Transcript Gene_diet interactions

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
[email protected]
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.
Plasma Lipoprotein Metabolism
Intestinal
epithelial cell
Arterial lumen
MTP
Skin
Intestine
CE
excretion
ACAT
Ovary
(esterification)
Atherosclerotic plaque/foam cells
Muscle
Adrenal
HDL
Synthesis –
Peripheral Tissues
Increased
liver LDL
receptor
activity
decreases
circulating
LDL-C
CM
HDL
Biliary Dietary
cholesterol cholesterol
Free
cholesterol
ABC G5
ABC G8
Cholesterol
Transporter
Luminal
cholesterol
Bile
acid
Micellar
cholesterol
uptake
Absorption –
Intestine
SR-B1
Liver
LDL/apo
B–E
Receptor
LDL
LDL
Decreased
liver LDL
receptor
activity
increases
circulating
LDL-C
Synthesis - Liver
Atherosclerotic plaque
Healthier artery with decreased plaque
Artery with increased plaque
Bays H et al. Expert Opin Pharmacother 2003;4:779-790.
Lipoprotein Metabolism
Exogenous - Pathway -
Endogenous
APOE
Dietary Fat
& Cholesterol
Bile Acids
+
Cholesterol
Peripheral
Tissues
LDL
Liver
Intestine
IDL
Chylomicron
Remnant
Chylomicron
LPL
FFA
VLDL
LPL
FFA
HDL
•
•
•
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 alleles
The Framingham Study
E2
E4
a
a
E2
200
150
E3
E4
10
b
5
d
100
c
c
Cholesterol (mg/dL)
Adjusted Rate/1000
250
E3
0
-5
-10
50
-15
Framingham
0
Men
Lahoz C et al. Atherosclerosis. 2001 15;154:529-37.
Women
Variability in LDL-C response following
Diet Therapy
10
5
5
Percent LDL-C response
10
Percent LDL-C response
0
-5
-10
-15
-20
-25
-30
-35
-40
Men
Baseline (HFHC)
0
-5
-10
-15
-20
-25
-30
-35
-40
NCEP Step 2
Women
Baseline (HFHC)
NCEP Step 2
LDL-C Response to a
Therapeutic Diet by APOE allele
MEN
WOMEN
% LDL-C Change
0
-5
b
-10
b
-15
b
b
-20
-25
a
Lopez-Miranda et al. J Lipid Res. 1994;35:1965-75.
b
E4
E3
E2
Pharmacogenetics of Statins:
Response is Gender Specific
PL
Ch
PL
Ch
Ch
artery
Pre-beta2
HDL
Ch
Pre-beta1 HDL
LCAT
Pre-beta3
HDL
HDL3
HL
HDL3
CETP
Ch
ApoA-I
HDL2a
HDL2b
HDL-R
FA
CE
Liver
Ch
CE TG
To apoB containing
lipoproteins
To periphery
The APOA1-APOC3-APOA4-APOA5 locus
High Density Lipoprotein
CHD Risk According to HDL-C
Levels: The Framingham Study
apoA-I
apoA-II
Phospholipids and
Free Cholesterol
Triglyceride and
Cholesteryl Esters
apoA-I
CHD risk ratio
4
3
2
1
0
25
45
HDL-Cholesterol (mg/dl)
MspI
SstI
347 360
65
mg/dl
Mean Plasma HDL-C and Apolipoprotein AI
by APOA1(-75G/A) Genotypes in the
Framingham Study
180
160
140
120
100
80
60
40
20
0
GG
GA+AA
HDL-C(M) APOA1(M)
HDL-C(F)
Ordovas et al. Am. J. Clin. Nutr. (2002)
APOA1(F)
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
1.8
HDL-C (mmol/L)
P<0.001
1.6
Unexpected!
More PUFA= More HDLC
Expected!
More PUFA= LESS HDLC
<4%
4%-8%
>8%
1.4
1.2
1
G/G
G/A
APOA1(-75G/A) Genotype
Ordovas et al. Am. J. Clin. Nutr. (2002)
A/A
Perilipin function and Gene Structure
Hormone sensitive
lipase
Perilipin
Triacylglycerols
Exon1 Exon2
Exon3
Exon4 Exon5 Exon6
Exon7
Exon8
Exon9
13041
(A>G)
14995
(A>T)
Perilipin
6209
(T>C)
10171
(A>T)
11482
(G>A)
Combined effect of the PLIN polymorphisms on
weight and BMI (Valencia,Spain)
29
28.5
28
27.5
BMI
27
11/11/11/11
11/11/2+/2+
2+/2+/11/11
2+/2+/2+/2+
26.5
26
25.5
25
24.5
PLIN1
24
Women
22
Qi, L. Clin Genet. 2004 Oct;66(4):299-310.
PLIN4 PLIN5 PLIN6
Men
Combined effect of the PLIN polymorphisms on
Weight and BMI (Santa Monica, CA)
33
32
31
BMI
30
11/11/11/11
11/11/2+/2+
2+/2+/11/11
2+/2+/2+/2+
29
28
27
26
25
24
PLIN1
PLIN4 PLIN5 PLIN6
Women
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
Baseline
3 Months
6 Months
12 Months
1
Percent weight change
0
-1
-2
-3
1_1
2 carrier
-4
-5
-6
-7
-8
Time on Diet
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.