Flashcards in Nutrition and Ageing L9-10 Deck (58):
Chronic diseases are multifactorial.
Name the 5 factors involved.
- Genetic factors
- Lifestyle factors (smoking, exercising, drinking, etc..)
- Molecular and cellular damage / metabolic pathways
Ageing = _______
Accumulation of damage
Define SNP (Single Nucleotide Polymorphism).
A Single Nucleotide Polymorphism is a DNA sequence variation occurring commonly within a population (e.g. 1%) in which a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes.
_____1_____ (no change in AA, genetic code degeneration)
_____2_____ (missense : change in AA /nonsense: premature STOP codon)
Most ______ have no functional effects. Some ______ affects key regulatory regions.
SNPs may fall within what 3 sequences/regions?
- Coding sequences
- Noncoding sequences
- Intergenic regions
What is the aim of the International HapMap Project.
Identification and catalog of common genetic variants that occur in human beings.
What 2 approaches are used to find SNP associated with a disease?
- Candidate SNP approach
- Hypothesis-free approach
Describe the pros and cons of Candidate SNP approach.
- Can take into account biomarkers of nutritional status (vit. conc, etc)
- Can take into account genetic interactions between SNPs (SNP combination)
- Biased: based on prior knowledge and selection of SNP of interest
- Typically 1-10 SNPs
Limited by characteristics of study population (100s-1000)
What studies is the Candidate SNP approach used for?
- Small number candidate SNPs
- SNPs in one metabolic pathway
What studies is the Hypothesis-free approach
- Genome-Wide Association Studies (GWAS)
______: naturally occurring form of folic acid (Vit B9) in the body.
Folates are important for what 5 points?
- DNA synthesis: purine/pyrimidine synthesis
- DNA repair
- Donors of methyl group in the Folate “1 Carbon” metabolism
- Key to methylation reactions
- DNA methylation (silencing of genes, cancer...)
- Lipid and protein methylation
- During pregnancy (supplementation, 400mg= 2*RNI)
- Neural tube formation in early stage of development
- Cell production, DNA/ RNA synthesis
Selenoprotein P (SePP):
Major ___1___ selenoprotein (60% ___1___ Se) and best biomarker of active Se.
Synthesized in the ___2___ from dietary Se.
Secreted in the ___1___, transports hepatic Se to other organs for synthesis of other selenoproteins.
2 ___1___ isoforms: 60kDa (10sec) and _3_kDa.
Define a Genome-wide association study (GWAS).
A study in which several hundred thousands to more than a million common genetic variations (SNPs), theoretically covering the entire human genome, are simultaneously tested for association with a observable trait/complex genetic disease in thousands of individuals (cases and controls).
Ageing rate (accumulation of damage) is a balance between what? (2)
- Cellular damage
- Repair and protection mechanisms
Define monogenic disease.
A disease which is the result of a single defective gene.
Inherited according to Mendelian genetics.
Define multifactorial disease.
A disease caused by the effects of multiple genes in combination with lifestyle and environmental factors.
Name a non-modifiable risk factor in multifactorial disease.
Name 4 modifiable risk factors in multifactorial disease.
- Alcohol consumption
Give examples of multifactorial diseases. (4)
- Heart disease
______ diseases are multifactorial.
When can a mutation become an SNP. (2)
- When the mutation is a single base change
- When the mutation becomes stable with a population (>1% of population)
What may the effects be of an SNP within the coding sequence of a promoter? (2)
- Altered expression
- Altered transcription factor binding site
What may the effects be of an SNP within the coding sequence of a splice site?
Altered mRNA processing
What may the effects be of an SNP within the coding sequence of a 5’ & 3’ untranslated region (UTR)? (2)
- Altered mRNA stability
- Altered regulatory regions
What may the effects be of an SNP within a nonsynonymous coding sequence? (2)
- Missense = change in AA
- Nonsense = premature stop codon
What may the effects be of an SNP within a synonymous coding sequence?
- No change in amino acid sequence = genetic code degeneration
What can happen if mRNA stability is affected?
Define linkage disequilibrium.
The occurrence in members of a population of combinations of linked genes in non-random proportions.
In the International HapMap project, which 3 ancestries were genetic data gathered from?
____1____ can modulate disease risk.
____2____ can result in disease.
An ____1____ in the lactase gene of C/T ____2____ to C/C causes lactose intolerance.
Describe the pros and cons of Hypothesis-free approach.
Pros = Looks at the genotype for all SNPs, therefore it can uncover novel targets.
Cons = Limited by statistical power. No biomarkers. No genetic interaction. Very large study size.
- Study effect of Genetic variations on dietary response
- SNPs can affect Individual nutritional requirements
- Interactions Nutrient - genetic factors affect on disease risk
- Identify sub-groups population at risk because of genetic + dietary factors
- Diet/ nutrients can affect gene expression and metabolic pathways
- Application of high-throughput genomics tools to nutrition research (genomics, transcriptomics, proteomics, metabolomics)
______ ______ =
- Aimed at providing advice for nutritionists and physicians to personalised dietary recommendations based on genetic make-up to match individual requirements to prevent disease
SNPs in genes involved in folate metabolism and/or poor folate status = metabolic and genetic risk factors for which diseases? (3)
- Cardiovascular disease
- Birth defects
Some evidence suggests an association between high plasma Homocysteine (Hcy) and increased risk of ______ ______.
______ can be used in methylation reactions, e.g. DNA methylation.
Sensitive to temperature change.
Low ______ intake =
↓ Conversion to 5-methyl THF
↓ Methyl group availability
↑ Plasma Hcy concentration
↑ Risk of CVD in TT
Evidence suggests that homozygous TT individuals on C677T SNP have higher folate requirement and potentially at ↑ risk of ____1____ but ↓ risk of ____2____ cancer.
Se mediates its biological actions via a group of proteins called ______.
Selenoproteins play a key role in biological processes known to be altered in ____1____ diseases and ageing processes (____2____ response mechanisms and cellular maintenance).
Selenium content of food is primarily dependent on what?
Selenium soil concentration of where the food was grown/produced.
How is dietary selenium incorporated into selenoproteins?
Selenium is first converted to selenocysteine (Sec). Sec is then incorporated into a recoded UGA codon (usually a stop codon) when the UGA codon is downstream of a Sec-insertion sequence. The selenoprotein is then translated.
Name the selenocysteine-transporting protein.
Selenoprotein P (SEPP1).
Functional SNPs have been identified in selenoprotein genes.
These SNPs affect:
- Se / Sec bioavailability: SNPs in transporter of Sec (____1____)
- Selenoprotein synthesis: SNPs in 3’UTR, affect Sec incorporation (____2____, SEP15)
- Selenoprotein activity: coding SNP affecting protein sequence and enzymatic activity (____3____)
- Promoter of selenoprotein genes: expression (SEPP1)
An SNP in 15kDa-selenoprotein (SEP15) gene affects ______ cancer risk and survival.
The SEP15 selenoprotein is highly expressed in prostate tissue.
It has a role in what?
Protein folding control in the endoplasmic reticulum.
SNP C718T in GPX4 affects UGA read-through efficiency.
(In terms of C variant)
- Has a stronger affinity for selenoprotein synthesis machinery
- Stronger inducer than T variant of translation of a reporter gene (IDI) in response to increased Se supply
- Major plasma selenoprotein (__1__% plasma Se) and best biomarker of active Se
- Synthesized in the ___2___ from dietary Se
- Secreted in the plasma, transports hepatic Se to other organs for synthesis of other selenoproteins
- 2 plasma ___3___: 60kDa (10sec) and 50kDa
Genetic variations in the SEPP1 gene: -2 common SNPs
- In coding region (SNPAla234Thr (A/T))
- In 3’UTR (rs7579)
SEPP1 SNP affecting Se delivery:
High Se = ?
Low Se = ?
High Se = no effect
Low Se = reduced Sec supply
GPx4 or SEP15 SNP affecting Sec incorporation efficiency:
High Se = ?
Low Se = ?
High Se = no effect
Low Se = reduced selenoprotein synthesis
SNPs that are linked (e.g. A and B) in that if you know one of them then you can work out the other (i.e. know A, other must be B. Know B, other must be A).
The 5' untranslated region (5′ UTR) (also known as a Leader Sequence or Leader RNA) is the region of an mRNA that is directly upstream from the ______ codon. This region is important for the regulation of translation of a transcript by differing mechanisms in viruses, prokaryotes and eukaryotes.