203.343!Concepts of GWAS

Nutrigenomics, Nutrigenetics, and the

Microbiome!Week 6!

Austen Ganley, August 17th, 2015

Ethics lectures assignment

Nutrigenetics: The study of the effects of gene variants on individual response to diet!

!Nutrigenomics: The study of

the effects of the diet on gene activity!

DIET

Metabolism

Phenotype

DIET

Metabolism

Phenotype

Nutrigenetics

DIET

Metabolism

Phenotype

Nutrigenomics

Fundamentals

Fenech et al, 2011 Journal of Nutrigenetics and Nutrigenomics 4: 69

Nutrigenetics

Nutrigenetics: classic example phenylketonuria (!)

Phenylketonuria is caused by a mutation in the phenylalanine hydroxylase (PAH) gene!

The failure to metabolise phenylalanine leads to severe intellectual disabilities and other consequences!

However, if phenylalanine is strictly limited in the diet, symptoms can virtually be nil!

Therefore, phenylketonuria is not completely penetrant, due to dietary differences!

Nutrigenetics example liver disease

Liver disease is a major health factor! A big contributor to this is fat accumulation in

the liver (hepatic steatosis), which can lead to cirrhosis and liver cancer!

Recent results suggest that a mutation in the PNPLA3 gene (I148M) may contribute to the development of hepatic steatosis!

Currently the function of the PNPLA3 gene is not fully understood!

Nutrigenetics example liver disease

This I148M mutation seems to interact with dietary factors to contribute to disease!

Specifically, the combination of this mutation and obesity has been shown to increase the risk of disease more than each factor independently!

Also, a correlation was found between adiposity levels and liver damage in children that have this I148M mutation!

In addition, there is a correlation between having this mutation and developing liver disease through alcohol consumption!

Nutrigenomics

Nutrigenomics Principle of nutrigenomics dietary

components affecting gene activity is nothing new!

Its part of the idea of healthy eating! Also, screening natural compounds for

activity against certain genes is big business! However, the goal is to find, in a dietary

context, what dietary components have beneficial genomic effects and what have detrimental genomic effects more difficult!!

Nutrigenomics and cancer One aspect of nutrigenomics is to look at the

effects of dietary components on DNA damage!

DNA damage is a major factor in cancer, therefore the goal is to reduce cancer incidence!

Two aspects to this what dietary components result in DNA damage, and what components protect from DNA damage!

Nutrigenomics and cancer A correlation between diary product

consumption and DNA damage, and red meat consumption and DNA damage, have both been found!

Furthermore, there is some evidence that consumption of these food groups each is associated with increased risk of developing cancer!

Thus, there may be a nutrigenomic link between these two correlations that explains how consumption results in cancer, but this has yet to be actually demonstrated!

Intersection of Nutrigenetics and Nutrigenomics - Caffeine

Caffeine is a widely-consumed stimulant that shows great variability in individual responses!

Is widely used for positive effects, such as increased alertness!

However, also has been documented with detrimental consequences, such as increased blood pressure leading to heart attacks!

Growing evidence that some of this variation in response is genetically determined!

Intersection of Nutrigenetics and Nutrigenomics - Caffeine

A cytochrome P450 enzyme encoded by the gene CYP1A2 is responsible for breaking down caffeine (for excretion)!

A SNP (rs762551) in this gene is associated with differences in caffeine metabolism:! A CC genotype is associated with slow caffeine

metabolism! A CA genotype is associated with intermediate

caffeine metabolism! A AA genotype is associated with fast caffeine

metabolism!

Intersection of Nutrigenetics and Nutrigenomics - Caffeine

Sachse et al, 1999 British Journal of Clinical Pharmacology 47: 445-

non-smoker smoker

Intersection of Nutrigenetics and Nutrigenomics - Caffeine

However, these effects are only strongly associated with smokers!

Why smokers? Smoking is known to stimulate expression of CYP1A2!

The magnitude of the effect may therefore be greater in smokers than non-smokers!

Intersection of Nutrigenetics and Nutrigenomics - Caffeine

Yes No

CC

CA

AA

smoker

gen

oty

pe

Yes No

CC

CA

AA

smoker

gen

oty

pe

Nutrigenetic effect

Intersection of Nutrigenetics and Nutrigenomics - Caffeine

Yes No

CC

CA

AA

smoker

gen

oty

pe

Yes No

CC

CA

AA

smoker

gen

oty

pe

Nutrigenomic effect

Nutrigenetics and Nutrigenomics Complications

In practice, finding good evidence for nutrigenetic and nutrigenomic effects is difficult why is this?!

Diet and the Microbiome

The Microbiome The microbiome refers to the collection of

microorganisms that lives in and on an individual (or sometime to their genomes)!

For simplicity, we are going to just consider the gastro-intestinal microbiome here (human gut microbiota), but it also includes all other areas of the body!

The microbiome primarily consists of bacteria, but there are also some fungi, archaea, and other single-celled eukaryotes present!

The human microbiome contains 10 times as many cells as the human body does!

The Role of the Microbiome The microbiome has roles in digesting food

and provide us with nutrients, help with the immune system, and compete with pathogens!

As >99% of the microbiome cannot be cultured, until recently the composition has basically been unknown!

Next-generation sequencing means we can now identify the species and their genomes!

This information has led to a growing understand of the importance of the microbiome for human health and disease!