title: Polymorphism of the Transcription Factor 7-Like 2 Gene (TCF7L2) Interacts with Obesity on Type-2 Diabetes in the PREDIMED Study Emphasizing the Heterogeneity of Genetic Variants in Type-2 Diabetes Risk Prediction: Time for Obesity-Specific Genetic Risk Scores.
abstract: Nutrigenetic studies analyzing gene-diet interactions of the TCF7L2-rs7903146 C > T polymorphism on type-2 diabetes (T2D) have shown controversial results. A reason contributing to this may be the additional modulation by obesity. Moreover, TCF7L2-rs7903146 is one of the most influential variants in T2D-genetic risk scores (GRS). Therefore, to increase the predictive value (PV) of GRS it is necessary to first see whether the included polymorphisms have heterogeneous effects. We comprehensively investigated gene-obesity interactions between the TCF7L2-rs7903146 C > T polymorphism on T2D (prevalence and incidence) and analyzed other T2D-polymorphisms in a sub-sample. We studied 7018 PREDIMED participants at baseline and longitudinally (8.7 years maximum follow-up). Obesity significantly interacted with the TCF7L2-rs7903146 on T2D prevalence, associations being greater in non-obese subjects. Accordingly, we prospectively observed in non-T2D subjects (n= 3607) that its association with T2D incidence was stronger in non-obese (HR: 1.81; 95% CI: 1.13-2.92,p= 0.013 for TT versus CC) than in obese subjects (HR: 1.01; 95% CI: 0.61-1.66;p= 0.979;p-interaction = 0.048). Accordingly, TCF7L2-PV was higher in non-obese subjects. Additionally, we created obesity-specific GRS with ten T2D-polymorphisms and demonstrated for the first time their higher strata-specific PV. In conclusion, we provide strong evidence supporting the need for considering obesity when analyzing the TCF7L2 effects and propose the use of obesity-specific GRS for T2D.
authors.affiliation: Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain. dolores.corella@uv.es.|CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. dolores.corella@uv.es.
authors.forename: Dolores
authors.initials: D
authors.lastname: Corella
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. oscar.coltell@uji.es.|Department of Computer Languages and Systems, School of Technology and Experimental Sciences, Universitat Jaume I, 12071 Castellón, Spain. oscar.coltell@uji.es.
authors.forename: Oscar
authors.initials: O
authors.lastname: Coltell
authors.affiliation: Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain. jose.sorli@uv.es.|CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. jose.sorli@uv.es.
authors.forename: Jose V
authors.initials: JV
authors.lastname: Sorlí
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. RESTRUCH@clinic.cat.|Department of Internal Medicine, Hospital Clinic, IDIBAPS, 08036 Barcelona, Spain. RESTRUCH@clinic.cat.
authors.forename: Ramón
authors.initials: R
authors.lastname: Estruch
authors.affiliation: Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain. laura.quiles@uv.es.|CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. laura.quiles@uv.es.
authors.forename: Laura
authors.initials: L
authors.lastname: Quiles
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. mamartinez@unav.es.|Department of Preventive Medicine and Public Health, University of Navarra-Navarra Institute for Health Research (IdisNa), 31009 Pamplona, Spain. mamartinez@unav.es.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Martínez-González
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. jordi.salas@urv.cat.|Human Nutrition Unit, Biochemistry and Biotechnology Department, IISPV, University Rovira i Virgili, 43003 Reus, Spain. jordi.salas@urv.cat.
authors.forename: Jordi
authors.initials: J
authors.lastname: Salas-Salvadó
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. ocastaner@imim.es.|Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain. ocastaner@imim.es.
authors.forename: Olga
authors.initials: O
authors.lastname: Castañer
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. aborau@secardiologia.es.|Department of Cardiology, Hospital Txagorritxu, 01009 Vitoria, Spain. aborau@secardiologia.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: Arós
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. 106mayorque104@gmail.com.|Department of Family Medicine, Distrito Sanitario Atención Primaria Sevilla, Centro de Salud Las Palmeritas, 41003 Sevilla, Spain. 106mayorque104@gmail.com.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ortega-Calvo
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. lluis.serra@ulpgc.es.|Research Institute of Biomedical and Health Sciences, University of Las Palmas de Gran Canaria, 35001 Las Palmas de Gran Canaria, Spain. lluis.serra@ulpgc.es.
authors.forename: Lluís
authors.initials: L
authors.lastname: Serra-Majem
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. egomezgracia@uma.es.|Department of Epidemiology, School of Medicine, University of Malaga, 29071 Malaga, Spain. egomezgracia@uma.es.
authors.forename: Enrique
authors.initials: E
authors.lastname: Gómez-Gracia
authors.affiliation: Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain. olga.portoles@uv.es.|CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. olga.portoles@uv.es.
authors.forename: Olga
authors.initials: O
authors.lastname: Portolés
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. miguel.fiol@ssib.es.|Palma Institute of Health Research (IdISPa), Hospital Son Espases, 07014 Palma de Mallorca, Spain. miguel.fiol@ssib.es.
authors.forename: Miquel
authors.initials: M
authors.lastname: Fiol
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. javierdiezesp@ono.com.|Department of Preventive Medicine and Public Health, University of Navarra-Navarra Institute for Health Research (IdisNA)-Servicio Navarro de Salud-Osasunbidea, 31009 Pamplona, Spain. javierdiezesp@ono.com.
authors.forename: Javier
authors.initials: J
authors.lastname: Díez Espino
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. jbasora.tarte.ics@gencat.cat.|Human Nutrition Unit, Biochemistry and Biotechnology Department, IISPV, University Rovira i Virgili, 43003 Reus, Spain. jbasora.tarte.ics@gencat.cat.
authors.forename: Josep
authors.initials: J
authors.lastname: Basora
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. MFito@imim.es.|Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain. MFito@imim.es.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Fitó
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. EROS@clinic.ub.es.|Lipid Clinic, Endocrinology and Nutrition Service, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clinic, 08036 Barcelona, Spain. EROS@clinic.ub.es.
authors.forename: Emilio
authors.initials: E
authors.lastname: Ros
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28029 Madrid, Spain. jose.ordovas@tufts.edu.|Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA. jose.ordovas@tufts.edu.|Department of Cardiovascular Epidemiology and Population Genetics, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029-IMDEA Alimentación, 28049 Madrid, Spain. jose.ordovas@tufts.edu.
authors.forename: José M
authors.initials: JM
authors.lastname: Ordovás
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D015994:Incidence; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D054647:Nutrigenomics; D009765:Obesity / Q000097:blood / Q000150:complications / Q000235:genetics*; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D015995:Prevalence; D011446:Prospective Studies; D012307:Risk Factors; D058118:Transcription Factor 7-Like 2 Protein / Q000097:blood / Q000235:genetics*
chemical_list: D005819:Genetic Markers; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein
keywords: PREDIMED study; T2D-genetic risk scores; TCF7L2; TCF7L2-predictive value; obesity; type-2 diabetes