Nutrition and Ageing: Nutrient X gene interactions and age-related disorders

Chronic Diseases

  • Chronic diseases can be monogenic or multifactorial.
  • Monogenic disorders:
    • Wilson disease
    • Menkes disease
    • Haemochromatosis
    • Cystic Fibrosis
  • Multifactorial disorders:
    • Cancer
    • Dementia
    • Type 2 Diabetes
    • Cardiovascular disease
    • Alzheimer’s disease
  • Monogenic disorders are early onset and rare, caused by a mutation in a single gene, and follow a Mendelian pattern of inheritance.
  • Multifactorial disorders are late onset, common, and complex, involving multiple genes (SNPs) and other factors, and follow a non-Mendelian pattern of inheritance.

Multifactorial Disease Risk

  • Multifactorial disease risk is a combination of genetic and environmental factors.
  • Disease mechanisms can be targeted for prevention through:
    • Gene x Environment interactions
    • Environmental & lifestyle factors (e.g., dietary factors)
    • SNPs (single base change in DNA sequence)
    • Genetic factors (multiple genetic variations in multiple genes)
  • Age and diet play a significant role.

Ageing Process

  • The ageing process is influenced by:
    • Diet
    • Lifestyle
    • Medications
    • Medical conditions
    • Pathogens
    • Environmental factors
    • Socio-economic factors

Nutrients and Dietary Factors

  • Dietary factors include different food components.
  • Nutrients are active chemical compounds provided by food.
    • Macronutrients: Carbohydrates, proteins, and fats provide energy and building blocks.
    • Micronutrients: Vitamins and minerals are needed in small amounts for health.
    • Non-nutrient bioactive food: Affects health but not vital (e.g., dietary flavonoids).
  • Alcohol is not a nutrient.

Gene x Nutrient Interaction: Lactose Intolerance

  • Our genome evolves to adapt to our environment and diet.
  • The interaction between genotype for SNP and nutrient can determine a trait or disease.
  • Diet can modify our genetic risk.
  • Example:
    • Lactose + Lactase (genetic variants) results in:
      • Lactose tolerance: +/- lactose -> no disease
      • Lactose intolerance: + lactose -> disease

Learning Outcomes

  • Aim: Understand how dietary and genetic factors influence the risk of age-related chronic diseases.
  • Learning Outcomes:
    • Concept of gene-nutrient interactions
    • Influence of gene-nutrient interactions on chronic diseases risk
    • Technologies/approaches: Nutritional genomics (Nutrigenetics & Nutrigenomics)
    • Applications to understand disease mechanisms

Underlying Research Questions

  • Why does the risk of developing chronic multifactorial diseases increase with age?
  • How do inter-individual genetic variations impact the risk of chronic diseases?
  • How do gene x nutrient interactions affect chronic disease risk?
  • How do we study these interactions?
  • How can we use this knowledge to reduce disease risk and better understand 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 over time.
  • Ageing rate = Rate of accumulation of damage (MacNee et al, 2014).
  • Consequences:
    • Increased susceptibility to environmental challenges, leading to cellular defects, tissue dysfunction, frailty, and age-related diseases.
    • Most complex multifactorial diseases occur in older age (85% deaths in the UK are caused by age-related disorders).
    • Ageing is a major risk factor for most chronic diseases, but not a disease itself.

Ageing and Multifactorial Complex Diseases

  • The 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 and cytotoxic or cytostatic lesions
    • Cell death and senescence
  • This leads to cellular function defects and a decline in DNA repair accuracy and efficiency.

Molecular Pathways Altered in Chronic Disorders

  • Most chronic disorders share a common basis for disease development such as impaired:
    • Cellular maintenance mechanisms: ER stress repair mechanisms, mitochondrial function
    • Immune response
    • Inflammatory response
    • Response to oxidative stress and damage
  • Ageing & chronic diseases share common mechanisms.

Summary: Links Between Ageing, Chronic Diseases, and Diet

  • Ageing is a major risk for most chronic diseases like cancer, diabetes, cardiovascular diseases, and dementia.
  • Common chronic diseases are influenced by genetics, diet, lifestyle factors, and environmental stressors.
  • The 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

  • Inter-individual genetic variations affect chronic disease risk/susceptibility.
  • SNPs (Single Nucleotide Polymorphisms) are common genetic variations.

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. SNPs are common (>90% of inter-individual genetic variations).
  • ~85M SNPs in the human genome (out of 3 billion bp) (Source: 1000 Genomes Project Nature 526, pages 68–74 (2015)).
  • SNP origin: Mutations in ancestors passed on to next generations, fixed through evolution because of selective advantage or neutrality.
  • SNPs are now heritable sequence variations present and stable in all populations.
  • Each individual has 2 alleles (1 inherited from each parent).

SNPs are NOT Mutations

  • SNPs: Minor allele T ≥ 1% general population, present in all populations.
  • Mutations: No known disease-causing mutation is present in ≥1% of the population, only in some individuals.
  • Genotypes:
    • 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 & 3’UTR: mRNA stability, regulatory regions
    • Intron: splice site, mRNA processing
    • Intergenic regions: Regions between genes, enhancer

Functional SNPs

  • Majority of SNPs have no functional effects (neutral).
  • Some SNPs affect key regulatory regions and have functional consequences.
  • Functional SNPs affect:
    • Gene expression
    • Protein synthesis, degradation, activity, and post-translational modifications
    • mRNA stability & processing
  • Mechanistic studies are essential to understand molecular mechanisms & pathways linking genotype to phenotype, and translating genotype data for use in the clinic.

SNPs and Inter-Individual Variations

  • SNPs are responsible for inter-individual variations.
  • SNPs are associated with:
    • Genetic diversity
    • Inter-individual variations in dietary requirements
    • Individual susceptibility to chronic diseases
    • Individual response to medicine

SNPs and Multifactorial Chronic Diseases

  • Genetic predisposition: Increased likelihood of developing a particular disease based on genetic makeup.
    • Genetic variations contribute to disease development but do 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 pathways 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 disorders:
    • Mendelian pattern of inheritance (Mendel’s laws, recessive, dominant, sex-linked): 1 mutation in 1 gene → disease.
    • Runs in family.
    • Weak effect of the environment.
  • Multifactorial disorders:
    • Polygenic: Multiple SNPs/gene variants in multiple genes contribute to disease risk (genetic predisposition).
    • Other factors: Diet, age, lifestyle factors.
    • 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) and Non-Mendelian Inheritance

  • Homologous chromosomes segregate in meiosis; each gamete receives 1 homolog.
  • Mendelian pattern of inheritance: Each parent transmits 1 out of 2 alleles to offspring; alleles at different loci are transmitted independently.
  • In reality, SNPs present on the same homologous chromosomes may be transmitted:
    • Independently (no linkage): Do not segregate together due to crossing over.
    • Together as a block (linked): Segregate as a unit called Haplotype—no recombination between 2 SNPs (Important for multifactorial diseases).

SNPs Linkage

  • SNPs not linked: Alleles segregate independently due to recombination in late prophase I, generating new/recombinant alleles combinations.
  • SNPs linked: Alleles are too close to be separated, no recombination between SNPs, alleles segregate as a unit called haplotype, alleles combination remains identical.
  • Linkage disequilibrium depends on the 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.
  • 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, reflecting the persistence of an ancestral association.
  • 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.
  • There is no recombination/crossover between these alleles, they are too close to each other so they are passed down through generations together.
  • transmitted to offspring as a haplotype block- persistence of an ancestral association.
  • 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

Consequence of Genetically Linked SNPs on Chronic Disease

  • If SNP2 is a causative (functional) SNP, e.g., G ↑ disease risk and T ↓ disease risk, then individuals of GG genotype for SNP2 will have an ↑ disease risk and also be homozygous AA for SNP1 and homozygous TT for SNP3.

SNP x Nutrient Interactions

  • Same allele in different environments can be detrimental (disease) or advantageous (selection).
  • 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.

Multifactorial Disease

  • Genetic predisposition is determined by the combined effects of multiple risk alleles for different SNPs in different/same gene(s).
  • One risk allele contributes a small % genetic risk, but together with other risk alleles, contributes to genetic susceptibility.
  • Environmental risk is determined by the combined effects of multiple environmental risk factors (including lifestyle, diet, age, gender, other diseases).

Multifactorial Disease – SNP x E and SNP x SNP interactions

  • SNP X SNP or Gene x Gene interactions:
    • One risk allele for a SNP can interact with another risk allele(s) for other SNPs, can either compensate risk carried by individual genetic variants and reduce risk carried by one variant, or increase risk (synergistic effects).
    • Susceptibility to diseases is determined by a combination of genotypes for different SNPs.
  • SNP X E(N) or Gene x E (N) interactions:
    • One risk allele for a SNP can interact with E (N) risk factors, can compensate risk carried by the risk allele & decrease genetic risk, or increase 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

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 years ago; mutations in the lactase gene conferred a selective advantage to some individuals (Northern Europe).
  • Today, 80% of Northern Europeans are lactose tolerant (VERY strong positive selection).
  • SNP (C/T) – functional SNP affecting binding TF to lactase gene promoter.
  • CC x Dairy interactions:
    • TT: Tolerant
    • CC + Milk → symptoms
    • CC – Milk → No symptoms

Nutritional Genomics

  • Nutritional genomics research field study interactions between nutrition & genome and application of high-throughput technologies to the study of Gene x Nutrient interactions.
  • Nutrigenetics: genomics, SNP, SNP x SNP and SNP X N interactions. Genes/molecular pathways involved in disease mechanism/prevention. Diet’s influence on the balance between health and disease depends on an individual’s genetic make-up.
  • Nutrigenomics: transcriptomics, proteomics, metabolomics, etc. Impact of nutrients on gene/protein expression and impact on molecular pathways.

Nutritional Genomics and Personalised Nutrition

  • Nutrigenetics & Nutrigenomics Applications:
    • Identification of SNPs/genes involved in disease process.
    • Identification of subgroup populations at risk because of genetic + dietary factors.
  • Personalised Nutrition: Aimed at providing advice for nutritionists and physicians to personalize dietary recommendations based on genetic makeup to match individual requirements to prevent disease.
  • Applications include identification of metabolic pathways/genes involved in disease (biomarkers) and understanding the mechanisms leading to disease.

SNP and Nutrition Summary

  • Polymorphism (SNPs):
    • Stable, ≥1% tot pop, 85 millions SNPS
    • 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)
  • SNP can affect molecular process/pathways influenced by dietary factors or can interact with dietary factors to modulate disease risk