2009 Annual Report
1a.Objectives (from AD-416)
To identify genetic markers for assessment of cardiovascular health related to plasma lipoprotein levels, diabetes and obesity and evaluate, the effects of specific gene-gene interactions in common metabolic pathways.
To investigate the interactions between genetics and nutrients in the development of cardiovascular disease (CVD), the major age-related disorder affecting life expectancy and quality of life in the United States (US). Emphasis is placed on elucidating mechanisms by which genetic variation interacts with dietary and behavioral factors to regulate the homeostasis of the cardiovascular system.
To identify genes newly associated with cardiovascular health and overall longevity and determine their expression response to dietary intervention using animal models of aging.
1b.Approach (from AD-416)
Because the response of the individual to nutrients contains a strong genetic component, our approach aims to uncover sets of genes involved in the dietary response and to describe specific gene-diet interactions. This will be tested using high throughput genotyping technics, both in ongoing studies of free-living populations and in the metabolic ward (intervention studies). Our primary focus is to describe gene-diet interactions affecting/influencing progression of the metabolic syndrome, in particular obesity, often a precursor to cardiovascular disease and diabetes. Cardiovascular candidate genes, both those previously described in the literature as well as those we identify through bioinformatics analysis, will be used to examine associations and interactions on various scales. These include genetic variations, disease-related phenotypes, and specific nutrients [fatty acids, cholesterol, plant sterols) and behavioral habits (alcohol consumption, smoking, physical (in)activity]. Rigorous statistical analysis will uncover the associations between phenotypes indicative of increased risk of metabolic syndrome and the genes responsible for such. Because cardiovascular disease and diabetes are traditionally considered diseases of the aged, we will also continue with our investigations to identify genes responsible for healthy aging. The principal approach taken for these studies involves gene expression microarray analysis of fruit fly D. melanogaster populations with a propensity for increased longevity. Candidate aging genes will then be studied in mammalian models as well in human populations.
Within the reporting period the project has had significant progress. We have identified and reported 30 genomic regions significantly associated with plasma lipoprotein concentrations, a major cardiovascular risk factor. Of those relevant genomic regions, eleven were novel, making this work one of the major contributions to the genetics of plasma lipids in humans. Understanding the molecular, cellular, and clinical consequences of the newly found genes and chromosomal regions will open new avenues for disease prevention and therapy. Moreover, we examined the consequences of joint presence of variants at those genes. Our analyses demonstrate that the proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides, all atherogenic factors, varied according to the presence of polymorphisms at those genes. These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia and consequently to coronary heart disease (CHD) risk. The above indicated accomplishment, which has been cited over 40 times since its publication in 2009, demonstrates the potential success of combining genetic information to predict individual disease risk; however, as previously indicated, our knowledge of the genes implicated in CHD risk is still limited and more comprehensive knowledge in this area is needed in order to create diagnostic tools with the required specificity and sensitivity to be used in the general population. In addition, we have explored both novel and previously known genes in terms of gene environment interactions that could potentially modulate the expression of the risk phenotype (i.e., obesity, dyslipidemia) in several large and well characterized populations. The knowledge generated from our work will provide the basis for a more successful prevention of chronic disorders impairing healthy aging.
The relation between dietary carbohydrates and obesity is modulated by variation at the perilipin (PLIN) gene. Perilipin (PLIN) is the major protein surrounding lipid droplets in adipocytes and regulates adipocyte metabolism by modulating the activity of enzymes that digest and release the fat in the adipocyte. We have previously identified numerous relationships between PLIN gene variants and measures of obesity. We examined whether dietary macronutrients (e.g. carbohydrates and fats) modulated the associations PLIN genetic variants with obesity. For this purpose, we studied a population-based sample of Caribbean-origin Hispanics living in the Boston area and with a high prevalence of obesity and related ailments. In these subjects we found a significant interaction between complex carbohydrate intake and a specific PLIN gene variant for waist circumference. When we divided the population between those with low (<144 grams/day) and high (>/=144 grams/day) complex carbohydrate intake, we found significantly different effects across PLIN genotypes. When complex carbohydrate intake was low, waist circumference was larger in carriers of the PLIN polymorphism. Conversely, when complex carbohydrate intake was high, waist and hip circumferences were less in carriers of the polymorphism. These interactions were not found for simple sugars or total carbohydrates. Therefore, we have identified a significant gene-diet interaction associated with obesity at the PLIN gene. In subjects with higher complex carbohydrate intake, the gene variant was protective against obesity, whereas in subjects with lower carbohydrate intake, the gene variant was associated with increased obesity. These interactions may be relevant to dietary management of obesity.
Provided evidence for the association of adiponectin gene, dietary monounsaturated fatty acids, and obesity risk. Adiponectin is a protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid catabolism. Adiponectin is exclusively secreted from adipose tissue into the bloodstream and is very abundant in plasma relative to many hormones. Levels of the hormone are inversely correlated with body fat percentage in adults. Genetic and environmental factors influence serum adiponectin and may contribute to risk of metabolic syndrome and Type 2 diabetes (T2D). Therefore, we investigated the effect of adiponectin gene variants on metabolic phenotypes and their modulation by dietary fat in a large population. blood adiponectin concentration was dependent on genetic variation at the adiponectin gene. Moreover, we found significant association between the adiponectin gene variants and obesity measures, including body mass index (BMI), waist and hip circumferences. Interestingly, the associations of the adiponectin gene with BMI and obesity risk were modified by dietary monounsaturated fatty acids (MUFAs). In subjects with relatively high MUFA intake (> or =13% of energy intake) carriers of a genetic variant had lower BMI and decreased obesity risk. However, we did not detect genotype-related differences for BMI or obesity in subjects with MUFA intake <13%. Our findings support a significant association between genetic variation at the adiponectin gene and obesity traits and the potential to moderate such effects using personalized dietary modification.
Discovery of new genes associated with blood lipids in humans. Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. Blood lipid concentrations are heritable, but most of their heritability remained unexplained by previously known genes and gene variants. To dissect the polygenic basis of these risk factors, we have thoroughly analyzed the genomes of 19,840 individuals and replicated promising findings in up to 20,623 individuals. We identified 30 distinct genes reproducibly associated with lipoprotein concentrations, including 11 genes that were found for the first time. The 11 newly defined genomic regions include common variants associated with LDL cholesterol (n=4); with HDL cholesterol (n=6); and with triglycerides (n=3) . The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to the accumulated number of variants at those genes. These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia and, consequently, to the coronary heart disease risk.
Warodomwichit, D., Shen, J., Arnett, D., Tsai, M., Kabagambe, E., Peacock, J., Hixson, J., Straka, R., Province, M., An, P., Lai, C., Parnell, L.D., Borecki, I., Ordovas, J.M. 2009. ADIPOQ Polymorphisms, Monounsaturated Fatty Acids, and Obesity Risk: The GOLDN Study. Obesity. 17:510-517.
Kabagambe, E.K., Ordovas, J.M., Tsai, M.Y., Borecki, I.B., Hopkins, P.N., Arnett, D.K. 2009. Smoking, inflammatory patterns, and postprandial hypertriglyceridemia. Atherosclerosis. 203(2):633-639.
Deram, S., Nicolau, C.Y., Perez-Martinez, P., Guazzelli, I., Halpern, A., Wajchenberg, B.L., Ordovas, J.M., Villares, S.M. 2008. Effects of Perilipin (PLIN) gene variation on metabolic syndrome risk and weight-loss in obese children and adolescents. Journal of Clinical Endocrinology and Metabolism. 93:4933-4940.
Smith, C.E., Tucker, K.L., Scott, T.M., Van Rompay, M., Parnell, L.D., Lai, C., Mattei, J., Junyent, M., Lee, Y., Garcia-Bailo, B., Ordovas, J.M. 2009. Apolipoprotein C3 polymorphism is associated with cognitive function in Caribbean Hispanics. PLoS One. 4(5):e5465.
Ordovas, J., Tai, E. 2009. Why study gene-environment interactions?. Current Opinion in Lipidology. 19(2):158-167.
Junyent, M., Arnett, D.A., Tsai, M.Y., Kabagambe, E.K., Straka, R.J., Province, M., An, P., Shen, J., Borecki, I., Parnell, L.D., Lai, C., Lee, Y., Ordovas, J.M. 2009. Genetic Variants at the PDZ-Interacting Domain of the Scavenger Receptor Class B Type I Interact with Diet to Influence the Risk of Metabolic Syndrome in Obese Men and Women. Journal of Nutrition. 139(6):842-848.
Kathiresan, S., Willer, C., Peloso, G., Demissie, S., Musunuru, K., Schadt, E., Kaplan, L., Bennett, D., Li, Y., Tanaka, T., Voight, B., Bonnycastle, L., Jackson, A., Crawford, G., Surti, A., Guiducci, C., Burtt, N., Parish, S., Clarke, R., Zelenika, D., Kubalanza, K., Morken, M., Scott, L., Stringham, H., Galan, P., Swift, A., Kuusisto, J., Bergman, R., Sundvall, J., Laakso, M., Ferrucci, L., Scheet, P., Sanna, S., Uda, M., Yang, Q., Lunetta, K., Dupius, J., De Bakker, P., O'Donnell, C., Scuteri, A., Schlessinger, D., Tuomilehto, J., Collins, F., Groop, L., Altshuler, D., Collins, R., Lathrop, G., Melander, O., Saloma, V., Peltonen, L., Orho-Melander, M., Ordovas, J., Boehnke, M., Abecasis, G., Mohlke, K., Cupples, A. 2009. Common variants at 30 loci contribute to polygenic dyslipidemia. Nature Genetics. 41:56-65.
Jang, Y., Paik, J., Hyun, Y., Chae, J., Kim, J., Choi, J., Lee, S., Shin, D., Ordovas, J., Lee, J. 2009. The apolipoprotein A5 -1131T>C promoter polymorphism in Koreans: association with plasma APOA5 and serum triglyceride concentrations, LDL particle size and coronary artery disease. Clinica Chimica Acta. 402(1-2):83-87.
Warodomwichit, D., Arnett, D.K., Kabagambe, E.K., Tsai, M.Y., Hixson, J.E., Straka, R.J., Province, M., An, P., Lai, C., Borecki, I., Ordovas, J. 2009. Polyunsaturated fatty acids modulate the effect of TCF7L2 gene variants on postprandial lipemia. Journal of Nutrition. 139:439-446.
Perez-Martinez, P., Lopez-Miranda, J., Cruz-Teno, C., Delgado-Lista, J., Jimenez-Gomez, Y., Fernandez, J.M., Gomez, M.J., Marin, C., Perez-Jimenez, F., Ordovas, J.M. 2008. Adiponectin Gene Variants are Associated with Insulin Sensitivity in Response to Dietary Fat Consumption in Caucasian Men. Journal of Nutrition. 138(9):1609-1614.
Perez-Martinez, P., Lopez-Miranda, J., Perez-Jimenez, F., Ordovas, J.M. 2008. Influence of genetic factors in the modulation of postprandial lipemia. Atherosclerosis Supplements. 9:49-55.
Williams, C.M., Ordovas, J.M., Lairon, D., Hesketh, J., Lietz, G., Gibney, M., Van Ommen, B. 2008. The challenges of molecular nutrition research 1- Linking genotype to healthy nutrition. Genes and Nutrition. 3(2):41–49.
Ordovas, J.M., Shen, J. 2008. Gene–Environment Interactions and Susceptibility to Metabolic Syndrome and Other Chronic Diseases. Journal of Periodontology. 79(8S):1508-1513.
Orho-Melander, M., Melander, O., Guiducci, C., Perez-Martinez, P., Corella, D., Roos, C., Tewhey, R., Rieder, M.J., Hall, J., Abecasis, G., Tai, E., Welch, C., Arnett, D.K., Lyssenko, V., Lindholm, E., Saxena, R., De Bakker, P., Burtt, N., Voight, B.F., Hirschhorn, J.N., Tucker, K., Hedner, T., Tuomi, T., Isomaa, B., Eriksson, K., Taskinen, M., Wahlstrand, B., Hughes, T.E., Parnell, L.D., Lai, C., Berglund, G., Peltonen, L., Vartiainen, E., Jousilahti, P., Havulinna, A.S., Salomaa, V., Nilsson, P., Groop, L., Altshuler, D., Ordovas, J.M., Kathiresan, S. 2008. A Common Missense Variant in the Glucokinase Regulatory Protein Gene (GCKR) Is Associated with Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations. Diabetes. 57:3112-3121.
Shen, J., Arnett, D.K., Perez-Martinez, P., Parnell, L.D., Peacock, J.M., Hixson, J.E., Tsai, M.Y., Lai, C., Straka, R.J., Hopkins, P.N., Ordovas, J.M. 2008. The effect of IL6-174C/G polymorphisms on postprandial triglycerides metabolism in the GOLDN study. Journal of Lipid Research. 49:1839-1845.
Ordovas, J.M. 2008. Genotype-phenotype associations: Modulation by diet and obesity. Obesity. 16:S40-S46.
Ordovas, J.M., Corella, D. 2008. Nutrition and Diet in the Era of Genomics. In: Willard, H.F. and Ginsburg, G.S, editors. Genomic and Personalized Medicine. vol. 1-2. New York, NY: Elsevier.
Ordovas, J.M. 2008. Genetic Influences on Blood Lipids and Cardiovascular Risk. In: Coulston, A., Boushey, C., editors. Nutrition in the Prevention and Treatment of Disease. 2nd Edition. Elsevier. p.485-513.
Junyent, M., Tucker, K., Smith, C., Garcia-Rios, A., Mattei, J., Lai, C., Parnell, L.D., Ordovas, J.M. 2008. The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study. Journal of Lipid Research. 50:565-573.
Smith, C., Tucker, K., Yiannakouris, N., Garcia-Bailo, B., Mattei, J., Lai, C., Parnell, L.D., Ordovas, J.M. 2008. Perilipin Polymorphism Interacts with Dietary Carbohydrates to Modulate Anthropometric Traits in Hispanics of Caribbean Origin. Journal of Nutrition. 138(10):1852-1858.
Lai, C., Parnell, L.D., Garcia-Bailo, B., Tucker, K., Ordovas, J.M. 2008. WDTC1, an ortholog of Drosphilia adipose gene, associates with human obesity. Obesity. 17(3):593-600.