Nutrigenetics and Nutrigenomics: Overview - UNC NRI...Nutrigenomics is not new...
Transcript of Nutrigenetics and Nutrigenomics: Overview - UNC NRI...Nutrigenomics is not new...
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Nutrigenetics and Nutrigenomics: Overview
Mar$n Kohlmeier, MD, PhD
University of North Carolina at Chapel Hill Department of Nutri7on
and UNC Nutri7on Research Ins7tute
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Defining nutrigene$cs and nutrigenomics
NGx has a long history
Responders vs. non-‐responders
The evolu$onary history of our gene$c blueprint
Why we need to know about NGx in research
What our gene$c differences mean
Prac$cal applica$ons
Outline
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Scope of nutrigenomics
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Nutrigenomics is not new
Archibald Garrod, Croonian Lecture, Royal College of Physicians, 1908
QUOD ALI CIBUS EST ALIIS FUAT ACRE VENENUM Titus Carus Lucre7us, around 60 BC
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1908 Garrod Inborn Errors of Metabolism (IEM): cys$nuria 1934 Følling Discovery of phenylketonuria (PKU)
1953 Bickel Effec$ve dietary therapy of PKU
1994 Calonge et al. Gene responsible for cys$nuria located
2003 HGP, Venter Human genome sequence decoded
2015 23andMe 1 million customers genotyped 2016 VeritasGene$cs $1000 personal genome sequence
1942 Waddington Epigene$cs: gene$c effects on development
1975 Riggs, Holliday DNA methyla$on sets epigene$c markers 2006 Waterland Maternal feeding alters fetal Agou$ gene
Nutrigenomics is not new
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We are all different
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Carrots or Broccoli?
Bell & Tepper, 2006
Non-‐taster
Taster
We are all different
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Responders vs. Non-‐responders
How much lactose can I tolerate?
11-‐12 g lactose in a 240 ml glass of milk
Lactase persistence
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Lactase persistence
Itan et al., 2010
Frequencies of LP in the Old World
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Humans have inhabited diverse ‘nutritopes’ throughout history and have adapted to new food paierns.
Small changes in the lactase gene of these people sustain enzyme expression into adulthood. This adapta$on helped them to consume lots of milk and survive in environments with otherwise sparse food supplies.
Xhosa in South Africa Arabs in Oman Vikings on Atlan$c Islands LCT -‐14,010 C LCT -‐13,915 G LCT -‐13,910 T
Where is nutrigene$c heterogeneity coming from?
Lactase persistence
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The normal state (65-‐70% world-‐wide) is loss of lactase expression aUer infancy. Pastoral popula7ons have evolved variants in the upstream enhancer region causing persistent expression in adulthood.
The effects of the diverse persistence alleles are dominant. -‐13910 T in more than 80% of Europeans -‐13915 G in more than 50% of Kuwai7s -‐13937 A in Xhosa, Brazilians -‐14009 G in Somalis -‐14010 C in Kenyans, Tanzanians
Why you want to know about this: Lactose intolerance oUen mimics the symptoms of inflammatory bowel disease. You can use predic7ve gene7c assessment to improve dietary guidance.
Lactase persistence
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Lactase persistence
Labrie et al., 2016
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Lactase persistence
Labrie et al., 2016
Genotype-‐specific decline of jejunal lactase expression with age is related to the progressive accumula$on of epigene$c changes
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Persistence-‐linked LCT allele -‐13910 T decreases abundance of the Bifidobacterium genus in the small intes$ne
Lactase persistence
Goodrich et al., 2016
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Lactase persistence
He et al., 2006
Genotype-‐specific decline of jejunal lactase expression with age is related to the progressive accumula$on of epigene$c changes
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Genistein-‐7-‐glucoside Daidzein-‐7-‐glucoside
Lactase persistence
Lactase is the only enzyme in the small intes$ne that cleaves glucosides of flavonoids and other common phytochemicals, some of which are highly toxic
Day AJ et al., 2003
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Why we need to know about NGx in research
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H1/H1 frequency 1 in 6
Zillikens MC et al., 2009
The need to know about NGx
It may be a maier of life and death for some
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Wilson CP et al., 2012
Genotype-‐specific response to 1.6 mg/day riboflavin
The need to know about NGx
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The need to know about NGx
Wilson CP et al., 2013
RCT in Ireland of treated hypertensive adults with MTHFR TT, achieving an average reduc$on of systolic BP by 5.6 mm Hg
16-‐week riboflavin supplementa$on lowered BP
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The need to know about NGx
5 per 100,000 of people in their fiqies die from lung embolism
5-‐8% of Americans have a thrombophilic muta$on such as factor V Leiden or prothrombin 20210A that increase risk.
Risk of deep vein thrombosis and lung embolism can be reduced with an$coagulant treatment, but most of those at high risk do not know.
Lung embolism
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The need to know about NGx
The Women’s Health Ini$a$ve randomized 39,876 women to 300 IU vitamin E/day or placebo for about 10 years.
Risk reduc$on for women with a F5 or F2 muta$on was 49% (p=0.014).
What should the treatment of choice be for an incidental asymptoma$c finding?
Vitamin E (49% risk reduc$on), or an$coagulant (>70% RR, risk of bleeding)
Lung embolism
Glynn RJ et al., 2007
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The need to know about NGx
Smith CE et al., 2008
Genotype-‐specific response to carbohydrate
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The need to know about NGx
Smith CE et al., 2008
PLIN itself is regulated by mi-‐R378, which is also polymorphic
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NGx Studies
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Integration of research data
2015
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Prac$cal Applica$ons
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Practical applications
Personalized nutri$on Gluten-‐free Lactose-‐free Genotype-‐specific Vegetarian Vegan Low-‐Carb
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Product development
Practical applications
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Regulations and policies
How much should the caffeine content be allowed to vary between brews?
Should these fava beans come with a safety warning?
Should high-‐dosed folate require a prescrip$on?
Practical applications
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Interven$on effects in gene$c subgroups are easily obscured by the lack of significant response of the majority.
Some nutri$onal interven$ons are only effec$ve, if they are targeted to gene$cally suscep$ble models or individuals.
The likely effect size of some genotype-‐specific interven$ons is
as large as that of medical treatments.
Final comments
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Ques$ons?