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

7

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

9

-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

12

APOE genotype and longevity

13

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