nutrigenomics and personalised nutrition an update on the...
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Anne-Marie Minihane Prof of Nutrigenetics, Department of Nutrition and Preventive Medicine, Norwich Medical School, UEA, UK
Nutrigenomics and personalised nutrition – an update on the latest
research and its implications for consumers
1
Genetic discoveries timeline:
Disease risk
prediction
3 billion base pairs
20,000-22,000 genes
88 million variants
2
Personalised/stratified
prevention and
therapeutic strategies
Considered the PANACEA and
one of the greatest ever medical
achievements
1850-1860s: Origin of genetics Darwin and Wallace Mendel
1953: DNA structure Watson, Crick, Franklin
2001-2004 Human genome sequence available Human Genome Project
2015 The 1000 Genomes Project Consortium (Genetic Variation) Nature: 1 Oct 2015
Foods/supplements/
drugs targeted at
genetic subgroups
Don’t throw the baby out with the bath water
Unrealistic expectations of what could be achieved in a short timeframe
Has the large amount of research activity and funding examining common gene variants-environment (including diet
composition)-health/disease associations been worth it
• …… is the research investment beginning to deliver on the promise
• …… are there tangible examples of consistent associations between common genotypes and phenotypes which may be used in disease risk prediction or the stratification or preventative or therapeutic interventions.
• YES
• Genotype-phenotype/disease analysis has also:
- identified new pathological pathways
- established causality for disease biomarkers
4
CONTENT…….
• Do we need stratification/personalisation of dietary recommendations?
• APOE genotype, longevity, chronic disease risk and response to dietary fat composition
• TCF7L2 genotype, diabetes and dietary intervention
• Genetics of coronary artery disease (CAD)
• Translation of research into public health reality and benefit
5
1. At a population level, knowledge of, and adherence to, most of the generic dietary recommendations is poor……
6 Newton JN et al., Lancet Published Online September 15, 2015
Minihane, 4d weighed diet diary (Aug 2015) It is difficult to meet all ~ 50 recommendations and keep
energy intake in check
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Nutrient Intake Intake + supplement
RNI
Energy (kcal) 1723 1723 2000
Protein (g) 62 62 45 (or 0.75g/kg)
Total fat (%E) 39.1 39.1 33
SFA (%E) 15.5 15.5 10
Fibre (g) 21.7 21.7 18/up to 30g
Iron (mg) 9.2 9.2 15
Selenium (µg) 44 194 60
Vitamin D (µg) 1.8 23.7 (10)
Recommended intake
Beneficial
response
Negative
effect
No response
Effect Size
2. At a population level responsiveness to dietary change is hugely variable
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-300
-250
-200
-150
-100
-50
0
50
100
150
200
0 50 100 150 200 250 300 350
% change TG on 1.8g EPA+DHA per day for 8 weeks, n=312
n=118/312 ↑ TG
One third of participants showed increase in TG in response to fish oils
Group average (n=312) -11%
R245: -250%
R109: +150%
Caslake MJ, Miles EA, Kofler BM, Lietz G, Curtis P, Armah CK, Kimber AC, Grew JP, Farrell L, Stannard J, Napper
FL, Sala-Vila A, West AL, Mathers JC, Packard C, Williams CM, Calder PC, Minihane AM. AJCN, 2008;88:618-629.
Examples of (nutri)genetics in action
Targeted/candidate gene
• APOE genotype, longevity, chronic disease risk and response to dietary fat composition
• TCF7L2 genotype, diabetes and dietary intervention
10
• Liver (80-90%), brain and macrophages
Apolipoprotein E
Hatters DM et al., 2006
E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, E4/E4
1% 12% 2% 63% 20% 3%
Amino acid differences 112 158
APOE2 Cys Cys
APOE3 Cys Arg
APOE4 Arg Arg
Liu CC et al., 2013; Hallman MD et al., 1991
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APOE genotype and longevity
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APOE genotype and cardiovascular disease (Wilson PW et al., 1996; Song Y et al., 2004; Bennet AM et al., 2007; Holmes MV et al., 2014; Khan TA et al., 2013
APOE genotype and fasting plasma lipids: Dose response in increase in TC and LDL-C from APOE2/E2 to APOE4/E4
14 Bennet AM et al., 2007
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
0 60 120 180 240 300 360 420 480
TG
(m
mo
l/l)
time (min)
TG levels according to APOE genotype >50y
E2 carriers (n=33)
E3/3 (n=77)
E4 carriers (n=35)
Higher lipaemia following fat consumption in APOE4 carriers
49g fat, 0min
29g fat, 330min
Carvalho-Wells AL, Jackson KG, Gill R, Olano-Martin E, Lovegrove JA, Williams CM, Minihane AM. Atherosclerosis
2010;212:481-487
APOE genotype, dementia and Alzheimer’s Disease (AD)
16 Corder EH et al., 1993; Bertram L et al., 2007
0
5
10
15
20
50 60 70 80 90 100
OR
of
dis
ease
age of onset (y)
APOE genotype, odds ratio (OR, 95% CI) and average age of onset of Alzheimer's Disease (AD)
E3/E3, OR 1.0, 84y E3/E4, OR 4.3, 76y E4/E4, OR 15.6, 68y
E4/E4
E3/E4
E3/E3
17
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
TC LDLC HDLC TG
E3E3
E3E4
E4E4
-0.2
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
TC LDLC HDLC TG
NCEP diet
NCEP diet+
cholesterol
Sarkkinen E et al., AJCN 1998
APOE4 individuals are particularly sensitive to dietary
total fat and saturated fat
APOE4 (males) demonstrate the greatest responsiveness to the TG of fish oils: FINGEN (n=312)
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
ch
an
ge
TG
, 0
-8w
k (
mm
oll/
l)
CO 0.7FO 1.8FO
all females males APOE2 APOE3 APOE4
APOE4 males: 15% and 23% ↓ TG in response to 0.7FO and 1.8FO versus
8% and 11% ↓ in the group as whole
Caslake MJ, Miles EA, Kofler BM, Lietz G, Curtis P, Armah CK, Kimber AC, Grew JP, Farrell L, Stannard J, Napper
FL, Sala-Vila A, West AL, Mathers JC, Packard C, Williams CM, Calder PC, Minihane AM. AJCN, 2008;88:618-629.
Plasma Platelet MNC N ' phil RBC Liver Brain Retina Sperm0
10
20
30
40
PC PE PL PL PL PE PS PE PL
ALNA
EPA
DHA
Co
ncen
trati
on
(%
to
tal
fatt
y a
cid
s)
Brain tissue is particularly enriched with DHA
Reviewed in Burdge & Calder 2006 19
APOE genotype status likely to be major determinant of cognitive response to EPA+DHA intervention with some evidence of lower/lack
of response in APOE4 carriers (Quinn et al., 2010, Huang et al., 2005; Whalley et al., 2008; Bargerger-Gateau et al., 2007)
20
21
TCF7L2 genotype, diabetes and dietary intervention
Estruch R et al., NEJM 2013 Corella D et al., Diabetes Care 2013
CONTENT…….
• Introduction: Do we need personalisation of dietary recommendations
• Basics of genetics and nutrigenetics
• APOE genotype, longevity, chronic disease risk and response to dietary fat composition
• TCF7L2 genotype, diabetes and dietary intervention
• Genetic architecture of coronary artery disease
• Translation of research into public health reality and benefit
22
Genetic architecture of coronary artery disease (CAD)
• The CARDIoGRAMplusC4D Consortium, Nat Genet 2013;45:25-33
- 46 significant loci for CAD (P<5x10-8)
- 104 additional loci strongly associated at 5% FDR
- explain 10.6% 0f CAD heritability
- confirm causal role of plasma lipid and BP in CAD
- establish causal role of inflammation
23
Where is the missing heritability? (Minihane AM, PNS, 2013)
• ‘Hidden’ not missing
- epistasis
- environment (diet) * genotype interactions
- lack of precision in defining phenotype
CONTENT…….
• Introduction: Do we need personalisation of dietary recommendations
• Basics of genetics and nutrigenetics
• APOE genotype, longevity, chronic disease risk and response to dietary fat composition
• TCF7L2 genotype, diabetes and dietary intervention
• Genetic architecture of coronary artery disease
• Translation of research into public health reality and benefit
24
Effective personalisation of dietary recommendations will need to be multi-faceted and based on overall status and not just
‘gene-centric’
25
Habitual diet Genes
Phenotype
•Disease/Physiological status
•Microbiota
•Clinical/biochemical measures
•AGE
•Gender
•etc
Other lifestyle
Food preferences Cultural/religious considerations Food availability
26
Bioinformatics, logarithms, technology
Small number of bespoke dietary recommendations +
Generic advice
Diet
Age
Biochemistry
Microbiota Current
recommendations
Preferences
BMI
Genetics Etc, etc
Conclusion: Genetics, health/disease and nutrition Where are we at….
• 2004-2015: significant progress (Lander ES, Nature 2011) has been made in understanding genetic basis of monogenic disease,
identification of novel pathways in health and disease
establishment of causality
establishment of genotype-environment-phenotype associations for select gene variants (APOE, TCF7L2, MTHFR etc.)
• APOE4 (20-25% populations) are at increased risk of CAD and dementia/AD
• APOE4 highly responsive to dietary fat and other dietary/environmental factors and would particularly benefit from targeted advice/products
• Gaining understanding of the genetic architecture of polygenic health/disease and response to environment is ongoing
• Future genetic risk score used to target (with specific recommendations and products) individuals at highest risk of disease
27
Thank you… • Nutrition Department/Nutrigenetics Group at UEA
• Kim Jackson, Christine Williams, Julie Lovegrove, Jan Luff, University of Reading, UK
• John Mathers, Georg Lietz, University of Newcastle, UK • Philip Calder, Elizabeth Miles, University of Southampton, UK • Muriel Caslake, Chris Packard, University of Glasgow, UK • Gerald Rimbach et al., University of Kiel, Germany • Melanie Plourde et al., University of Sherbrooke, Canada
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