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
Mendelian disorders imply that the presence of a pathogenic ______ is deterministic for disease.
However, genetic profiling in large datasets enables unbiased estimates of penetrance—the likelihood of a person with a pathogenic variant having disease—and expressivity—variation in severity of disease
Monogenic variant
For example,variation at a G-C-A codon to G-C-G will lead to an alanine in both scenarios; such coding DNA sequence variants without impact on amino acid sequence are termed _____ and tend to not have phenotypic consequences
Synonymous variants
Other coding variants can cause a variety of alterations in a protein such as
__________ - substitution of a single amino acid with another
__________ - premature introduction of a stop codon
__________ - scrambling of the amino acid sequence past the variant site
Insertion/Deletion of Amino acids
Missense
Nonsense
Frameshift
______ have been linked to congenital heart diseases as well as variation in atherosclerotic cardiovascular disease biomarkers, such as lipoprotein(a) [Lp(a)].
Copy number variants (CNVs)
In the early 2000s, various studies identified families with apparent incompletely dominant FH but without LDLR or APOB variants. Linkage analyses and subsequent positional cloning identified _____ as the causal gene.
Also in the early 2000s, linkage and cloning analyses of families with autosomal recessive FH prioritized a large region on chromosome 1. Ultimately, homozygous mutations in _____(previously known as ARH, autosomal recessive hypercholesterolemia) were implicated in several families of Sardinian origin
** Hypercholesterolemia and CAD
PCSK9
LDLRAP1
A technique termed _____ uses DNA sequence variants to address the question of whether an epidemiologic association between a risk factor and disease actually reflects causality
Mendelian randomization (MR)
In principle, if a DNA sequence variant directly affects an intermediate phenotype (e.g., a variant in the promoter of a gene encoding a biomarker that alters its expression) and the inter- mediate phenotype truly contributes to the disease, the DNA variant should be associated with the disease to the extent predicted by (1) the size of the effect of the variant on the phenotype and (2) the size of the effect of the phenotype on the disease
More recently, the same investigators used linkage analyses in three large families of Iranian ancestry with cosegregation of premature CAD and the metabolic syndrome to prioritize a region in chromosome 19.
Whole exome sequencing and focused analysis within the prioritized region identified a perfectly cosegregating missense variant in ____ in all three families.
Screening of morbidly obese individuals of European descent with CAD and multiple metabolic phenotypes identified a family with cosegregation of a different missense variant in DYRK1B
** Metabolic syndrome and CAD
DYRK1B
Carriers of these alleles have reduced antiplatelet effects from clopidogrel
CYP2C192, which disrupts splicing
CYP2C193, which is a nonsense variant
Frequencies:
CYP2C19*2
30% in South Asians and East Asians
17% in Europeans and Africans
10% in Latinos
CYP2C19*3
6% in East Asians.
In the genotype- guided group, carriers of CY2C192 or CYP2C193 received ticagrelor or prasugrel, while noncarriers received clopidogrel. All participants in the standard-of-care group received ticagrelor or prasugrel. The genotype-guided group was noninferior to the standard-treatment group with respect to thrombotic events and had a 2.7% absolute risk reduction in bleeding events.
