Original Paper Ann Nutr Metab 2010;57:124–131 DOI: 10.1159/000319453
Received: December 30, 2009 Accepted after revision: July 19, 2010 Published online: October 19, 2010
The rs1466113 Polymorphism in the Somatostatin Receptor 2 Gene Is Associated with Obesity and Food Intake in a Mediterranean Population Mercedes Sotos-Prieto Marisa Guillén Patricia Guillem-Sáiz Olga Portolés Dolores Corella Genetic and Molecular Epidemiology Unit, Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia and CIBER Fisiopatología de la Obesidad y Nutrición, Valencia, Spain
Key Words Nutrigenetics ⴢ Genetics ⴢ Body weight ⴢ Food consumption ⴢ Cardiovascular
Abstract Background: A genome-wide association study identified rs1466113 (G1C) in the somatostatin receptor 2 (SSTR2) gene as one of the polymorphisms most significantly associated with body mass index (BMI). As replication is required, we examined the association between this polymorphism and anthropometric variables and food intake in a Mediterranean population. Methods: We studied 945 high cardiovascular-risk subjects (340 men and 605 women) aged 67 8 6 years, participating in the PREDIMED-Valencia Study. Demographic, clinical, biochemical, dietary, genetic and anthropometric data were obtained. Results: We found recessive effects for the association between this polymorphism and anthropometric variables. Homozygous subjects for the C allele had significantly lower BMI than G-allele carriers (29.9 8 4.5 in CC vs. 31.0 8 4.9 in GG + GC; p = 0.035). Likewise, odds ratio for obesity was lower in CC subjects in comparison with G-allele carriers, even after adjustment for potential confounders (odds ratio: 0.60, 95% confidence interval: 0.38–0.94; p = 0.028). We also found significant differences
© 2010 S. Karger AG, Basel 0250–6807/10/0572–0124$26.00/0 Fax +41 61 306 12 34 E-Mail
[email protected] www.karger.com
Accessible online at: www.karger.com/anm
in food (meats, dairy products and legumes) and nutrient (protein) intakes between CC- and G-allele carriers. Conclusion: The rs1466113 polymorphism in the SSTR2 gene is associated with anthropometric variables in the Mediterranean population replicating previous results in the Framingham study. We also observed differences in food intake between genotypes. Copyright © 2010 S. Karger AG, Basel
Introduction
The polypeptide hormone somatostatin, widely distributed throughout the body, is an important regulator of endocrine and nervous systems. Somatostatin is produced by neuroendocrine, inflammatory and immune cells in response to ions, nutrients, neuropeptides, neurotransmitters, thyroid and steroid hormones, growth factors and cytokines, and has different and multiple physiological functions [1]. Initially, it was found to be a powerful inhibitor of the growth hormone in the hypothalamus [2], although somatostatin also fulfils other important functions in different areas. It inhibits other gastrointestinal hormones such as gastrin and ghrelin, gastrointestinal secretion and reduces the nutritional Dolores Corella, PhD Genetic and Molecular Epidemiology Unit School of Medicine, Valencia University Blasco Ibañez, 15, ES–46010 Valencia (Spain) Tel. +34 96 386 4417, Fax +34 96 386 4166, E-Mail dolores.corella @ uv.es
absorption rate [3, 4]. Currently, somastotatin is considered a very important regulator of the endocrine system. This hormone and its analogues (such as octreotide and lanreotide) have been used in trials in patients with hypothalamic obesity, some effects on food intake having been observed [5]. Somatostatin exerts its biological action by binding to specific high-affinity receptors [6]. These receptors constitute a family of 7 transmembrane domain G proteincoupled receptors with 5 subtypes (termed SSTR1–5) that are encoded by separate genes, segregated on different chromosomes [7]. The SSRT2 is the most widely distributed somatostatin receptor in normal tissues and tumors, and is apparently the predominant subtype expressed in somatostatin receptor-positive tumors [8]. Its gene is located in 17q24 and the SSTR2 gene is the one that contains at least 1 intron, in contrast to other members of the somatostatin receptor family that are intronless [9]. In a genome-wide scan [10], performed on 1,425 individuals of Hispanic descent to identify regions of the genome linked to obesity phenotypes, evidence for linkage to obesity traits was observed at 17q. Additional fine mapping identified the SSTR2 gene as a positional candidate for obesity. However, additional studies to identify the obesity-related polymorphisms were very scarce. Interestingly, a genome-wide association study (GWAS) carried out in the Framingham study [11] identified the common variant (rs1466113), consisting of a G1C change in intron 1 in the SSTR2 gene, as one of the polymorphisms most significantly associated with anthropometric variables. However, replication in other populations is considered a crucial criterion in GWAS to increase the causality level and the credibility of genotype-phenotype associations. As far as we know, there are no published studies in which the association between this variant and anthropometric variables has been examined. Therefore, our first aim was to study the potential association between the rs1466113 polymorphism in the SSTR2 gene and anthropometric variables in a Mediterranean population. The second aim was to analyze the association between the rs1466113 polymorphism and food intake in this population.
Material and Methods Subjects and Study Design We included 945 consecutive subjects (340 men and 605 women) entering the PREDIMED (Prevención con Dieta Mediterránea) study in the Valencia region, Spain. All these subjects had the SSTR2 polymorphism determined and valid data for the other anthropometric, biochemical and lifestyle variables. The PRE-
Somatostatin Receptor 2 Gene, Obesity and Food Intake
DIMED study is a multicenter clinical trial aimed at assessing the effects of the Mediterranean diet on the primary prevention of cardiovascular disease. Details of this study have been reported elsewhere [12]. This trial is currently taking place and the anticipated completion date is December 2011. In this report we present data of a cross-sectional analysis at baseline including subjects recruited over 5 years in the Valencia field center. From October 2003 to October 2008, potential high cardiovascular-risk subjects were selected by physicians in primary care centers affiliated to teaching hospitals in the Valencia region. Eligible subjects were community-dwelling people (55–80 years of age for men; 60–80 years of age for women) who fulfilled at least 1 of 2 criteria: type 2 diabetes and 3 or more cardiovascular risk factors: current smoking, hypertension (blood pressure 1149/90 mm Hg or treatment with antihypertensive drugs), low-density lipoprotein cholesterol (LDL-C) 6160 mg/dl (or treatment with hypolipidaemic drugs), low high-density lipoprotein cholesterol (HDL-C) ^40 mg/dl, body mass index (BMI) 625 or a family history of premature coronary heart disease. Exclusion criteria included a personal history of cardiovascular disease, any severe chronic illness and drug or alcohol addiction [12]. The Institutional Review Board of the Valencia University approved the study protocol, and all participants provided written informed consent. Anthropometric, Clinical and Biochemical Data The baseline examination included assessment of standard cardiovascular risk factors, medication use and sociodemographic factors. Height and weight were measured with light clothing and no shoes. BMI was calculated as the weight (in kg) divided by the squared height (in m). Obesity was defined as a BMI 630 and overweight as a BMI of 25–29.9 in accordance with WHO criteria. Waist circumference was measured midway between the lowest rib and the iliac crest using an anthropometric tape. Blood pressure was measured by trained personnel using a validated semiautomatic oscillometre (HEM-70CP; Omron) with the subject seated, following the procedures recommended by the Spanish Hypertension Society. Measurements were carried out in triplicate with a 5-min interval between each, and the mean of these values was recorded. Fasting blood samples were obtained for each participant and stored at –80 ° C until biochemical analyses. Fasting glucose, total cholesterol, triglycerides, HDL-C and LDLC were determined as previously reported [12]. Plasma glucose was analyzed by the glucose-oxidase method; triglycerides and total cholesterol were measured using standard enzymatic procedures, and HDL-C after precipitation with phosphotungstic acid and magnesium chloride. LDL-C concentrations were estimated using the Friedewald equation whenever triglycerides were !400 mg/dl.
Dietary Measurements Food consumption was determined by a previously validated semi-quantitative 137-item food frequency questionnaire [13]. Energy and nutrient intake were calculated from Spanish food composition tables [14]. The baseline examination also included the administration of a 14-item questionnaire indicating the degree of adherence to the traditional Mediterranean diet as an extension of a previously validated questionnaire [15]. Values of 0 or 1 were assigned to each of 14 dietary components. The higher the score obtained from the questionnaire, the greater the adherence to the Mediterranean diet.
Ann Nutr Metab 2010;57:124–131
125
Table 1. Anthropometric, clinical, biochemical, life-style and genetic characteristics of participants
Variable
Total (n = 945)
Age, years 67.386.2 Weight, kg 77.4812.4 BMI 30.985.1 Waist, cm 104.3811.8 TC, mg/dl 208840 HDL-C, mg/dl 53814 LDL-C, mg/dl 129836 TG, mg/dl 131881 Fasting glucose, mg/dl 123840 SBP, mm Hg 147822 DBP, mm Hg 82811 Score to MD adherence 8.4882.0 Obesity, % 52.1 Diabetes, % 48.5 Hypertension, % 79.7 Hypercholesterolemia, % 70.4 Current smokers, % 11.9 Ex-smokers, % 21.1 SSTR2 G>C (rs1466113) polymorphism GG, % (n = 382) 40.4 GC, % (n = 437) 46.3 CC, % (n = 126) 13.3
Male (n = 340)
Female (n = 605)
p
66.885.9 75.3812.2 29.484 105.2811.6 200838 49812 124837 137874 129842 147821 82811 8.682.0 41.7 56 71.4 66.1 26.7 45.5
67.6086.6 81.1811.8 31.785.2 103.7811.9 212840 56814 131836 127884 119839 146823 81811 8.482.0 57.6 44.3 84.4 72.8 3.6 7.5
0.053
