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United States Department of Agriculture

Agricultural Research Service

Research Project: NUTRITION, OBESITY, CARDIOVASCULAR HEALTH AND GENOMICS
2012 Annual Report


1a.Objectives (from AD-416):
1. Identify new human genes involved in the homeostasis of lipid metabolism using genome-wide association studies and bioinformatics.

2. Identify candidate genes for overweight and obesity in humans with special emphasis on those modulating the risk for the metabolic syndrome.

3. Identify genetic factors determining differential susceptibility towards chronic disorders in response to a Western-type diet and lifestyle in humans with differing ethnic backgrounds.

4. Identify new longevity genes and describe their modulation by nutritional and environmental factors in animals and humans.


1b.Approach (from AD-416):
Because the predisposition to most common ailments affecting healthy aging and the responses of the individual to nutrients both contain a strong genetic component, our approach aims to uncover sets of genes involved in the predisposition to alterations in fasting and non fasting lipid metabolism and obesity and dietary response and to describe specific gene-diet interactions. This will be tested, using high throughput genotyping techniques, both in ongoing studies of free-living populations from different ethnic groups 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 and dyslipidemia, often precursors to cardiovascular disease and diabetes. Cardiovascular candidate genes, both those previously described in the literature as well as those we identify through new genetic technologies and 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, fiber) 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 in silico analysis of animal models of aging and longevity. Candidate aging genes will then be studied in human populations.


3.Progress Report:
This progress report includes the work of one subordinate project at the HNRCA funded through a Specific Cooperative Agreement with TUFTS UNIVERSITY. For further information and progress reports, see 1950-51000-077-01S (Nutrition, cardiovascular health and Genomics).


4.Accomplishments
1. LAB: Nutrition and genomics: Plasma HDL cholesterol and risk of myocardial infarction. A Mendelian randomization study. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, in collaboration with an international consortium, have thoroughly analyzed whether high plasma HDL cholesterol is associated with reduced risk of myocardial infarction. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, the concept of Mendelian randomization can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. We performed two Mendelian randomization analyses. First , we used as an instrument a single nucleotide polymorphisms (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. Our findings clearly demonstrate that some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the long-held concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. Moreover, this information opens new paradigms for the prevention and treatment of cardiovascular diseases.

2. LAB: Nutrition and genomics: MicroRNA mediates gene-diet interaction related to obesity. ARS and ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, genotyped seven single nucleotide polymorphisms (SNPs) from men and women of mostly white European ancestry enrolled in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study and the Framingham Offspring Study. Carriers of one of the gene variants tended to weigh more and exhibit higher body mass index (BMI), which would increase their risk of becoming obese. Yet carriers with higher omega-3 fatty acid intakes tended to weigh less than carriers who consumed little or no omega-3 fatty acids. This is the first example of a genetic variant that creates a miR binding site that influences obesityrelated traits through gene-diet interaction. Although further research is necessary, the findings suggest that miRNA activity is indeed a possible target for dietarybased weight-loss therapies for obesity. We then conducted a genome-wide survey for SNPs altering microRNA seed sites as a means to identify in GWAS those SNPs of functional consequence. We focused on functional variants related to the binding of microRNAs (miR), utilizing SNP data, including newly released 1000 Genomes Project data, to perform a genome-wide scan of SNPs that abrogate or create miR recognition element seed sites (MRESS). We also gathered previously published links between gene expression activity and genetic variants supporting a functional role for four of these SNPs shown to associate with disease phenotypes. In summary, we have demonstrated the potential of publicly available resources to identify high priority candidate SNPs for functional studies and for disease risk prediction and more successful obesity prevention and therapy using targeted dietary recommendations.

3. LAB: Nutrition and genomics: Systems biology and gene networks approach to predict gene-environment (GxE)interactions. Gene networks were built based on protein-protein interactions, seeded by genes carrying variants known to show GxE interactions involving physical activity. ARS and ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, added data to this network from gene expression studies (response to exercise, baseline activity in key metabolic tissues), genetic association tests from the GOLDN study, a set of human disease genes published by a group at the National Institute of Aging, and assignments to biochemical and physiological pathways. The network itself and analysis of its constituent entities allowed identification of candidate variants involved in HDL-cholesterol and responsive to the level of physical activity. This knowledge will pave the way for more comprehensive tactics to disease prevention using both dietary and physical activity approaches.

4. LAB: Nutrition and genomics: Identification of genetic variants for genotyping, genotyping, analysis of genotyping for positive selection. Based on positive selection SNP databases, ARS and ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA identified and ranked a list of promising adaptive variants have been identified and ranked by combining with miRNA SNP and genome-wide association and sequence databases, and 1000 genome database. SNPs that alter microRNA seed sites are associated with higher levels of environmental adaptation. As a proof of concept, several SNPs were further tested in different populations for their association with CVD risk: (1) LPL rs13702 is associated with TG and HDL-C, and interact with PUFA intake in 10 populations; (2) GFOD2 rs12449157 is associated with LDL-C change in response to dietary intervention to prevent metabolic syndrome in Mexicans; (3) PSMD3 rs4795413 interacts with dietary n-3 PUFA intake influencing insulin resistance in GOLDN (HOMA-IR). In summary, identification of adaptive variants in the human genome may provide better insight about the implementation of specific dietary recommendations or dietary patterns in selected populations.

5. LAB: Nutrition and genomics: Statistical analysis of genotype data related to aging genes. Based on identified human orthologues of lifespan genes, ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA have identified and examined 41 candidate genes that may influence type 2 diabetes risk. We found six genes in the insulin signal pathway that show strong association and interaction with dietary fat intake influencing insulin resistance. We also found a set of diabetes risk genes displaying strong interactions with vitamin D and affecting insulin resistance. A similar approach was taken to examine if lifespan genes are associated with inflammation biomarkers. We identified a set of genes interacted with dietary intakes and lifestyles and exhibited strong association with inflammation biomarkers. Further, in collaboration with Zhejiang University Researchers in China, demonstrated that a set of aging genes were downregulated by dietary intake curcumin (curry), consumption of which increased the mean lifespan in flies. The results demonstrated that curry intake can promote healthy aging through regulating lifespan-related genes.


Review Publications
Parnell, L.D., Lee, Y., Lai, C. 2010. Adaptive genetic variation and heart disease risk. Current Opinion in Lipidology. 21(2):116-122.

Parnell, L.D., Lindenbaum, P., Shameer, K., Dall'Olio, G.M., Swan, D.C., Jensen, L.J., Cockell, S.J., Pedersen, B.P., Mangan, M.E., Miller, C., Albert, I. 2011. BioStar: an online question & answer resource for the bioinformatics community. PLoS Computational Biology. 7:e1002216.

Parnell, L.D. 2012. Advances in technologies and study design. In: Bouchard, C., Ordovas, J.M., editors. Progress in Molecular Biology and Translational Science. New York, NY: Elsevier Inc. 108:17-50.

Ye, X., Lai, C., Crott, J., Troen, A., Ordovas, J., Tucker, K. 2011. The folate hydrolase 1561 C>T polymorphism is associated with depressive symptoms in Puerto Rican adults. Psychosomatic Medicine. 73(5):385-392.

Gomez-Abellan, P., Madrid, J., Ordovas, J.M., Garaulet, M. 2012. Chronobiological aspects of obesity and metabolic syndrome. Endocrinology and Nutrition. 59(1):50-61.

Casasnovas, J.A., Alcalde, V., Civeira, F., Guallar, E., Ibanez, B., Jimenez-Borreguero, J., Laclaustra, M., Leon, M., Ordovas, J.M., Pocovi, M., Sanz, G., Fuster, V. 2012. Aragon workers' health study - design and cohort description. BioMed Central - Cardiovascular Disorders. 12(1):45.

Cowley, A.W., Nadeau, J.H., Baccarelli, A., Berecek, K., Fornage, M., Gibbons, G.H., Harrison, D.G., Liang, M., Nathanielsz, P.W., O'Connor, D.T., Ordovas, J.M., Peng, W., Soares, M., Szyf, M., Tolunay, H.E., Wood, K.C., Zhao, K., Galis, Z.S. 2012. Report of the National Heart, Lung, and Blood Institute Working Group on epigenetics and hypertension. Hypertension. 59(5):899-905.

Peter, I., Huggins, G.S., Ordovas, J.M., Haan, M., Seddon, J.M. 2011. Evaluation of new and established age-related macular degeneration susceptibility genes in the Women's Health Initiative Sight Exam (WHI-SE) Study. Journal of Ophthalmology. 152(6):1005-1013.

Gesteiro, E., Bastida, S., Vazquez-Valasco, M., Corella, D., Guillen, M., Ordovas, J.M., Sanchez-Muniz, F.J. 2011. Effects of APOA5 S19W polymorphism on growth, insulin sensitivity and lipoproteins in normoweight neonates. European Journal of Pediatrics. 170(12):1551-1558.

Smith, C.E., Arnett, D.K., Corella, D., Tsai, M.Y., Lai, C., Parnell, L.D., Lee, Y., Ordovas, J.M. 2012. Perilipin polymorphism interacts with saturated fat and carbohydrates to modulate insulin resistance. Nutrition, Metabolism and Cardiovascular Diseases. 22(5):449-455.

Tsai, A.K., Steffen, B.T., Ordovas, J.M., Straka, R.J., Zhou, X., Hanson, N.Q., Arnett, D.K., Tsai, M.Y. 2011. Short-term fenofibrate treatment reduces elevated plasma Lp-PLA2 mass and sVCAM-1 levels in a subcohort of hypertriglyceridemic GOLDN participants. Translational Research. 58(2):99-105.

Frazier-Wood, A.C., Ordovas, J.M., Straka, R.J., Hixson, J.E., Borecki, I.B., Tiwari, H.K., Arnett, D.K. 2012. The PPAR alpha gene is associated with triglyceride, low-density cholesterol and inflammation marker response to fenofibrate intervention: the GOLDN study. The Pharmacogenomics Journal. DOI: 10.1038/TPJ.2012.9.

Gomez-Abellan, P., Gomez-Santos, C., Madrid, J.A., Milagro, F.I., Campion, J., Martinez, J.A., Lujan, J.A., Ordovas, J.M., Garaulet, M. 2011. Site-specific circadian expression of leptin and its receptor in human adipose tissue. Nutricion Hospitalaria. 26(6):1394-1401.

Gomez-Abellan, P., Madrid, J.A., Lujan, J.A., Frutos, M.D., Gonzalez, R., Martinez-Augustin, O., Sanchez De Medina, F., Ordovas, J.M., Gauralet, M. 2012. Sexual dimorphism in clock genes expression in human adipose tissue. Obesity Surgery. 22(1):105-112.

Frazier-Wood, A.C., Glasser, S.P., Garvey, W.T., Kabagambe, E.K., Borecki, I.B., Tiwari, H.K., Tsai, M.Y., Hopkins, P.N., Ordovas, J.M., Arnett, D.K. 2011. Lipoprotein lipase S447X variant associated with VLDL, LDL and HDL diameter clustering in the MetS. Lipids in Health and Disease. 10:143.

Hernandez-Morante, J.J., Gomez-Santos, C., Margareto, J., Formiguera, X., Martinez-Carlos, M., Gonzalez, R., Martinez-Augustin, O., Madrid, J.A., Ordovas, J.M., Garaulet, M. 2011. Influence of menopause on adipose tissue clock gene genotype and its relationship with metabolic syndrome in morbidly obese women. Age. DOI 10.1007/s11357-011-9309-2.

Frazier-Wood, A.C., Kabagambe, E.K., Borecki, I.B., Tiwari, H.K., Ordovas, J.M., Arnett, D.K. 2012. Preliminary evidence for an association between LRP-1 genotype and body mass index in humans. PLoS One. 7(2):e30732.

Frazier-Wood, A.C., Glasser, S., Garvey, W.T., Kabagambe, E.K., Borecki, I.B., Tiwari, H.K., Tsai, M.Y., Hopkins, P.N., Ordovas, J.M., Arnett, D.K. 2011. A clustering analysis of lipoprotein diameters in the metabolic syndrome. Lipids in Health and Disease. 10:237.

Garaulet, M., Esteban Tardido, A., Lee, Y., Smith, C., Parnell, L.D., Ordovas, J. 2012. SIRT1 and CLOCK 3111T greater than C combined genotype is associated with evening preference and weight loss resistance in a behavioral therapy treatment for obesity. International Journal of Obesity. DOI: 10.1038/ijo.2011.270.

Van Rompay, M., Castaneda-Sceppa, C., Mckeown, N., Ordovas, J., Tucker, K. 2011. Prevalence of cardiovascular disease risk factors among older Puerto Rican adults living in Massachusetts. Journal of Immigrant and Minority Health. 13(5):825-833.

Bouchard, C., Ordovas, J.M. 2012. Fundamentals of nutrigenetics and nutrigenomics. Progress in Molecular Biology and Translational Science. 108:1-15.

Zachariah, J.P., Pencina, M.J., Lyass, A., Kaur, G., D'Agostino, R.B., Ordovas, J.M., Vasan, R.S. 2011. Circulating plasma cholesteryl ester transfer protein activity and blood pressure tracking in the community. Journal of Hypertension. 29(5):863-868.

Garaulet, M., Ordovas, J.M., Gomez-Abellan, P., Martinez, J.A., Madrid, J.A. 2011. An approximation to the temporal order in endogenous circadian rhythms of genes implicated in human adipose tissue metabolism. Journal of Cellular Physiology. 226(8):2075-2080.

Aslibekyan, S., Jensen, M.K., Campos, H., Linkletter, C.D., Loucks, E.B., Ordovas, J.M., Deka, R., Rimm, E.B., Baylin, A. 2012. Genetic variation in fatty acid elongases is not associated with intermediate cardiovascular phenotypes or myocardial infarction. European Journal of Clinical Nutrition. 66(3):353-359.

Aslibekyan, S., Jensen, M.K., Campos, H., Linkletter, C.D., Loucks, E.B., Ordovas, J.M., Deka, R., Rimm, E.B., Baylin, A. 2012. Fatty acid desaturase gene variants, cardiovascular risk factors, and myocardial infarction in the costa rica study. Frontiers in Genetics. 3:72.

Wojczynski, M.K., Glasser, S.P., Oberman, A., Kabagambe, E.K., Hopkins, P.N., Tsai, M.Y., Straka, R.J., Ordovas, J.M., Arnett, D.K. 2011. High-fat meal effect on LDL, HDL, and VLDL particle size and number in the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN): an interventional study. Lipids in Health and Disease. 10:181.

Ordovas, J., Robertson, R., Cleirigh, E. 2011. Gene-gene and gene-environment interactions defining lipid-related traits. Current Opinion in Lipidology. 22(2):129-136.

Aslibekyan, S., Campos, H., Loucks, E.B., Linkletter, C.D., Ordovas, J.M., Baylin, A. 2011. Development of a cardiovascular risk score for use in low- and middle-income countries. Journal of Nutrition. 141(7):1375-1380.

Mata, N., Alonso, R., Badimon, L., Padro, T., Fuentes, F., Muniz, O., Perez-Jimenez, F., Lopez-Miranda, J., Diaz, J.L., Vidal, J.I., Barba, A., Piedecausa, M., Sanchez, J.F., Irigoyen, L., Guallar, E., Ordovas, J.M., Mata, P. 2011. Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART). Lipids in Health and Disease. DOI: 10.1186/1476-511X-10-94.

Mattei, J., Demissie, S., Tucker, K.L., Ordovas, J.M. 2011. The APOA1/C3/A4/A5 cluster and markers of allostatic load in the Boston Puerto Rican Health Study. Nutrition Metabolism and Cardiovascular Disease. 21(11):862-870.

Smith, C.E., Ordovas, J.M., Sanchez-Moreno, C., Lee, Y., Garaulet, M. 2012. Apolipoprotein A-II polymorphism: relationships to behavioural and hormonal mediators of obesity. International Journal of Obesity. 36(1):130-136.

Ordovas-Montanes, J., Ordovas, J. 2012. Cholesterol, inflammasomes, and atherogenesis. Current Cardiovascular Risk Reports. 6(1):45-52.

Corella, D., Ordovas, J. 2012. Interactions between dietary n-3 fatty acids and genetic variants and risk of disease. British Journal of Nutrition. 107:S271-S283.

Richardson, K., Louie-Gao, Q., Arnett, D., Parnell, L.D., Lai, C., Davalos, A., Fox, C., Demissie, S., Cupples, L., Fernandez-Hernando, C., Ordovas, J. 2011. The PLIN4 variant rs8887 modulates obesity related phenotypes in humans through creation of a novel miR-522 seed site. PLoS One. 6(4):e17944.

Richardson, K., Lai, C., Parnell, L.D., Lee, Y., Ordovas, J. 2011. A genome-wide survey for SNPs altering microRNA seed sites identifies functional candidates in GWAS. Biomed Central (BMC) Genomics. 2:504.

Feng, R., Wu, Y., Jang, G., Ordovas, J.M., Arnett, D.K. 2011. A powerful test of parent-of-origin effects for quantitative traits using haplotypes. PLoS One. 6(12):e28909.

Corbalan-Tutau, M., Madrid, J., Ordovas, J., Smith, C., Nicolas, F., Garaulet, M. 2011. Differences in daily rhythms of wrist temperature between obese and normal-weight women: associations with metabolic syndrome features. Society for Chronobiology International Conference Proceedings. 28(5):425-433.

Garcia-Rios, A., Perez-Martinez, P., Mata, P., Fuentes, F., Lopez-Miranda, J., Alonso, R., Caballero, J., Mata, N., Perez-Jimenez, F., Ordovas, J.M. 2010. Polymorphism at the TRIB1 gene modulates plasma lipid levels: insight from the Spanish familial hypercholesterolemia cohort study. Nutrition Metabolism and Cardiovascular Disease. 21(12):957-963.

Feitosa, M., An, P., Ordovas, J., Ketkar, S., Hopkins, P., Straka, R., Arnett, D., Borecki, I. 2011. Association of gene variants with lipid levels in response to fenofibrate is influenced by metabolic syndrome status. Atherosclerosis. 215(2):435-439.

Kwak, J., Paik, J., Kim, O., Jang, Y., Lee, S., Ordovas, J., Lee, J. 2011. FADS gene polymorphisms in Koreans: association with _6 polyunsaturated fatty acids in serum phospholipids, lipid peroxides, and coronary artery disease. Atherosclerosis. 214(1):94-100.

Perez-Martinez, P., Ordovas, J.M., Garcia-Rios, A., Delgado-Lista, J., Delgado-Casado, N., Cruz-Teno, C., Camargo, A., Yubero-Serrano, E., Rodriguez, F., Perez-Jimenez, F., Lopez-Miranda, J. 2011. Consumption of diets with different type of fat influences triacylglycerols-rich lipoproteins particle number and size during the postprandial state. Nutrition Metabolism and Cardiovascular Disease. 21(1):39-45.

Shen, J., Lai, C., Mattei, J., Ordovas, J.M., Tucker, K.L. 2010. Association of vitamin B-6 status with inflammation, oxidative stress, and chronic inflammatory conditions: the Boston Puerto Rican Health Study. American Journal of Clinical Nutrition. 91(2):337-342.

Junyent, M., Tucker, K., Shen, J., Lee, Y., Smith, C., Mattei, J., Lai, C., Parnell, L.D., Ordovas, J. 2010. A composite scoring of genotypes discriminates coronary heart disesase risk beyond conventional risk factors in the Boston Puerto Rican Health Study. Nutrition Metabolism and Cardiovascular Disease. 20(3):157-164.

Lai, C. 2012. Adaptive genetic variation and population differences. In: Bouchard, C., Ordovas, J. M., editors. Recent Advances in Nutrigenetics and Nutrigenomics. Oxford, UK: Elsevier. 108:461-489. PMID.22656388.

Sanchez-Muniz, F., Schaefer, E.J., Ordovas, J. 2008. Serum lipid and antioxidant responses in hypercholesterolemic men and women receiving plant sterol esters vary by apolipoprotein E genotype. Journal of Nutrition. 139:13-19.

Laclaustra, M., Navas-Acien, A., Stranges, S., Ordovas, J., Guallar, E. 2009. Serum selenium concentrations and diabetes in U.S. adults: National Health and Nutrition Examination Survey (NHANES) 2003-2004. Environmental Health Perspectives. 117(9):1409-1413.

Cusano, N., Kiel, D., Demissie, S., Karasik, D., Cupples, L., Corella, D., Gao, Q., Richardson, K., Yiannakouris, N., Ordovas, J. 2012. A polymorphism in a gene encoding Perilipin 4 is associated with height but not with bone measures in individuals from the Framingham Osteoporosis Study. Calcified Tissue International. 90(2):96-197.

Shen, J., Arnett, D., Parnell, L.D., Lai, C., Straka, R., Hopkins, P., An, P., Feitosa, M., Ordovas, J. 2012. The effect of CYP7A1 polymorphisms on lipid responses to fenofibrate. Journal of Cardiovascular Pharmacology. 59(3):254-259.

Lluis-Ganella, C., Subirana, I., Lucas, G., Tomas, M., Munoz, D., Senti, M., Salas, E., Sala, J., Ramos, R., Ordovas, J.M., Marrugat, J., Elosua, R. 2012. Assessment of the value of a genetic risk score in improving the estimation of coronary risk. Atherosclerosis. 222(2):456-463.

Perez-Martinez, P., Delgado-Lista, J., Garcia-Rios, A., Mcmonagle, J., Gulseth, H.L., Ordovas, J.M., Shaw, D.I., Karlstrom, B., Kiec-Wilk, B., Blaak, E.E., Helal, O., Malczewska-Malec, M., Defoort, C., Riserus, U., Saris, W., Lovegrove, J.A., Drevon, C.A., Roche, H.M., Lopez-Miranda, J. 2011. Glucokinase regulatory proten genetic variant interacts with omega-3 PUFA to influence insulin resistance and inflammation in metabolic syndrome. PLoS One. 6(6):e20555.

Last Modified: 10/21/2014
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