Gene_diet interactions

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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 at Tufts
University jose.ordovas_at_tufts.edu
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Do we Really Need to Take this Uncertain Walk
Into the Future?
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Yes, Considering that this has been the Path of
Nutrition Recommendations
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Traditional Epidemiology
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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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Plasma Lipoprotein Metabolism
Biliarycholesterol
Dietarycholesterol
Intestinal epithelial cell
CE
excretion
(esterification)
Cholesterol Transporter
Freecholesterol
HDL
CM
HDL
Synthesis Peripheral Tissues
Absorption Intestine
SR-B1
Decreased liver LDLreceptor activity increases
circulating LDL-C
Increased liver LDLreceptor activity decreases
circulating LDL-C
Liver
LDL/apo BE Receptor
Synthesis - Liver
Bays H et al. Expert Opin Pharmacother
20034779-790.
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Lipoprotein Metabolism Exogenous - Pathway
- Endogenous
APOE
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• 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.

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CVD rates, plasma Cholesterol and APOE
alleles The Framingham Study
Lahoz C et al. Atherosclerosis. 2001
15154529-37.
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Variability in LDL-C response following Diet
Therapy
Men
Women
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LDL-C Response to a Therapeutic Diet by APOE
allele
b
b
b
b
b
a
Lopez-Miranda et al. J Lipid Res.
1994351965-75.
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Pharmacogenetics of Statins Response is Gender
Specific
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PL
PL
Ch
Ch
Ch
Pre-beta2 HDL
Ch
Pre-beta1 HDL
Pre-beta3 HDL
LCAT
HDL3
ApoA-I
HDL3
HDL-R
HL
HDL2b
HDL2a
CE
CETP
FA
Ch
Liver
CE
TG
Ch
To apoB containing lipoproteins
To periphery
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The APOA1-APOC3-APOA4-APOA5 locus
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Mean Plasma HDL-C and Apolipoprotein AI by
APOA1(-75G/A) Genotypes in the Framingham Study
Ordovas et al. Am. J. Clin. Nutr. (2002)
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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
Plt0.001
Unexpected! More PUFA More HDLC
Expected! More PUFA LESS HDLC
Ordovas et al. Am. J. Clin. Nutr. (2002)
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Perilipin function and Gene Structure
Hormone sensitive lipase
Perilipin
Triacylglycerols
Exon1 Exon2
Exon3 Exon4 Exon5 Exon6
Exon7 Exon8 Exon9
Perilipin
6209
10171 11482 13041
14995 (TgtC)
(AgtT) (GgtA)
(AgtG) (AgtT)
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Combined effect of the PLIN polymorphisms on
weight and BMI (Valencia,Spain)
PLIN1 PLIN4 PLIN5 PLIN6
Qi, L. Clin Genet. 2004 Oct66(4)299-310.
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Combined effect of the PLIN polymorphisms on
Weight and BMI (Santa Monica, CA)
PLIN1 PLIN4 PLIN5 PLIN6
Qi et al. Obes Res. 2004 Nov12(11)1758-65
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PLIN SNPs and Weight Loss
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Weight reduction, low caloric diet and PLIN
(11482GgtA ) polymorphism in obese subjects
Corella et al. J Clin Endocrinol Metab 90
51215126, 2005
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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 Jun29(6)1313-9.
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Limitations of the current approach
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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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