Gender, Nutrigenomics and CVD Jose M Ordovas, PHD

Director, Nutrition and Genomics LaboratoryJean Mayer USDA Human Nutrition Research Center on Aging at

Tufts University

jose.ordovas@tufts.edu

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

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

Traditional Epidemiology

Take Home Message

• The Population Mean does not properly describes/represents the individual within the population.

• One size does not fit all.

Healthier artery with decreased plaque

HDL HDL

Liver

SR-B1

LDL/apo B–E

Receptor

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 Increased liver LDLliver LDLreceptor receptor activity activity

decreases decreases circulating circulating

LDL-CLDL-C

CM

Atherosclerotic plaque

Artery with increased plaque

LDL LDL

Synthesis - LiverSynthesis - Liver

Absorption – Absorption – IntestineIntestine

Synthesis – Synthesis – Peripheral TissuesPeripheral Tissues

BiliaryBiliarycholesterolcholesterol

DietaryDietarycholesterolcholesterol

Intestinal Intestinal epithelial cellepithelial cell

CE

Freecholesterol

ABC G5ABC G8(esterification)

BileBileacidacid

uptakeuptake

LuminalLuminalcholesterolcholesterol

MicellarMicellarcholesterolcholesterol

Cholesterol Cholesterol TransporterTransporter

MTP

ACAT excretion

DecreaseDecreased liver d liver LDLLDLreceptor receptor activity activity increases increases circulating circulating LDL-CLDL-C

Lipoprotein Metabolism Exogenous - Pathway - Endogenous

Intestine

Dietary Fat& Cholesterol

LPL

ChylomicronChylomicron

Remnant

FFA

Liver

LPL

VLDLIDL

FFA

Bile Acids+

CholesterolLDL

PeripheralTissues

HDL

APOE

• 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.

• 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.

CVD rates, plasma Cholesterol and APOE allelesThe Framingham Study

-15

-10

-5

0

5

10

Framingham

Ch

oles

tero

l (m

g/d

L)

E2 E3 E4

Lahoz C et al. Atherosclerosis. 2001 15;154:529-37.

0

50

100

150

200

250

Men Women

Adj

uste

d R

ate/

1000

E2 E3 E4

a a

b

c c

d

-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

Baseline (HFHC) NCEP Step 2

Per

cen

t L

DL

-C r

esp

onse

-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

Baseline (HFHC) NCEP Step 2

Per

cent

LD

L-C

res

pons

e

Variability in LDL-C response following Diet Therapy

Men Women

-25

-20

-15

-10

-5

0

MEN WOMEN

% L

DL

-C C

hang

e

E4

E3

E2

LDL-C Response to a Therapeutic Diet by APOE allele

Lopez-Miranda et al. J Lipid Res. 1994;35:1965-75.

a

bb

b

b

b

Pharmacogenetics of Statins: Response is Gender Specific

artery

HDL3HDL3

Pre-beta3HDL

HDL3HDL3

Pre-beta2HDL

PLCh

HDL-R

CEFA

CE TGTo apoB containing lipoproteins

To periphery

CETPCETP

ChPLCh

Ch

Ch

Ch

LCATLCAT

HLHL

Pre-beta1 HDL

Liver

ApoA-I

HDL2aHDL2a HDL2bHDL2b

The APOA1-APOC3-APOA4-APOA5 locus

High Density LipoproteinHigh Density Lipoprotein

apoA-IapoA-IapoA-IIapoA-II

Phospholipids and Phospholipids and Free CholesterolFree Cholesterol

Triglyceride and Triglyceride and Cholesteryl EstersCholesteryl Esters

apoA-IapoA-I

SstI 360347MspI

0

1

2

3

4

25 45 65

HDL-Cholesterol (mg/dl)C

HD

ris

k r

ati

o

CHD Risk According to HDL-C CHD Risk According to HDL-C Levels: The Framingham StudyLevels: The Framingham Study

Mean Plasma HDL-C and Apolipoprotein AI by APOA1(-75G/A) Genotypes in the Framingham Study

0

20

40

60

80

100

120

140

160

180

HDL-C(M) APOA1(M) HDL-C(F) APOA1(F)

mg

/dl

GG

GA+AA

Ordovas et al. Am. J. Clin. Nutr. (2002)

1

1.2

1.4

1.6

1.8

G/G G/A A/A

APOA1(-75G/A) Genotype

HD

L-C

(m

mo

l/L

)

<4%

4%-8%

>8%

Polyunsaturated fatty acids modulate the effects of the APOA1-75(g/a) polymorphism on HDL-C levels in a genderSpecific 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

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

Combined effect of the PLIN polymorphisms on weight and BMI (Valencia,Spain)

PLIN1 PLIN4 PLIN5 PLIN6

22

24

24.5

25

25.5

26

26.5

27

27.5

28

28.5

29

Women Men

BM

I

11/11/11/11

11/11/2+/2+

2+/2+/11/11

2+/2+/2+/2+

Qi, L. Clin Genet. 2004 Oct;66(4):299-310.

Combined effect of the PLIN polymorphisms on Weight and BMI (Santa Monica, CA)

PLIN1 PLIN4 PLIN5 PLIN624

25

26

27

28

29

30

31

32

33

Women

BM

I

11/11/11/11

11/11/2+/2+

2+/2+/11/11

2+/2+/2+/2+

Qi et al. Obes Res. 2004 Nov;12(11):1758-65

PLIN SNPs and Weight Loss

Weight reduction, low caloric diet and PLIN (11482G>A ) polymorphism in obese subjects

-8

-7

-6

-5

-4

-3

-2

-1

0

1

Baseline 3 Months 6 Months 12 Months

Time on Diet

Per

cen

t w

eig

ht

chan

ge

1_1

2 carrier

Corella et al. J Clin Endocrinol Metab 90: 5121–5126, 2005

27

28

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.

Limitations of the current approach

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.