GRUP NUTRIGENÈTICA CARDIOVASCULAR I DE L’OBESITAT

• Dolores Corella Piquer, Catedràtica de Medicina Preventiva i Salut Pública, UV.
• Marisa Guillén Domínguez, Professor Ajudant, UV.
• José Vicente Sorlí Guerola, Professor Associat, UV.
• José Ignacio González Arráez, Professor Titular d’Universitat, UV.
• Carmen Sáiz Sánchez, Professor Titular d’Universitat, UV.
• Olga Portolés Reparaz, Professora Ajudant, UV.
• Antonio Sabater Pons, Professor Titular d’Universitat, UV.
• Paula Carrasco Espí, Investigador contractat, UV.
• Carolina Ortega Azorín, Investigador contractat CIBER.
• Mecedes Sotos Prieto, Llicenciada en CTA.
• Patricia Guillem Sáiz, Investigador contractat CIBER.
• Oscar Coltell Simón, Professor Titular d’Universitat, Universitat Jaume I. Col·laborador en Computació i Bioinformàtica.

El grup investigador és un grup multidisciplinar format per investigadors de diferents titulacions: Ciència i Tecnologia dels Aliments, Farmàcia, Medicina, Veterinària, Ciències Biològiques, Bioquímica, Informàtica, Psicologia, Nutrició i Dietètica.

Consta d’un nucli estable d’investigadors i de personal de suport a la investigació, així com d’un nombre d’investigadors i col·laboradors amb una permanència més temporal en el grup, durant el seu període de formació, contractes o convenis temporals, etc. A més, el grup de recerca manté una col·laboració permanent amb el grup de recerca del Nutrition and Genomics Laboratory del Human Nutrition Research Center-Tufts University a Boston, Estats Units, liderat pel Dr Ordovás. També manté col·laboracions estretes amb els membres de la Xarxa d’Investigació de l’estudi PREDIMED, així com amb investigadors del CIBER de Fisiopatologia de l’Obesitat i Nutrició, del qual forma part des de l’any 2006.

El grup va ser pioner en la integració de l’estudi dels factors de risc genètics en l’epidemiologia clàssica. Així, el 1998 va crear la primera Unitat de Recerca en Epidemiologia Genètica i Molecular d’Espanya. Des de llavors, les investigacions del grup s’han centrat en l’estudi de les interaccions gen-ambient en l’etiologia i prevenció de les malalties cardiovasculars i de l’obesitat.

De totes les interaccions gen-ambient, les interaccions gen-dieta són les que desperten un especial interès per al grup, contribuint al desenvolupament de la nutrigenètica. El grup ha participat en la publicació de diverses interaccions gen-dieta sobre fenotips cardiovasculars en poblacions de diversos continents. L’estudi de la dieta mediterrània i la seva contribució a la prevenció de les malalties cardiovasculars i de l’obesitat, així com l’estudi dels seus determinants genètics, és una altra de les línies de major interès actual del grup.

• Epidemiologia genètica i molecular de les malalties cardiovasculars
  IP: Dolores Corella Piquer
• Epidemiologia genòmica de l’obesitat
  IP: Dolores Corella Piquer
• Genòmica Nutricional de les malalties cardiovasculars i l’obesitat
  IP: Dolores Corella Piquer
• Assaigs clínics nutrigenètica en prevenció cardiovascular
  IP: Marisa Guillén Domínguez
• Efectes de la dieta mediterrània en la prevenció primària de les malalties cardiovasculars
  IP: Dolores Corella Piquer

• Modulación por polimorfismos genéticos de los efectos de la adherencia a la dieta mediterránea en la incidencia de la enfermedad isquémica del corazón en la cohorte EPIC (European Prospective Investigation into Cancer and Nutrition) de España. IP: Dolores Corella. Entitat finançadora: Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo. Referència: PI041224. Durada: 1/01/2005 – 31/12/2007.
• Modulación genética de los efectos de la dieta mediterránea en la prevención primaria de la enfermedad cardiovascular (ECV): Análisis transversal y prospectivo sobre fenotipos intermedios y finales de ECV en el estudio PREDIMED. IP: Dolores Corella. Entitat finançadora: Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo. Referència: PI041224. Durada: 1/01/2005-31/12/2007.
• Efectos de la Dieta Tipo Mediterráneo en la prevención primaria cardiovascular PREDIMED. IP: Dolores Corella. Entitat finançadora: Instituto de Salud Carlos III. Fondo de Investigación Sanitaria. Ministerio de Sanidad y Consumo. Durada: 1/01/2006-31/12/2006.
• Balance Beneficio/Riesgo del contenido en polifenoles y alcohol del vino: bases científicas de los efectos del consumo moderado de vino sobre el sistema cardiovascular. IP: Coordinador general: Ramón Estruch (Hospital Clínico de Barcelona). IP de la Universitat de València: Marisa Guillén. Entitat finançadora: Ministerio de Educación y Ciencia. Referència: AGL2006-11679-C3. Durada: 1/01/2007-31/12/2009.
• OBENUTIC. Modulación genética y ambiental en el consumo de alimentos y riesgo de obesidad. Un estudio de casos y controles con soporte informático integrado interoperable. IP: Dolores Corella. Entitat finançadora: Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo. Referència: PI061326. Durada: 1/01/2007-31/12/2009.
• Centro de Investigación Biomédica en Red (CIBER) “Fisiopatología de la Obesidad y de la Nutrición. IP: Dolores Corella. Entitat finançadora: Instituto de Salud Carlos III. Fondo de Investigación Sanitaria. Ministerio de Sanidad y Consumo. Referència: CB06/03/0035. Durada: 1/01/2007-31/12/2010.
• Bases moleculares de los efectos de la dieta mediterránea en la prevención primaria de la enfermedad cardiovascular: estudio de SNPs de nueva generación del 100K microarray en el Framingham Study. IP: Dolores Corella. Entitat finançadora: Instituto de Salud Carlos III. Fondo de Investigación Sanitaria. Ministerio de Sanidad y Consumo. Durada: 1/01/2008-31/12/2010.
• Genetic susceptibility in determining intermediate and final cardiovascular phenotypes and their modulation by a Mediterranean diet intervention. IP: Dolores Corella. Entitat finançadora: Centro de Nacional de Investigaciones Cardiovasculares. Instituto de Salud Carlos III. Fondo de Investigación Sanitaria. Ministerio de Sanidad y Consumo. Durada: 1/01/2008-31/12/2011.

• Diseño de la línea de investigación en Nutrigenómica en IMDEA. IP: Dolores Corella. Entitat finançadora: Instituto Madrileño de Estudios Avanzados (IMDEA). Durada: 1/12/2008-31/11/2009.

• Corella D, González JI, Bulló M, Carrasco P, Portolés O, Díez-Espino J, Covas MI, Ruíz-Gutierrez V, Gómez-Gracia E, Arós F, Fiol M, Herrera MC, Santos JM, Sáez G, Lamuela R, Lahoz C, Vinyoles E, Ros E, Estruch R.
  Polymorphisms cyclooxygenase-2 -765G>C and interleukin-6 -174G>C are associated with serum inflammation markers in a high cardiovascular risk population and do not modify the response to a Mediterranean diet supplemented with virgin olive oil or nuts. 
  J Nutr. 2009;139:128-34.
  PMID: 19056642.

Abstract: Inflammation is involved in cardiovascular diseases. Some studies have found that the Mediterranean diet (MD) can reduce serum concentrations of inflammation markers. However, none of these studies have analyzed the influence of genetic variability in such a response. Our objective was to study the effect of the -765G>C polymorphism in the cyclooxygenase-2 (COX-2) gene and the -174G>C polymorphism in the interleukin-6 (IL-6) gene on serum concentrations of IL-6, C-reactive protein, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1 as well as their influence on the response to a nutritional intervention with MD. An intervention study in a high cardiovascular risk Mediterranean population (314 men and 407 women) was undertaken. Participants were randomly assigned to consume a low-fat control diet or a MD supplemented with virgin olive oil or nuts. Measures were obtained at baseline and after a 3-mo intervention period. At baseline, the COX-2 -765G>C polymorphism was associated with lower serum IL-6 (5.85 +/- 4.82 in GG vs. 4.74 +/- 4.14 ng/L in C-allele carriers; P = 0.002) and ICAM-1 (265.8 +/- 114.8 in GG vs. 243.0 +/- 107.1 microg/L in C-carriers; P = 0.018) concentrations. These differences remained significant after multivariate adjustment. The IL-6 -174G>C polymorphism was associated with higher (CC vs. G-carriers) serum ICAM-1 concentrations in both men and women and with higher serum IL-6 concentrations in men. Following the dietary intervention, no significant gene x diet interactions were found. In conclusion, although COX-2 -765G>C and IL-6 -174G>C polymorphisms were associated with inflammation, consuming a MD (either supplemented with virgin olive oil or nuts) reduced the concentration of inflammation markers regardless of these polymorphisms.

• SCorella D, Peloso G, Arnett DK, Demissie S, Cupples LA, Tucker K, Lai CQ, Parnell LD, Coltell O, Lee YC, Ordovas JM.
  APOA2, dietary fat, and body mass index: replication of a gene-diet interaction in 3 independent populations.
  Arch Intern Med. 2009;169:1897-906.
  PMID: 19901143.

Background: Nutrigenetics studies the role of genetic variation on interactions between diet and health, aiming to provide more personalized dietary advice. However, replication has been low. Our aim was to study interaction among a functional APOA2 polymorphism, food intake, and body mass index (BMI) in independent populations to replicate findings and to increase their evidence level.METHODS: Cross-sectional, follow-up (20 years), and case-control analyses were undertaken in 3 independent populations. We analyzed gene-diet interactions between the APOA2 -265T>C polymorphism and saturated fat intake on BMI and obesity in 3462 individuals from 3 populations in the United States: the Framingham Offspring Study (1454 whites), the Genetics of Lipid Lowering Drugs and Diet Network Study (1078 whites), and Boston-Puerto Rican Centers on Population Health and Health Disparities Study (930 Hispanics of Caribbean origin).RESULTS: Prevalence of the CC genotype in study participants ranged from 10.5% to 16.2%. We identified statistically significant interactions between the APOA2 -265T>C and saturated fat regarding BMI in all 3 populations. Thus, the magnitude of the difference in BMI between the individuals with the CC and TT+TC genotypes differed by saturated fat. A mean increase in BMI of 6.2% (range, 4.3%-7.9%; P = .01) was observed between genotypes with high- (> or =22 g/d) but not with low- saturated fat intake in all studies. Likewise, the CC genotype was significantly associated with higher obesity prevalence in all populations only in the high-saturated fat stratum. Meta-analysis estimations of obesity for individuals with the CC genotype compared with the TT+TC genotype were an odds ratio of 1.84 (95% confidence interval, 1.38-2.47; P < .001) in the high-saturated fat stratum, but no association was detected in the low-saturated fat stratum (odds ratio, 0.81; 95% confidence interval, 0.59-1.11; P = .18).CONCLUSION: For the first time to our knowledge, a gene-diet interaction influencing BMI and obesity has been strongly and consistently replicated in 3 independent populations.

• Francès F, Verdú F, Portolés O, Castelló A, Sorlí JV, Guillen M, Corella D.
  PPAR-alpha L162V and PGC-1 G482S gene polymorphisms, but not PPAR-gamma P12A, are associated with alcohol consumption in a Spanish Mediterranean population. 
  Clin Chim Acta. 2008;398:70-4.
  PMID: 18786524.

Background: Peroxisome Proliferator-Activated Receptors (PPARs) and its co-activators are regulatory elements of the cellular lipid homeostasis and have been associated with feeding behavior modulation. Animal models suggest that these genes may be involved in alcohol consumption regulation. However, no studies in humans exist. Our aim is to estimate the possible association between polymorphisms in the PPAR-alpha, PPAR-gamma and PPAR-gamma co-activator 1A (PGC-1A) genes and alcohol consumption in humans.METHODS: We have conducted a cross-sectional study between the PPAR-alpha L162V, PPAR-gamma P12A and PGC-1A G482S polymorphisms, and alcohol consumption in a general Mediterranean Spanish population (303 men and 443 women).RESULTS: We have found an association between the L162V polymorphism and alcohol consumption in which, carriers of the V allele were more prevalent among alcohol consumers (19.4% vs. 9.8%; OR 2.69; 95% CI: 1.31-5.54, p=0.007). The G482S polymorphism showed a significantly higher frequency in the group of high alcohol drinkers than in non-high alcohol drinkers (33.4% vs. 20.6%; OR 2.28; 95% CI: 1.07-4.88, p=0.034). Mean alcohol consumption was higher as the number of G alleles increased (GG 8.6+/-12.8 g/day, GS 6.6+/-9.2 g/day, SS 5.6+/-7.8 g/day, p=0.003). These results remained statistically significant after covariate adjustment.CONCLUSIONS: PPAR-alpha L162V and PGC-1A G482S polymorphisms are associated with alcohol consumption in the Mediterranean population.

• Sorlí JV, Francés F, González JI, Guillén M, Portolés O, Sabater A, Coltell O, Corella D.
  Impact of the -1438G>a polymorphism in the serotonin 2A receptor gene on anthropometric profile and obesity risk: a case-control study in a Spanish Mediterranean population. 
  Appetite. 2008;50:260-5.
  PMID: 17804117

Abstract: Research into the genetic factors that regulate food intake is arousing great interest. The polymorphism -1438G>A in the serotonin 2A receptor or 5-hydroxytriptamine (5-HT) type 2A receptor (5-HTR2A) gene has been associated with alterations in food intake such as anorexia and bulimia. However, its association with obesity has not been studied to the same extent. Our aim, therefore, was to estimate the association between the -1438G>A polymorphism and obesity risk and related anthropometric variables in a Spanish Mediterranean population. A case-control study including 303 cases and 606 controls paired by gender and age was undertaken. The association between the -1438G>A polymorphism and obesity and other anthropometric measures was studied. No association with obesity risk was observed. However, when only the obese group was analyzed, it was observed that AA subjects presented a lower body mass index (BMI) than G allele carriers (35.2+/-5.3 kg/m2 vs 37.5+/-7.8 kg/m2; P=0.039). Moreover, significant differences were also obtained in waist perimeter that was lower in AA subjects compared to G allele carriers (105+/-11 cm vs 112+/-17 cm; P=0.011). In conclusion, although the -1438G>A polymorphism is not a relevant marker for obesity risk, this variant may play a role in determining BMI in obese subjects.

• Corella D, Qi L, Tai ES, Deurenberg-Yap M, Tan CE, Chew SK, Ordovas JM.
  Perilipin gene variation determines higher susceptibility to insulin resistance in Asian women when consuming a high-saturated fat, low-carbohydrate diet. 
  Diabetes Care. 2006;29:1313-9.
  PMID: 16732014.

Objective: To investigate the association between genetic variation in the adipocyte protein perilipin (PLIN) and insulin resistance in an Asian population as well as to examine their modulation by macronutrient intake.RESEARCH DESIGN AND METHODS: A nationally representative sample (Chinese, Malays, and Indians) was selected in the Singapore National Health Survey following the World Health Organization-recommended model for field surveys of diabetes. A total of 1,909 men and 2,198 women (aged 18-69 years) were studied. Genetic (PLIN 11482G–>A and 14995A–>T), lifestyle, clinical, and biochemical data were obtained. Homeostasis model assessment of insulin resistance (HOMA-IR) was used to evaluate insulin resistance. Diet was measured by a validated food frequency questionnaire in one of every two subjects.RESULTS: We did not find a significant between-genotype difference in insulin resistance measures. However, in women we found statistically significant gene-diet interactions (recessive model) between PLIN 11482G–>A/14995A–>T polymorphisms (in high linkage disequilibrium) and saturated fatty acids (SFAs; P = 0.003/0.005) and carbohydrate (P = 0.004/0.012) in determining HOMA-IR. These interactions were in opposite directions and were more significant for 11482G–>A, considered the tag polymorphism. Thus, women in the highest SFA tertile (11.8-19%) had higher HOMA-IR (48% increase; P trend = 0.006) than women in the lowest (3.1-9.4%) only if they were homozygotes for the PLIN minor allele. Conversely, HOMA-IR decreased (-24%; P trend = 0.046) as carbohydrate intake increased. These effects were stronger when SFAs and carbohydrate were combined as an SFA-to-carbohydrate ratio. Moreover, this gene-diet interaction was homogeneously found across the three ethnic groups.CONCLUSIONS: PLIN 11482G–>A/14995A–>T polymorphisms modulate the association between SFAs/carbohydrate in diet and insulin resistance in Asian women.

• Universitat de València
• Generalitat Valenciana
• Instituto de Salud Carlos III
• CIBER Fisiopatologia de la Obesidad y Nutrición