Nutrigenetics Today s Concept Tomorrow s Reality

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Julius Goodman
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1 Nutrigenetics Today s Concept Tomorrow s Reality Jose M Ordovas, PHD Director, Nutrition and Genomics Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University

2 Some recent nutrition and health messages towards the consumer

3 Some recent nutrition and health messages towards the consumer Is there really no effect of nutrition on health? Or are we doing something wrong here?

4 Why did this study produce poor results? Not all fats are equal (SAT, PUFA, MUFA, W- 3/W-6, etc) Not all women are equal (genotype, phenotype) Would the right (amount and type of) fat for the right woman have produced a much more pronounced effect?

5 Epidemiology or the morphing of reality Individual Real Population Virtual

6 Traditional Genetics:Number of statistically significant follow-up studies for 25 associations Bottom line 25 SNPs 301 Studies 59 with p< in same direction 12 in opposite direction Publication bias obvious Lohmueller, K. E., Pearce, C. L., Pike, M., Lander, E. S. & Hirschhorn, J. N. (2003) Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat. Genet. 33:

Two Sources of Cholesterol Synthesis and Absorption Intestine Ovary Increased liver LDL receptor activity decreases circulating LDL-C Muscle LDL Skin Adrenal Synthesis Peripheral Tissues HDL SR-B1

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

High Density Lipoprotein and Coronary Heart

Triglyceride and Cholesteryl Esters apoa-i CHD

9 High Density Lipoprotein and Coronary Heart Disease High Density Lipoprotein CHD Risk According to HDL-C Levels: The Framingham Study apoa-i Phospholipids and Free Cholesterol apoa-ii Triglyceride and Cholesteryl Esters apoa-i CHD risk ratio HDL-Cholesterol (mg/dl) MspI SstI

10 Mean Plasma HDL-C and Apolipoprotein AI by APOA1(-75G/A) Genotypes in the Framingham Study mg/dl HDL-C(M) APOA1(M) HDL-C(F) APOA1(F) GG GA+AA Ordovas et al. Am. J. Clin. Nutr. (2002)

12 Organization of regulatory elements within the APOA1 gene promoter Trans FA Saturated FA Mono- and PUFA a-tocopherol Ascorbic acid 25-OH Vit D3 DMSO Glucosamine IRCE Cr, Mg, V, Zn A B C CCAT TATA IRCE Sp1 Site A - TR, HNF-4, RARa,b, RXRa, C/EBP. ARP-1 PPARa, Rev-erba. Site B - HNF-3, glucorticoid receptor, estrogen receptor Site C HNF-4, ARP-1 TATA Basal transcription apparatus, ntre, ph-re

13 Polyunsaturated fatty acids modulate the effects of the APOA1-75(G/A) polymorphism on HDL-C levels: The Framingham Study 70 >8% 65 P<0.001 HDL-C (mg/dl) >8% <4% 4%-8% 4%-8% >8% <4% <4% 4%-8% 45 G/G G/A A/A Ordovas et al. Am. J. Clin. Nutr. (2002) APOA1(-75G/A) Genotype

Role of Hepatic Lipase and Lipoprotein Lipase

2 PL CE -763 (A/G) -710 (T/C) -514 (C/T) -250

14 Role of Hepatic Lipase and Lipoprotein Lipase in HDL Metabolism Endothelium LPL B TG C-II CMR/IDL B PL A-I CE TG CM/VLDL A-I Phospholipids and apolipoproteins Kidney HL HDL 2 PL CE -763 (A/G) -710 (T/C) -514 (C/T) -250 (G/A) HDL 3 Exon Slide Source LipidsOnline

15 Diet-induced changes on LDL- and HDL-C concentrations by LIPC Genotypes Predicted lipoprotein cholesterol L D L LDL HDL H D L? CC TT % Fat intake (% total energy) TT CC TT CC Ordovas et al. Circulation 2002;

16 déjà vu?

One size does not fit all and no all PUFA are Equal: APOA5, Remnants and PUFAs in the Framingham Heart Study PUFA N-6 Intake Tertile 1 Tertile 2 Tertile 3 PUFA N-3 Intake Tertile 1 Tertile

17 One size does not fit all and no all PUFA are Equal: APOA5, Remnants and PUFAs in the Framingham Heart Study PUFA N-6 Intake Tertile 1 Tertile 2 Tertile 3 PUFA N-3 Intake Tertile 1 Tertile 2 Tertile P interaction: P interaction: RLPC (mg/dl) RLPC (mg/dl) TT C carriers TT C carriers Lai et al. Circulation; May 2, Circulation 2006

18 Limitations of the current approach

19 Building Blocks to Personalized Health Technologies Quantitative assessment Databases Phenotype annotated Knowledge Linking Metabolism to Phenotype Recommendations

20 T-cell receptor signalling in human blood cells after high protein or high carbohydrate breakfast in a cross over intervention study HC HP # gene expressions changed in human white blood cells

21 Our Global Nutrigenetic Position

22 NuGO Rowett Un Oslo Un. Ulster Trinity Un Newcastle Un Lund Un Cork Un Reading EBI IFR Rivm Rikilt TNO Un Wageningen DiFE Un Maastricht Un Krakow NuGO Un Munich Inserm Marseille Un Florence European NutriGenomics Organisation Un Balearic Illes the European Nutrigenomics Organisation

23 and elsewhere.. Bruce N. Ames International Symposium on Nutritional Genomics (Davis, CA, October 22-24, 2004)

Pathophysiology of Lipid Disorders

Pathophysiology of Lipid Disorders Henry Ginsberg, M.D. Division of Preventive Medicine and Nutrition CHD in the United States CHD is the single largest killer of men and women 12 million have history