B P2 C7 Applications of Genetics to Cardiovascular Medicine

Question 1

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.

Answer 1

Purine - adenine (A) and guanine (G)

Pyrimidine - thymine (T) and cytosine (C)

Question 2

.Further chromatin condensation and packing yields the ______ of autosomal chromosomes and ____ of sex chromosomes.

Answer 2

22 pairs

1 (one) pair

Question 3

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.

Answer 3

“Central dogma”

Question 4

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

Answer 4

Messenger RNA (mRNA)

Question 5

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).

Answer 5

Translation

Question 6

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 _________.

Answer 6

Genotype

Phenotype

Question 7

_______ 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

Answer 7

Epigenetics - influences transcription

Silencing

Question 8

______ refers to the fraction of interindividual variability in risk for disease attributable to additive genetic variation.

Answer 8

Heritability

Heritability is a population-based construct without clear meaning for individuals.

Question 9

For a given individual, diseases can result from genetic variation at a single gene (monogenic), few genes (______), or several genes (polygenic)

Answer 9

Oligogenic

Question 10

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.

Answer 10

Mendelian disorder

Question 11

Translating Genetics to Cardiovascular Medicine

Identify causal factors that influence disease
Test epidemiologic associations for causal inference

Answer 11

Biomarkers titratable to disease risk

Question 12

Translating Genetics to Cardiovascular Medicine

Penetrance estimation

Answer 12

Disease risk prediction

Question 13

Translating Genetics to Cardiovascular Medicine

Therapeutic target prioritization

Answer 13

Novel therapeutic targets

Question 14

Translating Genetics to Cardiovascular Medicine

Therapeutic response prediction

Answer 14

Maximization of therapeutic benefit

Question 15

Translating Genetics to Cardiovascular Medicine

Discover and characterize the range of phenotypic consequences of therapeutic traits

Answer 15

Minimization of therapeutic side effects

Question 16

Translating Genetics to Cardiovascular Medicine

Diverse targeting strategies

Answer 16

Novel medicines

Question 17

______ 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.

Answer 17

Heritability

Question 18

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)

Answer 18

Genetic architecture

Question 19

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.

Answer 19

Mendelian disorder

Question 20

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.

Answer 20

Single defective copy of a gene

Question 21

Autosomal recessive disorders require _____ to be defective to lead to the phenotype

Answer 21

Both copies

Question 22

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

Answer 22

Familial hypercholesterolemia (FH)

Low-LDLR, PCSK9, or APOB.

Question 23

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.

Answer 23

one X chromosome - affected ang men

Question 24

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.

Answer 24

Fabry disease - GLA

Question 25

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

Answer 25

Monogenic variant

Question 26

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

Answer 26

Synonymous variants

Question 27

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

Answer 27

Missense

Nonsense

Frameshift

Question 28

______ have been linked to congenital heart diseases as well as variation in atherosclerotic cardiovascular disease biomarkers, such as lipoprotein(a) [Lp(a)].

Answer 28

Copy number variants (CNVs)

Question 29

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

Answer 29

PCSK9

LDLRAP1

Question 30

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

Answer 30

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

Question 30

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

Answer 30

DYRK1B

Question 31

Carriers of these alleles have reduced antiplatelet effects from clopidogrel

Answer 31

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.