Florianne Bauer

Obesity genes identified in genome-wide association studies are associated with adiposity measures and potentially with nutrient-specific food preference

BACKGROUND New genetic loci, most of which are expressed in the brain, have recently been reported to contribute to the development of obesity. The brain, especially the hypothalamus, is strongly involved in regulating weight and food intake. OBJECTIVES We investigated whether the recently reported obesity loci are associated with measures of abdominal adiposity and whether these variants affect dietary energy or macronutrient intake. DESIGN We studied 1700 female Dutch participants in the European Prospective Investigation into Cancer and Nutrition (EPIC). Their anthropometric measurements and intake of macronutrients were available. Genotyping was performed by using KASPar chemistry. A linear regression model, with an assumption of an additive effect, was used to analyze the association between genotypes of 12 single nucleotide polymorphisms (SNPs) and adiposity measures and dietary intake. RESULTS Seven SNPs were associated (P < 0.05) with weight, body mass index (BMI), and waist circumference (unadjusted for BMI). They were in or near to 6 loci: FTO, MC4R, KCTD15, MTCH2, NEGR1, and BDNF. Five SNPs were associated with dietary intake (P < 0.05) and were in or near 5 loci: SH2B1 (particularly with increased fat), KCTD15 (particularly with carbohydrate intake), MTCH2, NEGR1, and BDNF. CONCLUSIONS We confirmed some of the findings for the newly identified obesity loci that are associated with general adiposity in a healthy Dutch female population. Our results suggest that these loci are not specifically associated with abdominal adiposity but more generally with obesity. We also found that some of the SNPs were associated with macronutrient-specific food intake.

Common Variants in the Type 2 Diabetes KCNQ1 Gene Are Associated with Impairments in Insulin Secretion During Hyperglycaemic Glucose Clamp

Background Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients. Methodology The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp. Principal Findings We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07–1.35, p = 0.002). The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications. Conclusions Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism.

Gene-centric meta-analyses for central adiposity traits in up to 57,412 individuals of European descent confirm known loci and reveal several novel associations

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBIs Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.

Are recently identified genetic variants regulating BMI in the general population associated with anorexia nervosa

The influence of body mass index (BMI) on susceptibility to anorexia nervosa (AN) is not clear. Recently published genome‐wide association (GWA) studies of the general population identified several variants influencing BMI. We genotyped these variants in an AN sample to test for association and to investigate a combined effect of BMI‐increasing alleles (as determined in the original GWA studies) on the risk of developing the disease. Individual single nucleotide polymorphisms (SNPs) were tested for association with AN in a sample of 267 AN patients and 1,636 population controls. A logistic regression for the combined effect of BMI‐increasing alleles included 225 cases and 1,351 controls. We found no significant association between individual SNPs and AN. The analysis of a combined effect of BMI‐increasing alleles showed absence of association with the investigated condition. The percentages of BMI‐increasing alleles were equal between cases and controls. This study found no evidence that genetic variants regulating BMI in the general population are significantly associated with susceptibility to AN.

Variants in Neuropeptide Y Receptor 1 and 5 Are Associated with Nutrient-Specific Food Intake and Are Under Recent Selection in Europeans

There is a large variation in caloric intake and macronutrient preference between individuals and between ethnic groups, and these food intake patterns show a strong heritability. The transition to new food sources during the agriculture revolution around 11,000 years ago probably created selective pressure and shaped the genome of modern humans. One major player in energy homeostasis is the appetite-stimulating hormone neuropeptide Y, in which the stimulatory capacity may be mediated by the neuropeptide Y receptors 1, 2 and 5 (NPY1R, NPY2R and NPY5R). We assess association between variants in the NPY1R, NPY2R and NPY5R genes and nutrient intake in a cross-sectional, single-center study of 400 men aged 40 to 80 years, and we examine whether genomic regions containing these genes show signatures of recent selection in 270 HapMap individuals (90 Africans, 90 Asians, and 90 Caucasians) and in 846 Dutch bloodbank controls. Our results show that derived alleles in NPY1R and NPY5R are associated with lower carbohydrate intake, mainly because of a lower consumption of mono- and disaccharides. We also show that carriers of these derived alleles, on average, consume meals with a lower glycemic index and glycemic load and have higher alcohol consumption. One of these variants shows the hallmark of recent selection in Europe. Our data suggest that lower carbohydrate intake, consuming meals with a low glycemic index and glycemic load, and/or higher alcohol consumption, gave a survival advantage in Europeans since the agricultural revolution. This advantage could lie in overall health benefits, because lower carbohydrate intake, consuming meals with a low GI and GL, and/or higher alcohol consumption, are known to be associated with a lower risk of chronic diseases.

PTPN1 polymorphisms are associated with total and low-density lipoprotein cholesterol

Background The protein tyrosine phosphatase nonreceptor type 1 (PTPN1) gene encodes for the protein tyrosine phosphatase 1B, which suppresses the signaling pathway of insulin. Variations in PTPN1 may lead to changes in insulin sensitivity and consequent changes in protein tyrosine phosphatase 1B activity may also contribute to the development of metabolic endophenotypes. Our aim was to investigate the association between single nucleotide polymorphisms (SNPs) of the PTPN1 gene and metabolic endophenotypes and insulin sensitivity. Design and methods We used data from a population-based cross-sectional study of 382 Dutch Caucasian men aged between 40-80 years, in whom we genotyped and analyzed four tag SNPs in PTPN1. Results We show that the minor alleles of three tag SNPs of the PTPN1 gene (rs6067484, rs6020611, rs1060402) are associated with higher levels of total plasma cholesterol and low-density lipoprotein (LDL) cholesterol in men with a body mass index (BMI) below 26 kg/m2 (P < 0.05). We also show that men with a BMI below 26 kg/m2 and carrying the rs3487348 T allele tend to have a more beneficial profile for total plasma cholesterol and LDL cholesterol (P < 0.05). Haplotypes that comprised these alleles were also borderline statistically significant associated with higher levels of LDL and total cholesterol in men with BMI below 26 kg/m2. Conclusion Our results suggest that SNPs in the PTPN1 gene are associated with total plasma and LDL cholesterol levels.

No Association of PTPN1 Polymorphisms With Macronutrient Intake and Measures of Adiposity

The protein tyrosine phosphatase nonreceptor type1 (PTPN1) gene encodes for the protein tyrosine phosphatase 1B, which suppresses the signaling pathway of leptin. Variations of the PTPN1 gene may lead to changes in leptin sensitivity and thereby influence eating behavior and measures of obesity. This study investigated the association between single‐nucleotide polymorphisms (SNPs) of the PTPN1 gene and eating behavior and different measures of obesity, including visceral fat. We used data from a population‐based, cross‐sectional study of 382 Dutch white men aged 40–80 years. Self‐reported macronutrient intake was collected with a food frequency questionnaire. Anthropometrical measurements included BMI, waist and hip circumference, total lean and fat mass measured with dual‐energy X‐ray absorptiometry, and visceral and subcutaneous fat measured with ultrasound. Associations were studied using linear regression analysis. There were no statistically significant associations of SNPs in the PTPN1 gene with dietary phenotypes or measures of obesity.

Voedingspatronen en het risico op type 2 diabetes in personen met overgewicht en obesitas

SamenvattingVoeding, leefstijl en overgewicht spelen een belangrijke rol in de ontwikkeling van type 2 diabetes. Daarom vormen het voorkomen van gewichtstoename en overgewicht de belangrijkste pijlers van type 2 diabetespreventie. Voedingsinname beïnvloedt het risico op diabetes waarschijnlijk vooral door veranderingen in gewicht. Echter, er zijn aanwijzingen dat voeding ook onafhankelijk van (over)gewicht het risico op diabetes beïnvloedt.