gender, nutrigenomics and cvd jose m ordovas, phd director, nutrition and genomics laboratory jean...
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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.
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