Obesity In European Populations Research Articles

The Melanocortin 4 Receptor p.Ile269Asn Mutation Is Associated with Childhood and Adult Obesity in Mexicans.

Rare partial/complete loss-of-function mutations in the melanocortin-4 receptor (MC4R) gene are the most common cause of Mendelian obesity in European populations, but their contribution to obesity in the Mexican population is unclear. We investigated whether deleterious mutations in MC4R contribute to obesity in Mexican children and adults. We provide evidence that the MC4R p.Ile269Asn (rs79783591) mutation may have arisen in modern human populations from a founder event in native Mexicans. The MC4R Isoleucine 269 is perfectly conserved across 184 species, which suggests a critical role for the amino acid in MC4R activity. Four in silico tools (SIFT, PolyPhen-2, CADD, MutPred2) predicted a deleterious impact of the p.Ile269Asn substitution on MC4R function. The MC4R p.Ile269Asn mutation was associated with childhood (Ncontrols = 952, Ncases = 661, odds ratio (OR) = 3.06, 95% confidence interval (95%CI) [1.94-4.85]) and adult obesity (Ncontrols = 1445, Ncases = 2,487, OR = 2.58, 95%CI [1.52-4.39]). The frequency of the MC4R p.Ile269Asn mutation ranged from 0.52 to 0.59% and 1.53 to 1.59% in children and adults with normal weight and obesity, respectively. The MC4R p.Ile269Asn mutation co-segregated perfectly with obesity in 5 multigenerational Mexican pedigrees. While adults with obesity carrying the p.Ile269Asn mutation had higher BMI values than noncarriers, this trend was not observed in children. The MC4R p.Ile269Asn mutation accounted for a population attributable risk of 1.28% and 0.68% for childhood and adult obesity, respectively, in the Mexican population. The MC4R p.Ile269Asn mutation may have emerged as a founder mutation in native Mexicans and is associated with childhood and adult obesity in the modern Mexican population.

FTO gene polymorphisms and obesity risk in Chinese population: a meta-analysis.

There is tremendous increase in obesity worldwide. Many factors including diet, life style, genetic, and epigenetic changes contribute to obesity. The fat mass and obesity-associated (FTO) gene polymorphisms are strongly associated with obesity. It has been reported that FTO single-nucleotidepolymorphisms (SNPs) are associated with obesity in European populations; however, it was controversial in Chinese population. The present meta-analysis study was designed to investigate the association between FTO polymorphisms and obesity risk in Chinese population. The investigators searched studies using the following databases: PubMed, web of science, and Cochrane Central Register of Controlled Trials. A random-effects model was used to calculate the pooled odds ratios (ORs). The heterogeneity among the studies was measured by I2 value. Subgroup analysis was used to find out the potential factors influencing the heterogeneity. A total of 18 articles including 26 studies were included in the present meta-analysis. Overall, the FTO SNPs were significantly associated with obesity in Chinese population (OR 1.30; 95% CI 1.19-1.42; P < 0.001) under per-allele comparison. The subgroup analysis also showed strong association between four FTO SNPs (rs9939609, rs6499640, rs8050136, and rs1558902) and obesity risk. Furthermore, subgroup analysis stratified by children/adolescent and adult groups showed same trend. The present meta-analysis indicated that FTO SNPs are associated with obesity risk in both children/adolescents and adults in Chinese population.

Common variant of FTO gene, rs9939609, and obesity in Pakistani females.

Numerous studies confirmed the association of FTO (fat mass and obesity associated gene) common variant, rs9939609, with obesity in European populations. However, studies in Asian populations revealed conflicting results. We examined the association of rs9939609 variant of FTO gene with obesity and obesity-related anthropometric and metabolic parameters in Pakistani population. Body weight, height, waist circumference, hip circumference, and blood pressure (BP) were measured. BMI and waist-to-hip ratio (WHR) were calculated. Levels of fasting blood glucose (FBG), insulin, leptin, and leptin receptors were measured by enzyme linked immunosorbent assay (ELISA), and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. The results showed association of FTO gene, rs9939609, with obesity in females (>18 years of age). FTO minor allele increased the risk of obesity by 2.8 times (95% CI = 1.3–6.0) in females. This allele showed association with body weight, BMI, waist circumference, hip circumference, WHR, BP, plasma FBG levels, HOMA-IR, plasma insulin levels, and plasma leptin levels. In conclusion, FTO gene, rs9939609, is associated with BMI and risk of obesity in adult Pakistani females. Association of rs9939609 variant with higher FBG, plasma insulin, and leptin levels indicates that this polymorphism may disturb the metabolism in adult females and predispose them to obesity and type 2 diabetes. However, the above-mentioned findings were not seen in children or males.

PCSK1 rs6232 Is Associated with Childhood and Adult Class III Obesity in the Mexican Population

BackgroundCommon variants rs6232 and rs6235 in the PCSK1 gene have been associated with obesity in European populations. We aimed to evaluate the contribution of these variants to obesity and related traits in Mexican children and adults.Methodology/Principal FindingsRs6232 and rs6235 were genotyped in 2382 individuals, 1206 children and 1176 adults. Minor allele frequencies were 0.78% for rs6232 and 19.99% for rs6235. Rs6232 was significantly associated with childhood obesity and adult class III obesity (OR = 3.01 95%CI 1.64–5.53; P = 4×10−4 in the combined analysis). In addition, this SNP was significantly associated with lower fasting glucose levels (P = 0.01) and with increased insulin levels and HOMA-B (P = 0.05 and 0.01, respectively) only in non-obese children. In contrast, rs6235 showed no significant association with obesity or with glucose homeostasis parameters in any group.Conclusion/SignificanceAlthough rs6232 is rare in the Mexican population, it should be considered as an important risk factor for extreme forms of obesity.

Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.

Allelic clustering and ancestry-dependent frequencies of rs6232, rs6234, and rs6235 PCSK1 SNPs in a Northern Ontario population sample

The PCSK1 (proprotein convertase subtilisin/kexin type 1) locus encodes proprotein convertase 1/3, an endoprotease that converts prohormones and proneuropeptides to their active forms. Spontaneous loss-of-function mutations in the coding sequence of its gene have been linked to obesity in humans. Minor alleles of two common non-synonymous single-nucleotide polymorphisms (SNPs), rs6232 (T > C, N221D) and rs6235 (C > G, S690T), have been associated with increased risk of obesity in European populations. In this study, we compared the frequencies of the rs6232 and rs6234 (G > C, Q665E) SNPs in Aboriginal and Caucasian populations of Northern Ontario. The two SNPs were all relatively less frequent in Aboriginals: The minor allele frequency of the rs6232 SNP was 0.01 in Aboriginals and 0.08 in Caucasians (P < 4.10(-6)); for the rs6234 SNP, it was 0.20 and 0.32, respectively (P < 0.001). Resequencing revealed that the rs6234 SNP variation was tightly linked to that of the rs6235 SNP, as previously reported. Most interestingly, all carriers of the rs6232 SNP variation also carried the rs6234/rs6235 SNP clustered variations, but not the reverse, suggesting the former occurred later on an allele already carrying the latter. These data indicate that, in Northern Ontario Aboriginals, the triple-variant PCSK1 allele is relatively rare and might be of lesser significance for obesity risk in this population.

Meta‐analysis Added Power to Identify Variants in FTO Associated With Type 2 Diabetes and Obesity in the Asian Population

Several common variants in the intron 1 of FTO (fat mass and associated obesity) gene have been reliably associated with BMI and obesity in European populations. We analyzed two variants (rs9939609 and rs8050136) in 4,189 Chinese Han individuals and conducted a meta-analysis of published studies in Asian population to investigate whether these variants are associated with type 2 diabetes (T2D) and obesity in Asian population. In this study, both the minor allele A of rs9939609 and the minor allele A of rs805136 were associated with increased risk of T2D, independent of measures of BMI; the odds ratios (ORs) per copy of the risk allele were 1.19 for rs9939609 (95% confidence interval (CI), 1.04-1.37; P = 0.01) and 1.22 for rs8050136 (95% CI, 1.07-1.40; P = 0.004) after adjusting for age, sex, and BMI. Our results also showed association with risk of obesity (rs9939609: OR = 1.39 (95% CI 1.04-1.85), P = 0.02; rs8050136: OR = 1.45 (95% CI 1.09-1.93), P = 0.01) but no association with overweight. These results were consistent with the pooled results from our meta-analysis study (for diabetes, rs8050136, P = 1.3 x 10(-3); rs9939609, P = 9.8 x 10(-4); for obesity, rs8050136, P = 2.2 x 10(-7); rs9939609, P = 9.0 x 10(-9)). Our findings indicate that the two variants (rs9939609 and rs8050136) in the FTO gene contribute to obesity and T2D in the Asian populations.

Common PCSK1 Haplotypes Are Associated With Obesity in the Chinese Population

Prohormone convertase subtilisin/kexin type 1 (PCSK1) genetic polymorphisms have recently been associated with obesity in European populations. This study aimed to examine whether common PCSK1 genetic variation is associated with obesity and related metabolic phenotypes in the Chinese population. We genotyped nine common tag single-nucleotide polymorphisms (tagSNP) of the PCSK1 gene in 1,094 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study. One SNP in the PCSK1 gene (rs155971) were nominally associated with risk of obesity in the SAPPHIRe cohort (P = 0.01). A common protective haplotype was associated with reduced risk of obesity (23.79% vs. 32.89%, P = 0.01) and smaller waist circumference (81.71 +/- 10.22 vs. 84.75 +/- 10.48 cm, P = 0.02). Another common haplotype was significantly associated with increased risk of obesity (37.07% vs. 23.84%, P = 0.005). The global P value for haplotype association with obesity was 0.02. We also identified a suggestive association of another PCSK1 SNP (rs3811951) with fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA(IR)), triglycerides, and high-density lipoprotein cholesterol (P = 0.05, 0.003, 0.001, 0.04, and 0.04, respectively). These data indicate common PCSK1 genetic variants are associated with obesity in the Chinese population.

A genetic variation in the fat mass‐ and obesity‐associated gene is associated with obesity and newly diagnosed type 2 diabetes in a Chinese population

Recently, a genome-wide association study identified a strong association between the fat mass- and obesity-associated rs9939609 single nucleotide polymorphism (SNP) and the risk of obesity in European population. However, the results in Chinese population were reported to be contradictory. Therefore, our aim was to examine whether this SNP is associated with obesity and newly diagnosed type 2 diabetes (T2D) in Chinese population. We genotyped rs9939609 in 2587 subjects [obesity 243, overweight 976, normal weight 1368 or newly diagnosed T2D 877, impaired glucose regulation 305, normal glucose tolerance (NGT) 1405] using an allelic discrimination assay-by-design TaqMan method on ABI7900HT. We analysed associations of the rs9939609 SNP with obesity and newly diagnosed T2D through Logistic regression analysis. In obesity case-control study, we found that the A allele was strongly associated with obesity and overweight. The odds ratios for the allele A versus T were 1.447 for Obesity versus normal weight (95% CI 1.104-1.896, p = 0.007) and 1.363 for Overweight versus normal weight (95% CI 1.149-1.617, p < 0.0001). In T2D case-control study, the odds ratios for the allele A versus T were 1.305 for T2D versus NGT (95% CI 1.097-1.552, p = 0.003) and 1.280 for combined T2D and impaired glucose regulation (IGR) versus NGT (95% CI 1.089-1.503, p = 0.003). The associations of the A allele with T2D and combined T2D and IGR remained significant with adjustment for age, sex and body mass index (BMI). The fat mass- and obesity-associated gene rs9939609 SNP is strongly associated with risk of obesity and newly diagnosed T2D in the Chinese population.

Effects of TCF7L2 Polymorphisms on Obesity in European Populations

The transcription factor 7-like 2 (TCF7L2) rs7903146 T allele was previously associated with type 2 diabetes (T2D) and decreased BMI whereas haplotypes carrying the rs7903146 C and rs10885406 A alleles (HapA) were associated with increased BMI. The functional relevance of TCF7L2 polymorphisms and their effects on T2D and obesity remained to be further investigated. In white European populations, we found that the rs7903146 T allele was more associated with T2D in 3,547 non-obese individuals (odds ratio (OR) = 1.88 (1.69-2.10)) than in 1,110 class III obese subjects (OR = 1.24 (1.03-1.50)). No direct effect of the rs7903146 C allele and HapA was found on any form of obesity in 3,507 normal glucose tolerant (NGT) individuals, 1,106 pedigrees with familial obesity and 5,512 individuals from the French general population. However, in T2D subjects, the rs7903146 C allele was less prevalent in the 1,111 non-obese individuals (55.2%) compared to 659 class III obese subjects (67.5% OR = 1.69 (1.46-1.95)). Functional studies showed that the rs7903146 T allele is less prone to be bound by protein factors than the C allele in 3T3-L1, HepG2 and beta-TC3 cell lines and that TCF7L2 expression decreases in subcutaneous adipose tissue from NGT obese T/T carriers under calorie restriction. In conclusion, TCF7L2 is not a risk factor for obesity in European populations, but its effect on T2D risk is modulated by obesity. Furthermore, our data suggest that the rs7903146 T allele may be possibly functional and associated with a nominal decrease in TCF7L2 expression in adipose tissue of individuals under calorie restriction.