression by binding with cis-regulatory regions in target messenger RNA (mRNA). Polymorphisms in genes encoding miRNAs or in miRNA–mRNA binding sites confer deleterious epigenetic effects on cancer risk. miR-146a has a role in inflammation and may have a role as a tumour suppressor. The polymorphism rs2910164 in the MIR146A gene encoding pre-miR-146a has been implicated in several inflammatory pathologies, including cancers of the breast and thyroid, although evidence for the associations has been conflicting in different populations. We aimed to further investigate the association of this variant with these two cancers in an Irish cohort.MethodsThe study group comprised patients with breast cancer (BC), patients with differentiated thyroid cancer (DTC) and unaffected controls. Germline DNA was extracted from blood or from saliva collected using the DNA Genotek Oragene 575 collection kit, using crystallisation precipitation, and genotyped using TaqMan-based PCR. Data were analysed using SPSS, v22.ResultsThe total study group included 1516 participants. This comprised 1386 Irish participants; 724 unaffected individuals (controls), 523 patients with breast cancer (BC), 136 patients with differentiated thyroid cancer (DTC) and three patients with dual primary breast and thyroid cancer. An additional cohort of 130 patients with DTC from the South of France was also genotyped for the variant. The variant was detected with a minor allele frequency (MAF) of 0.19 in controls, 0.22 in BC and 0.27 and 0.26 in DTC cases from Ireland and France, respectively. The variant was not significantly associated with BC (per allele odds ratio = 1.20 (0.98–1.46), P = 0.07), but was associated with DTC in Irish patients (per allele OR = 1.59 (1.18–2.14), P = 0.002).ConclusionThe rs2910164 variant in MIR146A is significantly associated with DTC, but is not significantly associated with BC in this cohort.

Increased habenular connectivity in opioid users is associated with an α5 subunit nicotinic receptor genetic variant.

Opioid use disorder (OUD) is a chronic disorder with relapse based on both desire for reinforcement (craving) and avoidance of withdrawal. The aversive aspect of dependence and relapse has been associated with a small brain structure called the habenula, which expresses large numbers of both opioid and nicotinic receptors. Additionally, opioid withdrawal symptoms can be induced in opioid-treated rodents by blocking not only opioid, but also nicotinic receptors. This receptor co-localization and cross-induction of withdrawal therefore might lead to genetic variation in the nicotinic receptor influencing development of human opioid dependence through its impact on the aversive components of opioid dependence. We studied habenular resting state functional connectivity with related brain structures, specifically the striatum. We compared abstinent psychiatric patients who use opioids (N = 51) to psychiatric patients who do not (N = 254) to identify an endophenotype of opioid use that focused on withdrawal avoidance and aversion rather than the more commonly examined craving aspects of relapse. We found that habenula-striatal connectivity was stronger in opioid-using patients. Increased habenula-striatum connectivity was observed in opioid-using patients with the low risk rs16969968 GG genotype, but not in patients carrying the high risk AG or AA genotypes. We propose that increased habenula-striatum functional connectivity may be modulated by the nicotinic receptor variant rs16969968 and may lead to increased opioid use. Our data uncovered a promising brain target for development of novel anti-addiction therapies and may help the development of personalized therapies against opioid abuse. (Am J Addict 2017;26:751-759).

Association analysis of FTO gene polymorphisms and obesity risk among Egyptian children and adolescents

Obesity is a common disorder that has a significant impact on human health as it may lead to many serious diseases and sometimes morbidity. Previous genome-wide association studies (GWAS) confirmed that there is a relationship between some variants in the first intron of the fat mass and obesity associated (FTO) gene and obesity in adults and children in different ethnic groups. In our study, the association of the FTO rs9939609 and rs17817449 variants with obesity was investigated in Egyptian children and adolescents. We examined rs9939609 and rs17817449 polymorphisms in 100 control and 100 obese cases, we used the restriction fragment length polymorphism (RFLP) technique to genotype the samples. The current study showed that there were no significant differences (P > 0.05) between the cases and controls in both variants of rs17817449 and rs9939609 polymorphisms.However, there were significant correlations between rs17817449 and cholesterol and between rs9939609 and LDL. In Current Study although the two variants (rs9939609 and rs17817449) didn't show an association with obesity, but there was a correlation between the lipid profile and these two variants.

The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing β-Cell Function and Hepatic Insulin Sensitivity

OBJECTIVEIn this study, we aimed to explore the mechanism by which TCF7L2 rs7903146 risk allele confers susceptibility to impaired glucose tolerance (IGT) or type 2 diabetes (T2D) in obese adolescents.RESEARCH DESIGN AND METHODSThe rs7903146 variant in the TCF7L2 gene was genotyped in a multiethnic cohort of 955 youths. All subjects underwent an oral glucose tolerance test with the use of the Oral Minimal Model to assess insulin secretion, and 33 subjects underwent a hyperinsulinemic-euglycemic clamp. In 307 subjects, a follow-up oral glucose tolerance test was repeated after 3.11 ± 2.36 years.RESULTSThe TCF7L2 rs7903146 risk allele was associated with higher 2-h glucose levels in Caucasians (P = 0.006) and African Americans (P = 0.009), and a trend was seen also in Hispanics (P = 0.072). Also, the T allele was associated with decreased β-cell responsivity and IGT (P < 0.05). Suppression of endogenous hepatic glucose production was lower in subjects with the risk variant (P = 0.006). Finally, the odds of showing IGT/T2D at follow-up were higher in subjects carrying the minor allele (odds ratio 2.224; 95% CI 1.370–3.612; P = 0.0012).CONCLUSIONSThe rs7903146 variant in the TCF7L2 gene increases the risk of IGT/T2D in obese adolescents by impairing β-cell function, and hepatic insulin sensitivity predicts the development of IGT/T2D over time.

FTO gene polymorphisms (rs9939609 and rs17817449) as predictors of Type 2 Diabetes Mellitus in obese Iraqi population

BackgroundThe variation of the SNPs in FTO (fat mass and obesity associated) gene are improved to be associated with obesity and type 2 diabetes (T2DM) in some ethnic groups for example in European while, this consistency is controversial in Asians and there were few studies in Iraqi population about the effect of this gene on the development of T2DM in obese patients. Therefore, the objective of this study is to investigate the impact of the two common FTO gene variants in the development of T2DM in obese Iraqi patients. MethodsA case-control study in which the FTO gene variants rs9939609 and rs17817449 were genotyping in a total of 800 individuals, 400 T2DM obese patients (patients group) and 400 healthy control obese volunteers (control group) to explore the relation of these SNPs with T2DM in obese Iraqi population. The patients group was enrolled from diabetic clinic in Al Najaf al Ashraf based on WHO guidelines of T2DM. From whole blood the DNA was extraction and genotyped by using ScaI and AlwNI enzymes respectively in the PCR–RFLP technique. Multinomial logistic regression was applied to compare the proportions of genotypes and alleles. The odd's ratio, t-test P value at 95% confidence interval were measured before and after adjustment of BMI, age and sex adjustment. The genetic power, Hardy Weinberg equilibrium and haplotype analysis were tested in the present study. ResultsIt was observed that the presence of T allele in the two SNPs rs9939609 and rs17817449 in the FTO gene polymorphisms was associated with increased risk for the development of T2DM in Iraqi obese individuals. The minor allele (T) in rs9939609 was significantly higher (P=0.0001) in T2DM (31.25%) when compared with that of the control obese group (20%). The Homozygous genotype (TT) significantly (OR=3.25, CI 95% 1.87–5.64, P=0.000) increased the risk of T2DM by three folds with respect to those of wild type (AA) after adjustment for age, sex and BMI, furthermore, it was significantly increased the risk in the dominant, recessive and additive models (P=0.000,0.000 and 0.0001 respectively). The T allele in rs17817449 was also significantly higher (P=0.0001) in patients group (36.25%) when compared with that of the control group (27.25%). The Heterozygous genotype (TG) significantly (OR=2.24, CI 95% 1.65–3.04, P=0.000) increased the risk of T2DM more than two folds with respect to those of wild type (GG) after adjustment for age, sex and BMI, and it was significantly increased the risk in the dominant models (P=0.000). In the relation to the phenotypic parameters the two SNPs were significantly associated with increased BMI, LDL, insulin and HOMA-IR and a decrease the HDL levels. ConclusionThe FTO gene polymorphisms rs9939609 and rs17817449 play a role in the in the development of insulin resistance and hence occurrence of type 2 DM in obese patients.

Correlation between adiponectin level with common variant (rs9939609) of fat mass and obesity-associated gene in obese type 2 diabetic women

Introduction: It is well-known that there is an association between rs9939609 polymorphism of fat mass and obesity-associated (FTO) gene with obesity in people from different ethnic background. Objectives: This study aimed to assess the association of common polymorphism on adiposity indexes and type 2 diabetic mellitus (T2DM) and its association with adiponectin level in Iranian women. Patients and Methods: A sample population of 83 obese patients was investigated in a study with case-control design. The patients’ age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood sugar (FBS), insulin, insulin resistance, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), glycated hemoglobin, triglycerides (TG) and adiponectin level were measured. The genotype of FTO rs9939609 was considered using specific primers via PCR and sequencing. Results: There was a significant difference between two groups (diabetic and non-diabetic) in terms of their age, FBS, HbA1c, LDL-C, SBP and DBP. The mean ± standard error (SE) of these parameters except for DBP and SBP were higher in diabetic group. The frequency of the TA genotype (48.27%) was higher in the diabetic group. The levels of FBS, HbA1c and insulin resistance index (HOMA-IR) were high in mutant group in comparison with wild group. There was no significant correlation between adiponectin level and anthropometric and metabolic parameters. However, in diabetic patients significant moderate positive correlation was found between HDL-C and adiponectin level (r = 0.473, P = 0.01). Conclusion: The association of rs9939609 FTO polymorphism was significant with FBS, HbA1c, TG, insulin, HOMA and adiponectin level in obese diabetic women who harbored the mutant A allele.

Genome-Wide Association Study of Heavy Smoking and Daily/Nondaily Smoking in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Genetic variants associated with nicotine dependence have previously been identified, primarily in European-ancestry populations. No genome-wide association studies (GWAS) have been reported for smoking behaviors in Hispanics/Latinos in the United States and Latin America, who are of mixed ancestry with European, African, and American Indigenous components. We examined genetic associations with smoking behaviors in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (N = 12 741 with smoking data, 5119 ever-smokers), using ~2.3 million genotyped variants imputed to the 1000 Genomes Project phase 3. Mixed logistic regression models accounted for population structure, sampling, relatedness, sex, and age. The known region of CHRNA5, which encodes the α5 cholinergic nicotinic receptor subunit, was associated with heavy smoking at genome-wide significance (p ≤ 5 × 10-8) in a comparison of 1929 ever-smokers reporting cigarettes per day (CPD) > 10 versus 3156 reporting CPD ≤ 10. The functional variant rs16969968 in CHRNA5 had a p value of 2.20 × 10-7 and odds ratio (OR) of 1.32 for the minor allele (A); its minor allele frequency was 0.22 overall and similar across Hispanic/Latino background groups (Central American = 0.17; South American = 0.19; Mexican = 0.18; Puerto Rican = 0.22; Cuban = 0.29; Dominican = 0.19). CHRNA4 on chromosome 20 attained p < 10-4, supporting prior findings in non-Hispanics. For nondaily smoking, which is prevalent in Hispanic/Latino smokers, compared to daily smoking, loci on chromosomes 2 and 4 achieved genome-wide significance; replication attempts were limited by small Hispanic/Latino sample sizes. Associations of nicotinic receptor gene variants with smoking, first reported in non-Hispanic European-ancestry populations, generalized to Hispanics/Latinos despite different patterns of smoking behavior. We conducted the first large-scale genome-wide association study (GWAS) of smoking behavior in a US Hispanic/Latino cohort, and the first GWAS of daily/nondaily smoking in any population. Results show that the region of the nicotinic receptor subunit gene CHRNA5, which in non-Hispanic European-ancestry smokers has been associated with heavy smoking as well as cessation and treatment efficacy, is also significantly associated with heavy smoking in this Hispanic/Latino cohort. The results are an important addition to understanding the impact of genetic variants in understudied Hispanic/Latino smokers.

Correlation of Resistin Serum Level with Fat Mass and Obesity-Associated Gene (FTO) rs9939609 Polymorphism in Obese Women with Type 2 Diabetes

AimsThe aim of this study was to detect any association of fat mass and obesity-associated (FTO) rs9939609 variant to metabolic and anthropometric parameters and resistin level as adipokines in Iranian obese women with type 2 diabetes mellitus. Material and MethodsTotally, 42 diabetic and 36 non-diabetic women were selected. The PCR amplicons of FTO gene were sequenced and metabolic, anthropometric parameters and resistin level were measured. ResultsSerum resistin concentrations were not different between diabetic and non-diabetic subjects (p>0.05), while resistin level in diabetic group with AA genotype was lower than that with other genotypes in the same group. In rs9939609 SNP adjusted analysis, insulin and HOMA levels were high in AA genotype. While levels of FBS and HbA1c were higher in AA and AT genotypes. In diabetic group, only TG showed significant difference among three genotypes and mean of TG was higher in TA genotype. No significant correlation between resistin and anthropometric and metabolic parameters was found except for DBP in diabetic patients. ConclusionThere was no significant association between rs9939609 and resistin serum level in type 2 obese diabetic women while percentile ranges (25th, 50th and 75th) of resistin concentrations was high in diabetic group.

Melatonin Receptor 1B Gene Polymorphisms, Haplotypes and Susceptibility to Schizophrenia

Abstract Melatonin has an important role in the regulation of human sleep circadian rhythms. Sleep disturbances commonly exist in schizophrenia (SCZ) patients. To begin its performance, melatonin must interact to its receptor. In the present study, Single Nucleotide Polymorphisms (SNPs) of melatonin receptor gene 1 B (MTN1B) with SCZ development in Iranian population were investigated. The current case-control study was performed on 92 SCZ patients and 92 healthy control (HC) subjects. NESTED-PCR and ARMS-PCR modified methods (combination) and ARMSPCR method were used on the genotype. The impact of MTN1B rs3781637 (T/C) and rs10830963(C/G) polymorphism variants on the risk SCZ in the sample of Iranian population was investigated. The findings showed significant association between MTN1B rs10830963(C/G) variant and SCZ (OR=2.78, 95%CI=1.25-6.25, P=0.012, GG vs. CC, OR=1.66, 95%CI=1.09-2.51, P=0.021 G vs. C, OR=3.85 95%CI=.89-8.33, P&lt;0.0001, GG vs. CC+CG). There was no association between MTN1B rs3781637 (T/C) and SCZ risk. In addition, haplotype analysis revealed that TG and CC haplotype of rs3781637 (T/C) and rs10830963 (C/G) polymorphisms were associated with SCZ risk (P=0.039) and protective (P&lt;0.0001) effects, respectively. The findings revealed that MTN1B rs10830963 (C/G) polymorphism was associated with the risk of SCZ; while another SNP rs3781637 (T/C) MTN1B gene did not show any risk/protection association with SCZ. Further studies with larger sample sizes and different ethnicities are required to approve the results.

Association study of the FTO gene polymorphisms with the risk of pulmonary tuberculosis in a sample of Iranian population.

The aim of the present study was to find out the impact of fat mass and obesity-associated (FTO) gene on risk of pulmonary tuberculosis (PTB) in a sample of Iranian population. This case-control study was carried out on a total of 354 subjects including 185 PTB patients and 169 healthy subjects. Genotyping of FTO rs9939609 and rs8050136 variants was done using polymerase chain reaction-restriction fragment length polymorphism method. FTO rs9939609 variant showed no statistically significant difference in allele and genotype frequencies between PTB patients and controls. The rs8050136 polymorphism marginally increased the risk of PTB in dominant (OR = 1.53, 95% CI = 1.00-2.33, p = 0.055, CA+AA vs. CC) inheritance model tested, where rs8050136 A allele significantly increased the risk of PTB (OR = 1.42, 95% CI = 1.02-1.97, p = 0.045) compared with C allele. The finding of the present study showed an association between FTO rs9939609 variant and risk of PTB. Further studies with larger sample sizes and different ethnicities are necessary to confirm the findings.

Is FTO gene variant related to cancer risk independently of adiposity? An updated meta-analysis of 129,467 cases and 290,633 controls.

Previous studies have examined the association between the fat mass and obesity-associated (FTO) gene variant and risk of cancer in diverse populations. However, the results have been inconsistent. PubMed and Embase databases were searched for the eligible publications in English language by July, 2016. The associations of FTO variants with cancer risk were estimated by calculating the pooled odds ratios and 95% confidence intervals by meta-analyses. A total of 27 publications (129,467 cancer cases and 290,633 normal controls) were included in our meta-analysis. Overall, FTO rs9939609 variant (or its proxy) was not associated with cancer risk without adjustment for body mass index, as well as additional adjustment for body mss index. However, FTO rs9939609 variant was associated with some types of cancer in the subgroup analysis. In addition, overall, there was no significant association between FTO rs1477196 variant and cancer risk regardless of adjustment for body mass index. However, FTO rs11075995 variant risk allele was associated with breast cancer risk without adjustment for body mass index, but the association disappeared with further adjustment for body mass index. This study overall does not support that the FTO variant is associated with cancer risk independently of the adiposity.

Fat mass and obesity associated (FTO) gene influences skeletal muscle phenotypes in non-resistance trained males and elite rugby playing position

BackgroundFTO gene variants have been associated with obesity phenotypes in sedentary and obese populations, but rarely with skeletal muscle and elite athlete phenotypes.MethodsIn 1089 participants, comprising 530 elite rugby athletes and 559 non-athletes, DNA was collected and genotyped for the FTO rs9939609 variant using real-time PCR. In a subgroup of non-resistance trained individuals (NT; n = 120), we also assessed structural and functional skeletal muscle phenotypes using dual energy x-ray absorptiometry, ultrasound and isokinetic dynamometry. In a subgroup of rugby athletes (n = 77), we assessed muscle power during a countermovement jump.ResultsIn NT, TT genotype and T allele carriers had greater total body (4.8% and 4.1%) and total appendicular lean mass (LM; 3.0% and 2.1%) compared to AA genotype, with greater arm LM (0.8%) in T allele carriers and leg LM (2.1%) for TT, compared to AA genotype. Furthermore, the T allele was more common (94%) in selected elite rugby union athletes (back three and centre players) who are most reliant on LM rather than total body mass for success, compared to other rugby athletes (82%; P = 0.01, OR = 3.34) and controls (84%; P = 0.03, OR = 2.88). Accordingly, these athletes had greater peak power relative to body mass than other rugby athletes (14%; P = 2 x 10-6).ConclusionCollectively, these results suggest that the T allele is associated with increased LM and elite athletic success. This has implications for athletic populations, as well as conditions characterised by low LM such as sarcopenia and cachexia.

Physical Activity and Sedentary Behaviors Modify the Association between Melanocortin 4 Receptor Gene Variant and Obesity in Chinese Children and Adolescents.

Effects of MC4R variants in previous Chinese population studies were inconsistent. Gene-environment interactions might influence the effect of MC4R variants on obesity, which was still unclear. We performed the study to clarify the association of variants near MC4R gene with obesity-related phenotypes and gene-environment interactions in Chinese children and adolescents. Two common variants (rs12970134 and rs17782313) near MC4R were genotyped in 2179 children and adolescents aged 7–18 years in Beijing of China. Associations between the variants and obesity-related phenotypes together with gene-environment interactions were analyzed. The A-alleles of rs12970134 were nominally associated with risk of overweight/obesity (Odds Ratios (OR) = 1.21, 95%CI: 1.03–1.44, P = 0.025) and BMI (β = 0.33 kg/m2, 95%CI: 0.02–0.63, P = 0.025), respectively. The rs12970134 was also associated with HDL-C (β = -0.03mmol/L per A-allele, 95%CI: -0.05, -0.01, P = 0.013) independent of BMI. In the further analysis, we found the significant interaction of rs12970134 and physical activity/sedentary behaviors on BMI (Pinteraction = 0.043). The rs12970134 was found to be associated with BMI only in children with physical activity<1h/d and sedentary behaviors ≥2h/d (BMI: β = 1.27 kg/m2, 95%CI: 0.10–2.45, P = 0.034). The association was not detected in their counterparts with physical activity≥1h/d or sedentary behaviors <2h/d. We identified the effect of MC4R rs12970134 on overweight/obesity and BMI, and we also found physical activity and sedentary behaviors modified the association between the rs12970134 and BMI in Chinese children and adolescents.

SNP rs16969968 as a Strong Predictor of Nicotine Dependence and Lung Cancer Risk in a North Indian Population

Background:The 15q24-25 loci contain genes (CHRNA5 and CHRNA3) encoding nicotinic acetylcholine receptor subunits. We here determined for the first time the association of genetic variants rs16969968 and rs3743074 in CHRNA5 and CHRNA3, respectively, on nicotine dependence and lung cancer risk in a North Indian population by a case-control approach.Methods:Venous blood samples were obtained from 324 participants (108 lung cancer patients and 216 healthy individuals). DNA was extracted and PCR amplified with primers flanking the SNPs rs16969968 and rs3743074. Amplicons were subjected to sequencing and logistic regression was used to analyze association between variables.Results:The risk variant SNP rs16969968 in both heterozygous and homozygous forms appeared to exert a significant effect on nicotine dependence [GA (OR=2.77) and AA (OR=2.53)]. As expected, smoking was strongly associated with lung cancer (OR= 2.62). Risk allele rs16969968 in CHRNA5 also showed a significant association with increased lung cancer risk in our cohort, alone (OR= 4.99) and with smoking as a co-variable (OR= 4.28). Comparison of our analysis with other populations suggested that individuals with rs16969968 risk allele in the Indian population are more susceptible to lung cancer.Conclusion:Overall, the results strongly indicated that, in our cohort North Indian population, the genetic variant rs16969968, but not rs3743074, is significantly associated with both nicotine dependence and increased risk of lung cancer. While the results are significant, there is further need to increase the sample size and improve precision of our risk prediction.

Distinct Penetrance of Obesity-Associated Susceptibility Alleles in the Hungarian General and Roma Populations

Aims: The aim of our study was to explore differences in genetic predisposition to obesity between the Hungarian general and Roma populations. Methods: A total of 1,152 samples from the Hungarian Roma population and 1,743 samples from the Hungarian general population were genotyped for 20 single nucleotide polymorphisms (SNPs) associated with the risk of obesity. Two types of multilocus genetic risk scores were constructed to estimate the combined effect of selected SNPs. Results: Risk allele frequencies differed significantly between the two populations for 11 SNPs, with no enrichment in any of the two study groups. Variants (rs1558902, rs1121980, rs9939609, and rs9941349) in the fat mass and obesity-associated (FTO) gene exhibited strong but ethnicity-independent association with obesity. Genetic risk scores showed stronger associations with obesity in the Roma population compared with the Hungarian general population; however, without significant gene-population interaction. Conclusion: Differences in obesity prevalence between the Hungarian general and Hungarian Roma populations could not be explained by their distinct genetic susceptibility, rather by ethnicity-related environmental and behavioral factors. Nonetheless, particular gene-environment interactions might contribute to the distinct penetrance of the obesity-associated genetic factors in populations of different ethnic backgrounds.

Glucose tolerance and free fatty acid metabolism in adults with variations in TCF7L2 rs7903146

ObjectiveTCF7L2 variant rs7903146 is associated with increased risk for type 2 diabetes. We investigated the effect of TCF7L2 variant rs7903146 and glucose tolerance on free fatty acid (FFA) metabolism. Research Design and MethodsWe recruited 120 individuals, half homozygous for the major CC allele and half homozygous for the minor TT allele at rs7903146; each underwent a 2-h, 75g oral glucose tolerance test (OGTT). Plasma glucose, insulin and free fatty acid concentrations were measured on blood collected before and during the OGTT. ResultsTotal FFA concentrations and percent FA species during OGTT were not different in CC and TT carriers when males and females were considered together. However, monounsaturated fatty acid (MUFA) concentrations and percentages were greater in TT than CC females during the OGTT. TT carriers with high HOMA-IR had significantly greater fasting FFA concentrations, lower disposition index (DI) and greater AUC of glucose than high HOMA-IR CC carriers, whereas no such differences were observed in the low HOMA-IR group. We found that fasting (826±25 vs. 634±22μmol/L, P<0.0001) and OGTT plasma FFA concentrations were greater in IGT than NGT subjects, and the difference remained after adjusting for sex, age, BMI, and genotype. Finally, IGT subjects had greater MUFA concentrations and percentages than NGT subjects during OGTT. ConclusionsDespite similar fasting insulin and glucose, fasting plasma FFA are greater in IGT than NGT adults. Insulin resistance and sex influence plasma FFA responses amongst carriers of the minor T allele of TCF7L2 rs7903146.

Association study between near-MC4R variants and obesity-related variables in Portuguese young adults

The aim of this study was to investigate in a population sample of Portuguese young adults i) the association of near-MC4R variants with obesity measures; and ii) the presence of mutations in MC4R coding region contributing to severe obesity. Polymorphisms rs17782313, rs12970134 and rs9944545 were genotyped in 544 subjects (225 males, 319 females; mean age 20.7years) by TaqMan assay. Body Mass Index (BMI) was calculated (kg/m2) and percentage of body fat (%FAT) was measured using bioimpedance analysis. The coding region of MC4R gene was examined in nine severe obese subjects (BMI>35kg/m2) by Sanger sequencing. Linear regression showed no associations between variants rs17782313, rs12970134 and rs9944545 and BMI (P=0.459, P=0.691 and P=0.611, respectively) or %FAT (P=0.853, P=0.678 and P=0.434, respectively). The logistic regression, in the additive model, revealed no statistically significant interactions with overweight/obesity for any SNP (P=0.717, P=0.771 and P=0.417, respectively). Also, haplotype analysis revealed no significant associations testing for BMI, %FAT or the obesity status. Genomic DNA sequencing of the MC4R coding region revealed no variations explaining the severely obese phenotype. As main conclusion, this study in young Portuguese adults does not replicate previous findings evidencing the association of near-MC4R polymorphisms with human obesity. Nevertheless, the obtained data is in accordance with several studies reporting no such associations.

A Common Variant and the Transcript Levels of MC4R Gene Are Associated With Adiposity in Children: The IDEFICS Study.

The melanocortin-4 receptor gene (MC4R) plays a pivotal role in the regulation of body fat and food and energy intake. The objectives of the study were as follows: 1) to evaluate the association of variants rs17782313 and rs17700633 near the coding region of MC4R and 2) to evaluate the association of the transcript levels of MC4R with adiposity indices and percentage of energy from fat, carbohydrates, and protein in children. The Identification and Prevention of Dietary- and Lifestyle-Induced Health Effects in Children and Infants (IDEFICS) cohort was used, with examinations at baseline (T0) and after 2 years (T1). A total of 16 228 schoolchildren (2-9 y) from eight European countries participated in the study. A random sample of 4381 children genotyped for MC4R variants and a subsample of 410 children with MC4R expression data in peripheral blood cells (PBCs) were included in the analyses. Anthropometric measures and energy intake (total and from fat, carbohydrates, and protein) served as outcomes for adiposity status and for dietary behavior, respectively. At T0, the C allele of rs17782313 (minor frequency allele 23%) was significantly associated with higher values of adiposity indices (all P < .001). No association was found between rs17700633 (minor frequency allele 28%) and the variables under study. At T1, the C allele of rs17782313 was associated with a significantly higher increase in the adiposity indices over time (all P < .05). The MC4R expression levels in PBCs were inversely associated with body fat and energy intake from carbohydrates and directly with energy from fat (all P ≤ .05) but were not influenced by variants rs17782313 and rs17700633. The common variant rs17782313 near MC4R was cross-sectionally and longitudinally associated with body mass index and measures of body fatness in children aged 2-9 years. We showed, for the first time in humans, that MC4R expression levels in PBCs are related to body fat distribution and percentage of energy intake from carbohydrates and fat.

Association of a common rs9939609 variant in the fat mass and obesity-associated (FTO) gene with obesity and metabolic phenotypes in a Taiwanese population: a replication study.

It is a key challenge to conduct reproducibility in genetic research, especially association studies in obesity. While susceptibility of a single-nucleotide polymorphism (SNP), rs9939609, in the fat mass and obesity-associated (FTO) gene to obesity has been reported in various populations, data from Asians is less conclusive. This replication study was carried out to test whether the FTO rs9939609 SNP is a predictive factor for obesity and obesity-related metabolic traits in a Taiwanese population. A total of 1188 Taiwanese subjects were recruited for this study. The FTO rs9939609 SNP was genotyped by the Taqman assay. Obesity-related metabolic traits such as triglyceride, waist circumference, systolic and diastolic blood pressure, total cholesterol, creatinine, alanine aminotransferase and fasting glucose were measured. Our data revealed that the FTO rs9939609 SNP exhibited a significant association with obesity (BMI ≥ 30 kg/m²) among the subjects (P = 0.026). However, the FTO rs9939609 SNP did not exhibit any significant association with obesity-related metabolic traits among the subjects. Our results indicated that the FTO rs9939609 SNP may be linked with the risk of obesity in Taiwanese subjects.