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Associations of the FTO rs9939609 and the MC4R rs17782313 polymorphisms with type 2 diabetes are modulated by diet, being higher when adherence to the Mediterranean diet pattern is low

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      Abstract

      Background

      Although the Fat Mass and Obesity ( FTO) and Melanocortin-4 Receptor ( MC4R) genes have been consistently associated with obesity risk, the association between the obesity-risk alleles with type 2 diabetes is still controversial. In some recent meta-analyses in which significant results have been reported, the associations disappeared after adjustment for body mass index (BMI). However gene-diet interactions with dietary patterns have not been investigated. Our main aim was to analyze whether these associations are modulated by the level of adherence to the Mediterranean Diet (MedDiet).

      Methods

      Case-control study in 7,052 high cardiovascular risk subjects (3,430 type 2 diabetes cases and 3,622 non-diabetic subjects) with no differences in BMI. Diet was assessed by validated questionnaires. FTO-rs9939609 and MC4R-rs17782313 were determined. An aggregate genetic score was calculated to test additive effects. Gene-diet interactions were analyzed.

      Results

      Neither of the polymorphisms was associated with type 2 diabetes in the whole population. However, we found consistent gene-diet interactions with adherence to the MedDiet both for the FTO-rs9939609 (P-interaction=0.039), the MC4R-rs17782313 (P-interaction=0.009) and for their aggregate score (P-interaction=0.006). When adherence to the MedDiet was low, carriers of the variant alleles had higher type 2 diabetes risk (OR=1.21, 95%CI: 1.03-1.40; P=0.019 for FTO-rs9939609 and OR=1.17, 95%CI:1.01-1.36; P=0.035 for MC4R-rs17782313) than wild-type subjects. However, when adherence to the MedDiet was high, these associations disappeared (OR=0.97, 95%CI: 0.85-1.16; P=0.673 for FTO-rs9939609 and OR=0.89, 95%CI:0.78-1.02; P=0.097 for MC4R-rs17782313). These gene-diet interactions remained significant even after adjustment for BMI. As MedDiet is rich in folate, we also specifically examined folate intake and detected statistically significant interaction effects on fasting plasma glucose concentrations in non-diabetic subjects. However these findings should be interpreted with caution because folate intake may simply reflect a healthy dietary pattern.

      Conclusions

      These novel results suggest that the association of the FTO-rs9939609 and the MC4R-rs17782313 polymorphisms with type 2 diabetes depends on diet and that a high adherence to the MedDiet counteracts the genetic predisposition.

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      Most cited references 56

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      A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.

      Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.
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        Common variants near MC4R are associated with fat mass, weight and risk of obesity.

        To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.
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          Diagnosis and classification of diabetes mellitus.

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            Author and article information

            Affiliations
            [1 ]Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, Valencia, Spain
            [2 ]CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
            [3 ]Department of Computing Languages and Systems, University Jaume I, Castellon, Spain
            [4 ]Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
            [5 ]Department of Preventive Medicine and Public Health, School of Medicine, University of Navarra, Pamplona, Spain
            [6 ]Human Nutrition Unit, Faculty of Medicine, IISPV, University Rovira i Virgili, Reus, Spain
            [7 ]Cardiovascular Epidemiology Unit, Municipal Institut for Medical Research (IMIM), Barcelona, Spain
            [8 ]Department of Cardiology, Hospital Txagorritxu, Vitoria, Spain
            [9 ]Department of Family Medicine, Primary Care Division of Sevilla, San Pablo Health Center, Sevilla, Spain
            [10 ]Department of Clinical Sciences, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
            [11 ]Department of Epidemiology, School of Medicine, University of Malaga, Málaga, Spain
            [12 ]University Institute for Health Sciences Investigation, Hospital Son Dureta, Palma de Mallorca, Spain
            [13 ]Department of Biochemistry, School of Medicine, University of Valencia, Valencia, Spain
            [14 ]Lipids and Vascular Risk Unit, Internal Medicine, Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
            [15 ]Primary Care Division, Catalan Institute of Health, Barcelona, Spain
            [16 ]Lipid Clinic, Endocrinology and Nutrition Service, Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain
            [17 ]Department of Cardiovascular Epidemiology and Population Genetics, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
            [18 ]IMDEA Alimentación, Madrid, Spain
            [19 ]Department of Internal Medicine, Hospital Clinic, IDIBAPS, Barcelona, Spain
            [20 ]Genetic and Molecular Epidemiology Unit, Valencia University, Blasco Ibañez, 15, 46010, Valencia, Spain
            Contributors
            Journal
            Cardiovasc Diabetol
            Cardiovasc Diabetol
            Cardiovascular Diabetology
            BioMed Central
            1475-2840
            2012
            6 November 2012
            : 11
            : 137
            23130628
            3495759
            1475-2840-11-137
            10.1186/1475-2840-11-137
            Copyright ©2012 Ortega-Azorín et al.; licensee BioMed Central Ltd.

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

            Categories
            Original Investigation

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