B P2 C7 Applications of Genetics to Cardiovascular Medicine Flashcards
Genes are encoded in DNA, a polymeric molecule with two intertwining strands of a deoxyribose phosphate backbone surrounding a ladder of paired purine and pyrimidine bases in a double helical configuration. The purine nucleotides are _____, and the pyrimidine nucleotides are ____. Purines and pyrimidines link complementarily by hydrogen bonds across opposing strands:A-T,T-A,C-G,and G-C.
Purine - adenine (A) and guanine (G)
Pyrimidine - thymine (T) and cytosine (C)
.Further chromatin condensation and packing yields the ______ of autosomal chromosomes and ____ of sex chromosomes.
22 pairs
1 (one) pair
The ______ of molecular biology refers to the flow of information from DNA to ribonucleic acid (RNA) to proteins. Traditionally, a gene is a DNA sequence that encodes a functional protein, and roughly 20,000 genes leading to distinct proteins have been described.
“Central dogma”
Transcription copies the information in the DNA sequence into a single-stranded coding RNA, also known as a _____
This polymer is structurally similar to DNA but uses uracil (U) in place of thymine (T).Of the 6.4 billion base pairs in the human genome, just over 1% represent exons, or DNA regions that directly encode mRNA
Messenger RNA (mRNA)
This procees copies the information in an mRNA into a sequence of amino acids that make up a protein, which can service in a variety of roles (e.g., structural elements, enzymes, hormones, gene expression regulation).
Translation
Variation in DNA sequence, or _________, may influence protein function or abundance directly through alteration of the amino acid sequence when occurring within exons or indirectly when occurring in noncoding regions, including effects on splicing or mRNA transcript abundance.
Such effects on a protein may lead to variation in an observable characteristic, or _________.
Genotype
Phenotype
_______ refers to phenotypic changes caused by factors beyond the DNA base pair sequence that influence the process of transcription.
The most common such modification is methylation of cytosine bases, typically those in CpG dinucleotides, which generally results in reduced transcription or “________” of a gene
Epigenetics - influences transcription
Silencing
______ refers to the fraction of interindividual variability in risk for disease attributable to additive genetic variation.
Heritability
Heritability is a population-based construct without clear meaning for individuals.
For a given individual, diseases can result from genetic variation at a single gene (monogenic), few genes (______), or several genes (polygenic)
Oligogenic
In scenarios where a single gene defect is necessary to yield sufficiently large risk for disease, the condition is termed a _______ because it will obey classical modes of inheritance.
Mendelian disorder
Translating Genetics to Cardiovascular Medicine
Identify causal factors that influence disease
Test epidemiologic associations for causal inference
Biomarkers titratable to disease risk
Translating Genetics to Cardiovascular Medicine
Penetrance estimation
Disease risk prediction
Translating Genetics to Cardiovascular Medicine
Therapeutic target prioritization
Novel therapeutic targets
Translating Genetics to Cardiovascular Medicine
Therapeutic response prediction
Maximization of therapeutic benefit
Translating Genetics to Cardiovascular Medicine
Discover and characterize the range of phenotypic consequences of therapeutic traits
Minimization of therapeutic side effects
Translating Genetics to Cardiovascular Medicine
Diverse targeting strategies
Novel medicines
______ refers to the fraction of interindividual variability in risk for disease attributable to additive genetic variation. Heritability is a population-based construct without clear meaning for individuals.
Among individuals, 99.9% of the 6.4 billion base pairs are the same; genetic analyses leverage the 0.1% differences to understand trait or disease variation.
It is estimated that CAD is 40% to 60% heritable,based on the aforementioned family-based methods or statistical genetics approaches.
Heritability
The “_____________” of a disease refers to the number and magnitude of genetic risk factors that exist in each patient and in the population, as well as their frequencies and interactions.
For a given individual, diseases can result from genetic variation at a single gene (monogenic), few genes (oligogenic), or several genes (polygenic)
Genetic architecture
In scenarios where a single gene defect is necessary to yield sufficiently large risk for disease, the condition is termed a ___ because it will obey classical modes of inheritance.
Mendelian disorder
In autosomal dominant disorders, a ______ (with most genes having two copies, one inherited from the mother and one from the father) suffices to cause the phenotype.
Single defective copy of a gene
Autosomal recessive disorders require _____ to be defective to lead to the phenotype
Both copies
This is characterized by severely elevated blood cholesterol values and markedly increased risk for premature CAD, typically occurs due to single genetic variants in _____
However,if both gene copies are disrupted,a more severe phenotype occurs,and thus the inheritance pattern is termed incomplete dominance
Familial hypercholesterolemia (FH)
Low-LDLR, PCSK9, or APOB.
In X-linked disorders, the defective gene resides on the X chromosome.
Given that men have only ____ and women have two X chromosomes, men who carry the defective copy are affected with the disorder whereas women tend to be unaffected carriers, with some exceptions.
one X chromosome - affected ang men
This is a lysosomal storage disease sometimes manifesting as cardiomyopathy due to disruptive mutations in ____ on the X chromosome, is typically more severe in hemizygous men (due to there being one X chromosome, and thus one GLA copy) than heterozygous women (due to there being two GLA copies). Thus, Fabry is not classically X-linked recessive and is generally simply termed X-linked.
Fabry disease - GLA