Nutrition and Ageing: Nutrient X Gene Interactions and Age-Related Disorders

Chronic Diseases

  • Can be monogenic or multifactorial.

  • Monogenic disorders:

    • Wilson disease

    • Menkes disease

    • Hemochromatosis

    • Cystic Fibrosis

    • Familial forms of cancer, Alzheimer’s disease, etc.

    • Caused by a single MUTATION

    • Early Onset and RARE

    • Follow a Mendelian Pattern of inheritance

  • Multifactorial disorders:

    • Cancer

    • Dementia

    • Type 2 Diabetes

    • Cardiovascular disease

    • Alzheimer’s disease

    • Caused by multiple SNPs

    • Late Onset and COMMON & COMPLEX

    • Multiple genes and other factors involved

    • Non-Mendelian Pattern of inheritance

Multifactorial Disease Risk

  • Combination of genetics & environmental factors.

  • Disease Mechanisms can be targeted for PREVENTION Mechanisms

  • Target molecular pathways.

  • Gene x E interactions

  • Environmental & lifestyle factors e.g. dietary factors, lifestyle factors, environmental exposure

  • SNP: single base change in DNA sequence

  • Genetic factors multiple genetic variations (risk alleles for SNPs) in multiple genes involved in disease pathways (polygenic)

  • AGE & Diet play major roles.

Ageing Process

  • Influenced by:

    • Diet

    • Lifestyle

    • Medications/drugs

    • Medical conditions

    • Pathogens

    • Environmental factors

    • Socio-economic factors

Nutrients and Dietary Factors

  • Dietary factors: Different food components.

  • Nutrients: Food provides a range of different nutrients (active, chemical compounds)

  • Macronutrients: Carbohydrate, protein & fat, provide energy and building blocks for growth and maintenance of a healthy body.

  • Micronutrients: Vitamins & minerals needed in small amounts, essential to keep us healthy.

  • Non-nutrient bioactive food: Not vital to human health (non-nutritive), but has been shown to affect it (e.g. dietary flavonoids & phyto-oestrogens).

  • Alcohol is not a nutrient!!!

Gene x Nutrient Interaction: Lactose Intolerance

  • Our genome has evolved to adapt to our environment, including our diet.

  • Interaction genotype for SNP x nutrient can determine a trait/disease.

  • Diet can modify our genetic risk

  • Lactose + Lactase (genetic variants) -

    • Lactose tolerant: - lactose→ no disease +/- lactose→ no disease

    • Lactose intolerant: + lactose→ disease

Learning Outcomes

  • Aim: Understand how combination of dietary and genetic factors influence our risk for age-related chronic diseases

  • Learning Outcomes:

    • Concept gene-nutrient interactions

    • Influence of gene-nutrient interactions on chronic diseases risk

    • Technologies/ approaches used to study gene-nutrient interactions: Nutritional genomics (Nutrigenetics & Nutrigenomics)

    • Applications of this knowledge to gain a better understanding of the disease mechanisms

Increased Risk of Chronic Disease with Age

  • Age is a major risk factor for many chronic complex diseases

  • The ageing process and chronic diseases share common molecular pathways/mechanisms

Ageing: Lifelong Accumulation of Damage

  • Ageing process: Progressive and random accumulation of unrepaired molecular damage (in nucleic acids, proteins, and lipids) over time.

  • Ageing rate = Rate of accumulation of damage

  • Consequences:

    • Damage can ↑ susceptibility to environmental challenges leading to cellular defects and tissue dysfunction resulting in ↑ frailty and age-related diseases that ultimately can cause death.

    • Most complex multifactorial diseases occur in older age (85% deaths in the UK caused by age-related disorders).

    • Ageing is not a disease but a MAJOR risk factor for most chronic diseases.

Ageing and Multifactorial Complex Diseases

  • Ageing process shares common molecular pathways with multifactorial complex diseases

  • Accumulation of cellular damage

    • Intrinsic stress: ROS, reactions

    • Extrinsic stress: lifestyle (diet, exercise), Environment (carcinogens)

    • Mutagenic lesions

    • Cytotoxic or cytostatic lesions

    • Cell death & senescence

    • Cancer

    • Cellular function defects

    • AGEING

    • Decline in DNA repair accuracy and efficiency

    • DNA repair mechanisms

    • Limited control over exposure + inter-individual variations in response to extrinsic factors

Molecular Pathways Altered in Most Chronic Disorders

  • Cellular maintenance mechanisms: ER stress repair mechanisms, mitochondrial function.

  • Immune response

  • Inflammatory response

  • Response to oxidative stress and damage

  • Most chronic disorders share a common basis for disease development such as impaired:

Links Between Ageing, Chronic Diseases, and Diet

  • Accumulation of damage over time.

  • Major risk for most chronic diseases.

  • Common chronic diseases:

    • Cancer

    • Diabetes

    • Cardiovascular diseases

    • Dementia, etc.

  • Genetic, Diet, Lifestyle factors, Environmental stressors

  • Ageing

  • Multifactorial common molecular pathways between ageing-chronic disease

  • Ageing process shares common molecular pathways with multifactorial complex chronic diseases that can be influenced by both genetic and dietary factors

Inter-Individual Genetic Variations

  • Affect chronic disease risk / susceptibility

    1. Genetic variations - Single Nucleotide Polymorphisms (SNPs) definition

    2. Origin of SNPs

    3. Functional versus non-functional SNPs

    4. Inheritance pattern

    5. Linkage disequilibrium

Genetic Variations: Single Nucleotide Polymorphisms (SNPs)

  • Definition of SNP –single base change (2 genetic variants = 2 alleles/SNP)

    • Minor (rare) allele frequency: MAF ≥1% total pop

    • Common –>90% of inter-individual genetic variations

    • ~85M SNPs in human genome (out of 3 billion bp)

    • Major allele (most frequently observed in general pop.) AGATGTC

    • Minor allele (least frequently observed in pop, but ≥ 1% pop) AGACGTC

  • SNP origin:

    • Mutations in ancestors passed on to next generations, fixed through evolution because

      • selective advantage

      • neutral (no advantage or disadvantage)

    • Now heritable sequence variation present and stable in ALL pop.

SNPs are NOT Mutations

SNP

Mutation

Minor allele

T ≥ 1% general population SNP present in all pop Each of us have 2 alleles (1 inherited from each parent )

No known disease-causing mutation is present in ≥1% pop Only in some individuals, most people WT allele

Genotype

§homozygous for WT allele §heterozygous §Homozygous for Mutant allele

  • What makes us unique is our unique combination of SNPs

Types of SNPs

  • Coding SNPs

    • Synonymous: no change in AA, genetic code degeneracy

    • Nonsynonymous:

      • missense : change in AA

      • nonsense: premature STOP codon

  • Non-coding SNPs

    • Promoter

      • gene expression

      • TF binding site

    • 5’UTR

      • mRNA stability

      • regulatory regions

    • 3’UTR

      • mRNA stability

      • regulatory regions

    • Intron

      • splice site

      • mRNA processing

    • Intergenic regions

      • regions between genes, enhancer…)

Functional SNPs

  • Majority of SNPs - no functional effects (neutral)

  • Some SNPs affect key regulatory regions

  • Functional SNPs have functional consequences

  • Functional SNPs affect key regulatory regions

    • Gene expression

    • Protein

      • Synthesis

      • Degradation

      • Activity

      • Post-translational modifications

    • mRNA stability & processing

  • Mechanistic studies

    • understand molecular mechanisms & pathways linking genotype to phenotype

    • important step in translating genotype data for use in the clinic

SNPs are responsible for inter-individual variations

  • Genetic diversity

  • Inter-individual variations in dietary requirements

  • Individual susceptibility to chronic diseases

  • Individual response to medicine

SNPs and Multifactorial Chronic Diseases

  • Genetic predisposition: ↑likelihood of developing a particular disease based on a person’s genetic makeup; combination of

    • Genetic variations; only contribute to disease development but does not directly cause it

    • lifestyle/ environmental factors (diet, exercise, smoking..)

    • Interaction between SNP x lifestyle/ environmental factors

  • Functional SNPs associated with chronic diseases are likely to be located in genes in molecular pathway (s) involved in:

    • cellular maintenance mechanisms

    • response to stress and damage /environmental factors

    • immune and inflammatory signalling/response

    • disease - specific mechanisms/ tissue-specific function

Non-Mendelian Pattern of Inheritance

  • Monogenic

    • Mendelian pattern of inheritance (Mendel’s laws, recessive, dominant, sex-lined): 1 mutation in 1 gene→ disease

    • Runs in family

    • Weak effect of the environment

  • Multifactorial disorders

    • Polygenic i.e.

      • multiple SNPs/ gene variants (allele) in multiple genes contribute to disease risk (-> genetic predisposition)

    • Other factors: diet, age, lifestyle factors, etc.

    • Interaction SNPs x nutrient

    • Non-Mendelian pattern of inheritance

    • Multiple risk alleles for multiple SNPs

    • Linkage disequilibrium (i.e. alleles at different loci are not always inherited independently)

Linkage Disequilibrium (LD)

  • Mendelian pattern of inheritance:

    • each parent transmit 1 out of 2 alleles to offspring

    • alleles at different loci are transmitted independently

    • Law of dominance

  • In reality, SNPs present on the same homologous chromosomes may be transmitted:

    • independently (no linkage): do not segregate together, due to crossing over occurring in late prophase I of meiosis

    • together as a block (linked): segregate as a unit called Haplotype-no recombination between 2 SNPs

    • Important for multifactorial diseases

SNPs not linked

  • Alleles segregate independently, due to recombination in late prophase I

  • generation new / recombinant alleles combinations (1A, 2b) , (1a, 2B)

SNPs linked

  • Alleles are too close to be separated

  • NO recombination between SNPs

  • Alleles segregate as a unit called haplotype

  • Alleles combination REMAINs identical

  • Homologous chromosomes segregate in meiosis, each gamete receives 1 homolog

  • Linkage disequilibrium depends on distance between SNPs on the same chromosome

Haplotypes

  • Linkage disequilibrium (LD) is a measure of how often two alleles or specific sequences are inherited together, with alleles that are always co- inherited said to be in linkage disequilibrium.

  • Because of linkage disequilibrium sets of alleles for different SNPs/loci close together on the same chromosome tend to occur together more often than is expected by chance. These blocks of alleles are called haplotypes.

  • A haplotype is a set of alleles at multiple loci located on the same homologous chromosome and inherited together from a single parent because of genetic linkage. These alleles are transmitted to offspring as a haplotype block-> reflect persistence of an ancestral association

Haplotype Block

  • Haplotype: Set of alleles at multiple loci located on the same homologous chromosome, that tend to be inherited together from a single parent because of genetic linkage, i.e. there is no recombination/ crossover between these alleles, they are to close to each other so they are passed down through generations together.

  • -> transmitted to offspring as a haplotype block- persistence of an ancestral association

  • SNP 1 A/G(Heterozygous); SNP 2 G/T (Heterozygous); SNP 3 T/C (Heterozygous)

  • so if a child inherits SNP1 = A allele then the child also inherits SNP2 = G allele and SNP3= T allele, located on the same chromosome

  • Genetically linked SNPs are transmitted as a haplotype

Consequence of genetically linked SNPs on Chronic disease

  • If SNP2 is a Causative (functional) SNP, “causing a trait”, e.g :

    • G ↑ disease risk

    • T ↓ disease risk

  • Then individuals of GG genotype for SNP2 will

    • have an↑ disease risk

    • also be homozygous AA for SNP1 and homozygous TT for SNP3

SNP x Nutrient Interactions

  1. Origin and Definition SNP x Nutrient interactions

  2. Example of lactose tolerance

  3. Nutritional Genomics: study of Gene x Nutrient interactions

Origin of gene X nutrients interactions

  • Human evolution: genetic variations present partly result from adaptation through evolution to an often scarce & unpredictable food supply.

  • Several gene variants (alleles) that arose through positive selection are modern-day candidates for disease risk alleles

  • Same allele in different environments

    • Detrimental → disease

    • Advantageous → Selection

    • Immunity, Diet, Ageing

Multifactorial Disease

  • Genetic predisposition

    • Determined by combined effects of multiple risk alleles for different SNPs in different / same gene (s)

    • 1 risk allele only contributes to small % genetic risk but…

    • together with other risk alleles contributes to genetic susceptibility

  • Environmental risk

    • Mostly determined by combined effects of multiple environmental risk factors (including lifestyle, diet, age, gender, other diseases…)

SNP x E and SNP x SNP interactions

  • SNP X SNP or Gene x Gene interactions

    • 1 risk allele for a SNP can interact with (an)other risk allele (s) for other SNPs, can either

      • compensate risk carried by individual genetic variants and reduce risk carried by 1 variant

      • ↑ ↑ risk – synergistic effects

    • Susceptibility to diseases determined by combination of genotypes for different SNPs

  • SNP X E(N) or Gene x E (N) interactions

    • 1 risk allele for a SNP can interact with E (N) risk factor, can

      • compensate risk carried by risk allele & ↓ genetic risk

      • ↑ ↑ risk – synergistic effects

    • SNP effect on disease risk can be modified by environmental / dietary exposure

    • Individuals with different genotypes may have different dietary requirements for a given nutrient

    • Combined effect of dietary and genetic factors on a (disease) trait

  • Other confounding factors: age, other diseases, smoking, …

  • Consequences: difficult to predict risk for a person to develop

Example of G x N interaction: lactose intolerance

  • Lactose intolerance: loss of ability to digest lactose in children and adults (lactase gene- OFF)

  • Lactose tolerance:

    • Appeared ~10,000 year ago

    • Mutations in Lactase gene conferred a selective advantage to some individuals (Northern Europe)

    • Today 80% Northern Europeans -lactose tolerant VERY strong positive selection (stable in pop)

    • now SNP (C/T) – functional SNP affecting binding TF to lactase gene promoter

    • CC x Dairy interactions

      • TT

      • CC + Milk → symptoms

      • CC – Milk → No symptoms

Nutritional Genomics

  • Branch of science studying interactions between nutrition & genome

  • Application of high-throughput technologies to the study of Gene x Nutrient interactions

  • Nutrigenetics & Nutrigenomics

Nutrigenetics vs Nutrigenomics

Nutrigenetics

Nutrigenomics

genomics

SNP, SNP x SNP and SNP X N interactions Genes/ molecular pathways involved in disease mechanism/prevention Diet’s influence on balance between health and disease depends on an individual’s genetic make-up

transcriptomics, proteomics, metabolomics, etc Impact of nutrients on gene/protein expression Impact on molecular pathways SNP

Personalised Nutrition

Aimed at providing advice for nutritionists and physicians to personalised dietary recommendations based on genetic makeup to match individual requirements to prevent disease.

Identification of metabolic pathways /genes involved in disease (biomarkers) understanding the mechanisms leading to disease

SNP and Nutrition

  • Stable, ≥1% tot pop, 85 millions SNPS started as mutations but now “fixed” in pop.

    • Thus we ALL have a genotype for each SNP

  • Associated with inter-individual variations, population diversity, individual susceptibility to diseases, response to medicine & diet (individual dietary requirements)

  • Can be used to identify gene involved in a disease (Tag SNP, functional SNP)

  • Occur in all region of the genome; most not functional, some functional (regulatory regions)

  • Can modulate disease risk (different from mutation can cause disease)