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Gender, Nutrigenomics and CVD Jose M Ordovas, PHD Director, Nutrition and Genomics Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging.

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Presentation on theme: "Gender, Nutrigenomics and CVD Jose M Ordovas, PHD Director, Nutrition and Genomics Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging."— Presentation transcript:

1 Gender, Nutrigenomics and CVD Jose M Ordovas, PHD Director, Nutrition and Genomics Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University jose.ordovas@tufts.edu

2 Do we Really Need to Take this Uncertain Walk Into the Future?

3 Yes, Considering that this has been the Path of Nutrition Recommendations

4 Traditional Epidemiology

5 Take Home Message The Population Mean does not properly describes/represents the individual within the population. One size does not fit all.

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7 Healthier artery with decreased plaque HDL Liver SR-B1 LDL/apo B–E Recepto r Bays H et al. Expert Opin Pharmacother 2003;4:779-790. Arterial lumen Atherosclerotic plaque/foam cells Plasma Lipoprotein Metabolism Ovary Intestine Muscle Skin Adrenal Increased liver LDL receptor activity decreases circulating LDL-C CM Atherosclerotic plaque Artery with increased plaque LDL Synthesis - Liver Absorption – Intestine Absorption – Intestine Synthesis – Peripheral Tissues Biliary cholesterol Dietary cholesterol Intestinal epithelial cell CE Free cholesterol ABC G5 ABC G8 (esterification) Bile acid uptake Luminal cholesterol Micellar cholesterol Cholesterol Transporter MTP ACAT excretion Decreased liver LDL receptor activity increases circulating LDL-C

8 Lipoprotein Metabolism Exogenous - Pathway - Endogenous Intestine Dietary Fat & Cholesterol LPL Chylomicron Remnant FFA Liver LPL VLDL IDL FFA Bile Acids + Cholesterol LDL Peripheral Tissues HDL APOE

9 Since our beginning in 1948, the Framingham Heart Study, under the direction of the National Heart, Lung and Blood Institute; NHLBI (formerly known as the National Heart Institute) has been committed to identifying the common factors or characteristics that contribute to cardiovascular disease (CVD). We follow CVD development over a long period of time in a large group of participants who had not yet developed overt symptoms of CVD or suffered a heart attack or stroke. Our Study began by recruiting an Original Cohort of 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts and since has added an Offspring Cohort (1971) and a Third Generation Cohort, which began in 2002.Original CohortOffspring CohortThird Generation Cohort Over the years, careful monitoring of the Framingham Study population has led to the identification of several major CVD risk factors, as well as a collection of valuable information on the effects of these factors such as blood pressure, blood triglyceride and HDL cholesterol levels, age, gender, and psychosocial issues. Risk factors for other physiological conditions such as dementia have been and continue to be investigated. In addition, the relationships between physical traits and genetic patterns are being studied.

10 CVD rates, plasma Cholesterol and APOE alleles The Framingham Study Lahoz C et al. Atherosclerosis. 2001 15;154:529-37. a a b c c d

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12 Variability in LDL-C response following Diet Therapy Men Women

13 LDL-C Response to a Therapeutic Diet by APOE allele Lopez-Miranda et al. J Lipid Res. 1994;35:1965-75. a b b b b b

14 Pharmacogenetics of Statins: Response is Gender Specific

15 HDL3 Pre-beta3 HDL HDL3 Pre-beta2 HDL PL Ch HDL-R CE FA CETG To apoB containing lipoproteins To periphery CETP Ch PL Ch LCAT HL Pre-beta1 HDL Liver ApoA-I HDL2a HDL2b

16 The APOA1-APOC3-APOA4-APOA5 locus High Density Lipoprotein apoA-I apoA-II Phospholipids and Free Cholesterol Triglyceride and Cholesteryl Esters apoA-I SstI 360347 MspI CHD Risk According to HDL-C Levels: The Framingham Study

17 Mean Plasma HDL-C and Apolipoprotein AI by APOA1(-75G/A) Genotypes in the Framingham Study Ordovas et al. Am. J. Clin. Nutr. (2002)

18 Polyunsaturated fatty acids modulate the effects of the APOA1-75(g/a) polymorphism on HDL-C levels in a gender Specific manner: The Framingham Study P<0.001 Ordovas et al. Am. J. Clin. Nutr. (2002) Expected! More PUFA= LESS HDLC Unexpected! More PUFA= More HDLC

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20 Perilipin function and Gene Structure Triacylglycerols Perilipin Hormone sensitive lipase 6209 10171 11482 13041 14995 (T>C) (A>T) (G>A) (A>G) (A>T) Exon1 Exon2 Exon3 Exon4 Exon5 Exon6 Exon7 Exon8 Exon9 Perilipin

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22 Combined effect of the PLIN polymorphisms on weight and BMI (Valencia,Spain) PLIN1 PLIN4 PLIN5 PLIN6 22 Qi, L. Clin Genet. 2004 Oct;66(4):299-310.

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24 Combined effect of the PLIN polymorphisms on Weight and BMI (Santa Monica, CA) PLIN1 PLIN4 PLIN5 PLIN6 Qi et al. Obes Res. 2004 Nov;12(11):1758-65

25 PLIN SNPs and Weight Loss

26 Weight reduction, low caloric diet and PLIN (11482G>A ) polymorphism in obese subjects Corella et al. J Clin Endocrinol Metab 90: 5121–5126, 2005

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29 PLIN, Diet and Metabolic Syndrome Corella D et al. Perilipin gene variation determines higher susceptibility to insulin resistance in Asian women when consuming a high-saturated fat, low-carbohydrate diet. Diabetes Care 2006 Jun;29(6):1313-9.

30 Limitations of the current approach

31 Summary Genotype/Phenotype associations may be gender dependent. Gene-environment interactions are also gender dependent. For this type of studies, gender-specific statistical analyses should be part of the “Standard Operating Procedures” and therefore included as part of the experimental design. There is potential for future personalized dietary recommendations to decrease risk of chronic disorders, but gender must be part of the equation.

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