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Exam Of Advanced Pathophysiology

A, Double helix. Shown with the phosphodiester backbone as a ribbon on top and a space-filling model on the bottom. The bases protrude into the interior of the helix where they hold it together by base pairing. The backbone forms two grooves, the larger major groove and the smaller minor groove. B, Base pairing holds strands together. The hydrogen (H)-bonds that form between A and T and between G and C are shown with dashed lines. These produce AT and GC base pairs that hold the two strands together. This always pairs a purine with a pyrimidine, keeping the diameter of the double helix constant. A, Adenine; C, cytosine; G, guanine; T, thymine. (From Raven PH et al: Biology, ed 8, New York, 2008, McGraw-Hill.)

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V1 (2:12)

V2 ( 5: 23)

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DNA (cont’d)

Chromosomes contain genes.

Genes are the basic unit of inheritance and are composed of DNA.

DNA subunit or nucleotide contains:

One pentose sugar (deoxyribose)

One phosphate group

One nitrogenous base

Cytosine (C), thymine (T), adenine (A), guanine (G)

DNA has a double helix structure.

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DNA as the Genetic Code

DNA provides the code for all body proteins.

Proteins are composed of one or more polypeptides.

Polypeptides are composed of amino acids; there are twenty (20) amino acids:

The sequence of three bases (codons) direct the production of amino acids.

Termination and nonsense codons stop the production of protein.

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Replication

The DNA strand is untwisted and unzipped.

Single strand acts as a template.

DNA polymerase pairs the complementary bases.

Adenine-thymine; cytosine-guanine

DNA polymerase adds new nucleotides and “proofs” the new protein; if not correct, the incorrect nucleotide is excised and replaced.

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-The DNA bases code for amino acids which in turn make up proteins. The amino acids are specified by triplet codons od nitrogenous bases

-Transcription and translation are 2 processes in which proteins are specified by DNA and involves RNA. RNA is chemically similar to DNA except it is single stranded and has Uracil instead of Thymine as one of its 4 bases.

-Meiosis is process by which haploid cells are made from diploid cells

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Replication (cont’d)

Replication process

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Replication (cont’d) Question 1

Which information is correct regarding DNA polymerase?

DNA polymerase functions to:

Signal the end of a gene.

Pull apart a portion of a DNA strand.

Add the correct nucleotides to a DNA strand.

Provide a template for the sequence of mRNA nucleotides.

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Mutation

Is any inherited alteration of genetic material.

Chromosome aberrations in number or structure

Base pair substitution or missense mutation

One base pair is substituted for another; may result in changes in amino acid sequence.

May or may not cause disease or problems.

Frameshift mutation

Involves the insertion or deletion of one or more base pairs to the DNA molecule.

Mutagens: Are agents, such as radiation and chemicals, that increase the frequency of mutations.

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From Genes to Proteins

DNA is formed in the nucleus; protein is formed in the cytoplasm.

Transcription and translation: DNA code is transported from the nucleus to the cytoplasm, and protein is subsequently formed.

Ribonucleic acid (RNA) mediates both processes.

RNA is a single strand.

Uracil rather than thymine is one of the four bases; all the rest are the same as DNA.

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Transcription

RNA is synthesized from the DNA template via RNA polymerase.

RNA polymerase binds to the promoter site on DNA.

DNA specifies a sequence of mRNA.

Transcription continues until the termination sequence is reached.

mRNA then moves out of the nucleus and into the cytoplasm.

Gene splicing occurs.

Introns and extrons

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Transcription (cont’d)

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General Scheme of RNA Transcription. In transcription of messenger RNA (mRNA), a DNA molecule “unzips” in the region of the gene to be transcribed. RNA nucleotides already present in the nucleus temporarily attach themselves to exposed DNA bases along one strand of the unzipped DNA molecule according to the principle of complementary pairing. As the RNA nucleotides attach to the exposed DNA, they bind to each other and form a chainlike RNA strand called a messenger RNA (mRNA) molecule. Notice that the new mRNA strand is an exact copy of the base sequence on the opposite side of the DNA molecule. As in all metabolic processes, the formation of mRNA is controlled by an enzyme—in this case, the enzyme is called RNA polymerase. (From Ignatavicius DD, Workman LD: Medical-surgical nursing, ed 6, St Louis, 2010, Saunders.)

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Translation

Is the process by which RNA directs the synthesis of a polypeptide via the interaction with transfer RNA (tRNA).

tRNA contains a sequence of nucleotides (anticodon) complementary to the triad of nucleotides on the mRNA strand (codon).

Ribosome is the site of protein synthesis.

Ribosome helps mRNA and tRNA make polypeptides.

When ribosome arrives at a termination signal on the mRNA sequence, translation and polypeptide formation cease.

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Ribosomes are key

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Translation (cont’d) Question 2

At what site does protein synthesis occur?

The site of protein synthesis is the:

Codon

Intron

Ribosome

Anticodon

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Chromosomes

Somatic cells

Contain 46 chromosomes (23 pairs)

One member from the mother; one from the father

Diploid cells

Gametes

Sperm and egg cells

Contain 23 chromosomes

Haploid cells

One member of each chromosome pair

Meiosis

Formation of haploid cells from diploid cells

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-Human cells consist of diploid somatic cells (body cells) and haploid gametes (sperm and egg cells)

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Chromosomes (cont’d)

Autosomes

Are the first 22 of the 23 pairs of chromosomes in males and females.

The two members are virtually identical and are thus said to be homologous.

Sex chromosomes

Make up the remaining pair of chromosomes.

In females, it is a homologous pair (XX).

In males, it is a nonhomologous pair (XY).

Karyotype

The length and centromere location determine the ordered display of chromosomes.

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-Humans have 23 pairs of chromosomes ; 22 of the 23 pairs are autosomes ( are homologous/the same) in both males and females. The remaining pair consists of sex chromosomes.

-Females have 2 homologous X chromosomes as the sex chromosomes. Males have an X and Y nonhomogolous chromosome.

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Chromosomal Aberrations

Euploid cells

Have a multiple of the normal number of chromosomes.

Haploid and diploid cells are euploid forms.

Polyploid cells: An euploid cell has more than the diploid number.

Triploidy: Is a zygote that has three copies of each chromosome.

Tetraploidy: Has four copies of each chromosome (92 total).

Triploid and tetraploid fetuses do not survive or are stillborn or spontaneously aborted.

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Chromosomal Aberrations (cont’d)

Aneuploidy

Is a somatic cell that does not contain a multiple of 23 chromosomes.

Trisomy (trisomic): Is a cell that contains three copies of one chromosome.

Infants can survive with trisomy of certain chromosomes.

Monosomy

Is the presence of only one copy of any chromosome.

Is often fatal.

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-Aneuploid cells contain 3 copies of one chromosome is known as trisomy

-Monosomy is the presence of only one copy of a chromosome in a diploid cell

-Abnormalities of chromosomal structure include deletions, duplications, inversions, and translocations.

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Chromosomal Aberrations (cont’d)

Aneuploidy of sex chromosomes

Usually presents less serious consequences than autosomes.

Y chromosome usually causes no problems since it contains little genetic material.

For the X chromosome, inactivation of extra chromosomes largely diminishes their effect.

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Chromosomal Aberrations (cont’d)

Nondisjunction

Is usually the cause of aneuploidy.

Is the failure of homologous chromosomes or sister chromatids to separate normally during meiosis or mitosis.

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-Difficulty in separation of chromosomes

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Chromosomal Aberrations (cont’d)

Nondisjunction (cont’d)

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Nondisjunction Causes Aneuploidy When Chromosomes or Sister Chromatids Fail to Divide Properly. (From Jorde LB et al: Medical genetics, ed 5, Philadelphia, 2016, Elsevier.)

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Autosomal Aneuploidy

Trisomy

Chromosomes 13, 18, and 21 can survive; most others do not.

Partial trisomy

Only an extra portion of a chromosome is present in each cell.

Is not as severe as trisomies.

Chromosomal mosaics

Are trisomies that occur in only some cells of the body.

Body has two or more different cell lines, each of which has a different karyotype.

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Autosomal Aneuploidy (cont’d)

Down syndrome

Is the best-known example of aneuploidy.

Trisomy 21

Occurs 1 in 800 live births.

Manifestations: Mental challenges; low nasal bridge; epicanthal folds; protruding tongue; flat, low-set ears; and poor muscle tone.

Risk increases with maternal age.

Has an increased risk of congenital heart disease, respiratory infections, and leukemia.

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Autosomal Aneuploidy (cont’d)

Down syndrome (cont’d)

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 Down Syndrome. A, The karyotype of Down syndrome consists of 47 chromosomes and shows trisomy 21. B, A child with Down syndrome. (From Damjanov I: Pathology for the health professions, ed 4, Philadelphia, 2012, Saunders.)

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Sex Chromosome Aneuploidy

Occurs 1 in 400 males and 1 in 650 females.

Trisomy X is one of the most common aneuploidy.

Females have three X chromosomes.

Occurs 1 in 1000 female births.

Symptoms are variable and include sterility, menstrual irregularity, and/or cognitive deficits.

Symptoms worsen with each additional X chromosome.

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-Mental function is more severely impaired with greater number of trisomy in X chromosomes, for example some patients have 4-5 X chromosomes instead of just 3.

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Sex Chromosome Aneuploidy (cont’d)

Turner syndrome

Females have only one X chromosome

Denoted as karyotype 45,X.

Characteristics include:

Absence of ovaries (sterile)

Short stature

Webbing of the neck

Widely spaced nipples

High number of aborted fetuses

X chromosome that is usually inherited from the mother

Occurs 1 in 2500 female births.

Teenagers receive estrogen.

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-Most teenagers treated with estrogen to promote development of secondary sexual characteristics. Dose is then reduced to maintain characteristics and help avoid osteoporosis. Human growth hormone sometimes given to increase stature.

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Sex Chromosome Aneuploidy (cont’d)

Turner syndrome (cont’d)

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Turner Syndrome. A sex chromosome is missing, and the person’s chromosomes are 45,X. Characteristic signs are short stature, female genitalia abnormality, webbed neck, shieldlike chest with underdeveloped breasts and widely spaced nipples, and imperfectly developed ovaries. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)

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Sex Chromosome Aneuploidy (cont’d)

Klinefelter syndrome

Individuals with at least one Y and two X chromosomes.

Characteristics include:

Male appearance

Femalelike breasts (gynecomastia)

Small testes

Sparse body hair

1 in 1000 male births

Some individuals can be XXXY and XXXXY; will have male appearance; abnormalities will increase with each X; can also have an extra Y chromosome.

Disorder increases with the mother’s age.

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-Stature is often elevated along with moderate degree of mental impairment.

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Sex Chromosome Aneuploidy (cont’d)

Klinefelter syndrome (cont’d)

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Klinefelter Syndrome. This young man exhibits many characteristics of Klinefelter syndrome: small testes, some development of the breasts, sparse body hair, and long limbs. This syndrome results from the presence of two or more X chromosomes with one Y chromosome (genotypes XXY or XXXY, for example). (Courtesy Nancy S. Wexler, PhD, Columbia University. Picked up from Patton KT, Thibodeau GA: Anatomy & physiology, ed 9, St Louis, 2016, Mosby.)

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Sex Chromosome Aneuploidy (cont’d) Question 3

A female has one X chromosome. Which diagnosis will the nurse observe documented on the chart?

Trisomy X syndrome

Klinefelter syndrome

Fragile X syndrome

Turner syndrome

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Abnormalities of Chromosomal Structure

Effects may or may not have serious consequences.

Chromosome breakage

If a chromosome break occurs, then the break is usually repaired with no damage.

Breaks can stay or can heal in a way that alters the structure of the chromosome.

Can occur spontaneously.

Agents of chromosome breakage include Ionizing radiation, chemicals, and viruses.

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Abnormalities of Chromosomal Structure (cont’d)

Deletions

Chromosome breakage or loss of DNA

Example: Cri du chat syndrome or “cry of the cat”

Low birth weight, mentally challenged, and microcephaly

Duplications

Excess genetic material

Usually have less serious consequences

Inversion

Chromosomal rearrangement in which a chromosome segment is inverted: ABCDEFG becomes ABEDCFG

Usually affects offspring

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Abnormalities of Chromosomal Structure (cont’d)

Infant with cri du chat (5p deletion) syndrome

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-Occurs as a result of deletion of part of short arm portion of chromosome 5. Although one copy of chromosome is normal, serious consequences can still occur with deletions.

-Name derived from distinctive cry of newborn with this condition,

-Other symptoms include severe mental retardation, microcephaly, heart defects, and typical facial appearance seen in figure above.

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Abnormalities of Chromosomal Structure (cont’d)

Fragile sites (cont’d)

Fragile X syndrome

Site is on the long arm of the X chromosome; has an elevated number of repeated DNA sequences.

Is associated with being mentally challenged; is second in occurrence to Down syndrome.

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-Caused by an elevated number of repeated DNA sequences (more than 200) in the first exon of the fragile X gene. DNA replication becomes unstable, more than 20 genetic diseases are linked to this mechanism.

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Elements of Formal Genetics

Genetic inheritance

Mechanisms by which an individual’s set of paired chromosomes produces traits.

Explains the patterns of inheritance for traits and diseases that appear in families.

Mendelian traits

Are inherited traits primarily attributed to single genes.

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Elements of Formal Genetics (cont’d)

Locus: Is the location occupied by a gene on a chromosome.

Allele: Is one of several different forms of a gene at a locus.

One member of a gene from the mother; one member of a gene from the father

Homozygous: When genes are identical

Heterozygous: When genes are different

Polymorphism or polymorphic

Is a locus that has two or more alleles that occur with appreciable frequency.

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The way chromosomes are paired can produce specific traits.

Elements of Formal Genetics (cont’d)

Genotype: Is the composition of genes at a given locus.

Phenotype

Is the outward appearance of an individual.

Results from genotype and the environment.

Example: Infant with phenylketonuria (PKU) has the PKU genotype.

If left untreated, the infant will have cognitive impairments, which is the PKU phenotype.

If treated, the infant will still have the PKU genotype but can have a normal phenotype.

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-An individual’s genotype is his or her genetic makeup, and the phenotype reflects the interaction of the genotype and environment

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Elements of Formal Genetics (cont’d)

Dominance and recessiveness

If two alleles are found together, then the allele that is observable is dominant and the one whose effects are hidden is recessive.

In genetics, the dominant allele = a capital letter, and the recessive allele = a lowercase letter.

Alleles are either heterozygote or homozygote.

Alleles can be co-dominant; that is, both alleles are expressed.

Carrier

Has a disease allele but is phenotypically normal.

Can pass disease to offspring.

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-At a heterozygous locus, a dominant gene’s effects mask those of a recessive gene. The recessive gene is expressed only when it is present in 2 copies.

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Transmission of Genetic Diseases

Mode of inheritance: Is the inherited patterns through the generations of a family.

Mendel’s two laws

Principle of segregation

Homologous genes separate from one another.

Each cell carries only one of the homologous genes.

Principle of independent assortment

Hereditary transmission of one gene has no effect on the transmission of another.

Chromosome theory of inheritance

Chromosomes follow Mendel’s two laws.

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Transmission of Genetic Diseases (cont’d)

Four major types of genetic diseases

Autosomal dominant

Autosomal recessive

X-linked dominant

X-linked recessive

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Genetic diseases caused by a single gene usually follows autosomal dominant, autosomal recessive, or X-linked recessive modes of inheritance

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Transmission of Genetic Diseases (cont’d)

Pedigree

Is the tool used to study specific genetic disorders within families.

Begins with the proband.

Propositus (male) or proposita (female)

Usually the first person in the family diagnosed or seen in a clinic

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-Pedigree charts are important tools in the analysis of modes of inheritance

-Propositus/proposita is the individual who usually is the first diagnosed or seen in clinic with the disease

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Autosomal Dominant Inheritance

Diseases are rare.

Occurs in fewer than 1 of 500 individuals.

The union of a normal parent with an affected heterozygous parent usually produces the affected offspring.

An affected parent can pass either a disease gene or a normal gene to his or her children; each event has a probability of 0.5; on average, half will be heterozygous and will express the disease and half will be normal.

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– No generational skipping occurs.

-Condition is expressed equally in males and females, and males and females are equally likely to pass the gene to his or her offspring.

-Recurrence risk: probability that family member will have genetic disease

-When one parent is affected by an autosomal dominant disease and the other is normal, the occurrence and recurrence risks for each child are one half.

-Each birth is an independent event.

-New mutation: Is when no history of an autosomal dominant condition is present, but the child develops the mutation.

-Offspring of affected child will have 50% chance of genetic disease (recurrence risk)

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Autosomal Dominant Inheritance (cont’d)

Characteristics of autosomal dominant inheritance

Condition is expressed equally in males and females, and males and females are equally likely to pass the gene to his or her offspring.

Approximately one-half of children of an affected heterozygous parent will express the condition (all or none of the children may have the condition).

No generational skipping occurs.

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Autosomal Dominant Inheritance (cont’d)

Recurrence risk (cont’d)

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Review figure 4-20 on page 153

Punnett Square and Autosomal Dominant Traits. A, Punnett square for the mating of two individuals with an autosomal dominant gene. Here both parents are affected by the trait. B, Punnett square for the mating of a normal individual with a carrier for an autosomal dominant gene.

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Autosomal Dominant Inheritance (cont’d)

Pedigree

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Achondroplasia. A, Pedigree showing the transmission of an autosomal dominant disease. B, Achondroplasia. This girl has short limbs relative to trunk length. She also has a prominent forehead, a low nasal bridge, and redundant skin folds in the arms and legs. (From Jorde LB et al: Medical genetics, ed 5, Philadelphia, 2016, Elsevier.)

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Autosomal Recessive Inheritance

Is rare, but many individuals are carriers.

Abnormal allele is recessive, and the person must be homozygous to express the disease.

Trait usually appears in the children, not in the parents.

Example: Cystic fibrosis

Gene forms sodium channels with defective transport, which leads to a salt imbalance that results in abnormally thick, dehydrated mucus. The lungs and pancreas are affected; the person does not survive past 40 years of age.

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Autosomal Recessive Inheritance (cont’d)

Characteristics

Condition is expressed equally in males and females.

Is observed in siblings but not in parents.

Approximately one-quarter of offspring will be affected.

Consanguinity may be present.

Marriage between related individuals

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Autosomal Recessive Inheritance (cont’d)

Recurrence risk

When both parents are heterozygous carriers of an autosomal recessive disease, the occurrence and recurrence risks for each child are 25%; one-quarter of the offspring are normal, and one-half are carriers.

Carrier detection tests are available.

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Autosomal Recessive Inheritance (cont’d)

Recurrence risk (cont’d)

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X-Linked Inheritance

Is a disorder that involves X and Y chromosomes.

Y-linked disorders are uncommon because the Y chromosome contains relatively few genes.

Females: Have two X chromosomes; can be homozygous for the disease, homozygous for normal, or heterozygous.

Males: Have one X chromosome; are always hemizygous; if inherits an X recessive gene, then he will express the disease because no normal allele is present to counteract the diseased allele; males are affected more often with X recessive conditions.

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-X-linked genes are those that are located on the X chromosome. X-linked recessive genes cause nearly all known X-linked diseases.

-Males are affected more often with X recessive conditions.

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X-Linked Inheritance (cont’d)

X inactivation

Is a process by which one X chromosome in the somatic cells of females is permanently inactivated.

Barr bodies: Inactivated X chromosome

Females have 1 inactive X chromosome.

Males have no inactive X chromosomes.

Is always one less than the number of X chromosomes in the cell.

Occurs early in embryonic development.

Can have incomplete inactivation.

X-inactive specific transcript (XIST) gene which causes X inactivation uses methylation.

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X-Linked Inheritance (cont’d)

Sex determination

Begins during the sixth week of gestation.

One copy of the Y chromosome is sufficient to initiate the process of gonadal differentiation that produces a male fetus.

Number of X chromosomes does not alter this process.

Sex-determining region on the Y chromosome (SRY) gene begins male gonadal development.

Triggers other genes.

Can cross over to the X chromosome; is an apparently normal XX karyotype but with a male phenotype.

Can be deleted from the Y chromosome: XY female

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X-Linked Inheritance (cont’d)

Characteristics of X-linked recessive inheritance

Occurs significantly more often in males than in females.

Females must inherit two copies of the recessive allele (one from each parent) to express the disease, whereas males need only one copy (from the mother) to express the disease.

Because a father can give a son only a Y chromosome, the trait is never transmitted from father to son.

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-Sex-influenced trait: Is a trait that occurs significantly more often in one sex than in the other.

-Sex-limited trait: Is a trait that can occur in only one of the sexes.

X-Linked Inheritance (cont’d)

Characteristics of X-linked recessive inheritance (cont’d)

Gene can be transmitted through a series of female carriers, causing the appearance of a skipped generation.

Gene is passed from an affected father to all of his daughters, who, as phenotypically normal carriers, transmit it to approximately one-half of their sons, who are then affected.

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X-Linked Inheritance (cont’d)

Characteristics of X-linked recessive inheritance (cont’d)

Example: Duchenne muscular dystrophy (DMD)

Occurs 1 in 3500 males.

Exhibits progressive muscular degeneration.

Deletion of DMD gene causes dystrophin not to work properly; consequently, muscle cells do not survive.

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X-Linked Inheritance (cont’d)

Recurrence risks for X-linked recessive inheritance:

Outcomes for the offspring of an unaffected father and a heterozygous unaffected carrier mother (most common scenario)

Outcomes for the offspring of an affected father and a homozygous unaffected mother

Outcomes for the offspring of an affected father and a heterozygous unaffected carrier mother

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X-Linked Inheritance (cont’d)

Sex-limited trait: Is a trait that can occur in only one of the sexes.

Sex-influenced trait: Is a trait that occurs significantly more often in one sex than in the other.

Evaluation of pedigrees:

Is sometimes difficult to predict.

Uses computer programs and statistical techniques.

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X-Linked Inheritance (cont’d) Question 4

Which information indicates that the nurse has a good understanding of X-linked recessive inheritance?

The gene is passed from an affected father to all of his daughters.

The trait is observed significantly more often in females than in males.

Males are said to be heterozygous for the X chromosome.

A sex-limited trait is one that occurs significantly more often in one sex than in the other.

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Linkage Analysis and Gene Identification

Loci that are linked do not follow the principle of independent assortment.

Crossing over can create new alleles.

Recombination is the formation of new alleles.

Map units and pedigrees can help identify recombination rates.

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-During meiosis, crossing over occurs and can cause recombinations of alleles located on the same chromosome.

-The frequency of recombinations can be used to infer the map distance between loci on the same chromosome

-Loci that are on the same chromosome are syntenic

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Linkage Analysis and Gene Identification (cont’d)

Genetic testing and computer programs can help with analysis and identification and can:

Confirm the diagnosis of a genetic disease.

Identify carriers of recessive diseases.

Presymptomatically identify individuals who are at risk for inheriting a disease with delayed age of onset.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

Chapter 5

Genes, Environment-Lifestyle, and Common Diseases

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

Concepts of Incidence and Prevalence

Is the number of new cases of a disease reported during a specific period (typically 1 year) divided by the number of individuals in the population.

Incidence Rate

Prevalence Rate

Is the proportion of the population affected by a disease at a specific point in time.

Varies from population to population.

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-New cases of HIV in Dade county in May 2018 is incidence rate

-Current number of overall HIV cases in Dade county at the current moment or any give moment is the prevalence rate

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Analysis of Risk Factors

Relative risk

Is the incidence rate of a disease among individuals exposed to a risk factor divided by the incidence rate of the disease among individuals not exposed to a risk factor.

Many factors, including age, gender, diet, exercise, and family history of the disease, can influence the risk.

Complex interactions occur among genetic and nongenetic factors; each factor can be quantified in terms of relative risks.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Relative risk is a common measure of the effect of a specific risk factor. It is expresses as a ratio of the incidence rate of the disease among individuals exposed to a risk factor divided by the incidence of the disease among individuals not exposed to a risk factor. Risk factors can include age, gender, diet, exercise and family hx of disease

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Analysis of Risk Factors (cont’d) Question 1

Which information is correct regarding relative risk?

Relative risk indicates the:

Number of new cases of a disease in a specific time period

Proportion of a population with a disease at one time point

Chance of developing a disease relative to an exposure

Ability of a causative factor to produce a disease

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Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

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Principles of Multifactorial Inheritance

Polygenic traits

Effects of multiple genes cause the variations in traits.

Focus is on the genes—usually many (poly) genes.

Multifactorial traits

Genetic and environmental or lifestyle factors cause the variations in traits.

Additive effects of many genetic and environmental factors cause multifactorial traits.

Quantitative traits

Are measured on a continuous numeric scale.

Follow a normal bell curve for distribution.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Traits in which the combined effects of multiple genes are thought to be the cause of variation are known as polygenic

-Multifactorial is used when environmental factors are also believed to cause variation in the trait

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Recurrence Risks

Is hard to determine in multifactorial diseases.

Number of genes contributing to the disease is usually not known, precise allelic constitution of the parents is also not known, and the extent of environmental effects can vary substantially.

Empirical risks: Is based on direct observation of data; is specific for each multifactorial disease.

Recurrence risks of multifactorial diseases can substantially change because the gene frequencies, environment, and lifestyle factors can differ among populations.

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67

Recurrence Risks (cont’d)

Recurrence risk becomes higher if more than one family member is affected.

If the expression of the disease in the proband is more severe, then the recurrence risk is higher.

If the proband is of the less commonly affected sex, then the recurrence risk is higher.

Recurrence risk for the disease usually decreases rapidly in remotely related relatives.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Recurrence risks of multifactorial diseases can substantially change because the gene frequencies, environment, and lifestyle factors can differ among populations.

-Hard to determine in multifactorial diseases

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Recurrence Risks (cont’d) Question 2

Recurrence risk in multifactorial diseases is:

Higher if more than one family member is affected.

Lower if the disease is more severe in the proband.

Higher if the proband is the more commonly affected sex.

Rapidly increased when more distant relatives are affected.

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Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

69

Nature and Nurture: Disentangling the Effects of Genes and Environment

Nature

Genetics

Nurture

Environment-lifestyle

Attempting to determine the relative influence of the genetic and environmental factors is useful.

Two research strategies are often used to estimate the relative influence of genes and environment: twin studies and adoption studies.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Family members share genes and a common environment; therefore resemblance in traits such as HBP, reflects both genetic and environmental factors- nature and nurture respectively.

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Nature and Nurture: Disentangling the Effects of Genes and Environment (cont’d)

Twin studies

Monozygotic (MZ) twins: Identical; natural clones

Dizygotic (DZ) twins: Fraternal

Twin studies usually consist of comparisons between MZ and DZ twins.

Concordant trait

Both members of a twin pair share a trait.

Discordant trait

A twin pair does not share a trait.

‹#›

Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Two research studies are often used to estimate relative influence of genes and environmental and lifestyle factors: twin studies and adoption studies.

-Reviews monozygotic and dizygotic twins to examine types of traits carried

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Nature and Nurture: Disentangling the Effects of Genes and Environment (cont’d)

Adoption studies

Children born to parents who have a disease but are then subsequently adopted by parents lacking the disease are studied for disease recurrence.

A preliminary indication of the extent to which genetic factors may cause a multifactorial disease is provided.

Gene-environment interaction

A genetic predisposition may interact with an environmental factor to increase the risk for a disease to a much higher level than either factor would alone.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

Genetics of Common Diseases

Congenital malformations

Congenital diseases are present at birth.

Most congenital diseases are multifactorial.

Environmental factors can cause congenital malformations.

Having other disorders along with the congenital disease is common.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Congenital diseases are present at birth and most of them are multifactorial in their origins

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Multifactorial Disorders in the Adult Population

Coronary heart disease

Potential myocardial infarction caused by atherosclerosis in the arteries supplying blood to the heart

Potential cerebrovascular accident (stroke) caused by atherosclerosis in the arteries supplying blood to the brain

Risk increases if:

More affected relatives exist.

Affected relatives are female rather than male.

Age of onset is younger than 55 years.

Autosomal dominant familial hypercholesterolemia, high-fat diet, lack of exercise, smoking, and obesity increase risk

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-Risk is significant with more relatives affected and onset age of 55 years or younger

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Multifactorial Disorders in the Adult Population (cont’d)

Hypertension

Is a risk factor for heart disease, stroke, and kidney disease.

Between 20% and 40% of blood pressure variations are genetic, which means that environmental factors are important.

Important environmental factors include sodium intake, lack of exercise, stress, and obesity.

Blood pressure regulation is complex.

Research that focuses on individual components for gene involvement include the renin-angiotensin system, nitric oxide, and kallikrein-kinin system.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Only 20-40% genetic thus environment plays a huge role. Important to educate patient on prevention

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Renin-Angiotensin-Aldosterone System

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Multifactorial Disorders in the Adult Population (cont’d)

Cancer

Is the second leading cause of death in the United States.

Many major cancers occurs in families.

Environmental and lifestyle choices affect the risk for cancer.

Tobacco use accounts for one-third of all cancers.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Many cancers run in families, such as Prostate, Breast, Colon

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Multifactorial Disorders in the Adult Population (cont’d)

Breast cancer

Affects 12% of American women who live to 85 years of age.

If a woman has a first-degree relative with breast cancer, then her risk doubles.

Recurrence risk increases if the age of onset in the affected relative is early and if the cancer is bilateral.

An autosomal dominant form (5%) has been linked to chromosomes 13 (BRCA2) and 17 (BRCA1).

This form causes a 50% to 80% lifetime risk of developing breast cancer and increases the risk for ovarian cancer.

Other genes are implicated.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-First degree relative doubles the risk of disease

-Autosomal dominant chromosome identified and can be tested (BRAC 1 and BRAC 2)

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Multifactorial Disorders in the Adult Population (cont’d) Question 3

Which statement made by the nurse indicates an accurate understanding of breast cancer?

“BRCA1 is on chromosome 13.”

“If a woman has one affected first-degree relative, then her risk of developing breast cancer triples.”

“Alterations in the kallikrein-kinin system increases the risk for breast cancer.”

“Women who inherit a mutation in BRCA2 experience a 50% to 80% lifetime risk of developing breast cancer.”

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Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

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Multifactorial Disorders in the Adult Population (cont’d)

Colorectal cancer

Is second only to lung cancer in the number of cases occurring annually in the United States.

The risk is two to three times higher than the general population in those with one affected first-degree relative.

Clusters in families.

Inherited adenomatous polyposis coli (APC) gene mutations play a vital role in familial adenomatous polyposis.

Somatic mutations are involved in common colon cancers.

Mutations in any of six genes cause hereditary nonpolyposis colorectal cancer.

Environmental factors include a high-fat, low-fiber diet.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Clusters in families but also heavily based on environmental factors as well

-2-3 times higher risk with first degree relative affected

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Multifactorial Disorders in the Adult Population (cont’d)

Diabetes mellitus

Is complex and not fully understood.

Is the leading cause of blindness, heart disease, and kidney failure.

Two major types

Type 1 (insulin-dependent diabetes mellitus)

Type 2 (non–insulin-dependent diabetes mellitus)

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81

Multifactorial Disorders in the Adult Population (cont’d)

Type 1 diabetes

Is caused by the autoimmune destruction of insulin-producing beta cells in the pancreas.

T-cell activation and autoantibody production

Individuals with type 1 diabetes need insulin for life.

Siblings of individuals with type 1 diabetes face a substantial elevation in risk.

Incidence is higher in the offspring of diabetic fathers.

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-Risk of DM1 significantly increased for close relatives and offspring of diabetic fathers

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Multifactorial Disorders in the Adult Population (cont’d)

Type 1 diabetes (cont’d)

Twin studies: MZ and DZ pairs have a 30% to 50% and a 5% to 10% increased risk, respectively.

Association of specific human leukocyte antigen (HLA) class II alleles is 40%.

Insulin gene: Genetic variation here is associated with a 10% increased risk.

Other genes are also implicated.

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83

Multifactorial Disorders in the Adult Population (cont’d)

Type 2 diabetes

More than 90% of all individuals with diabetes have type 2.

Neither HLA nor autoantibodies are present.

Insulin resistance is present, or insulin production is diminished.

Risk factors include obesity and a positive family history.

Exercise has a preventive effect.

Recurrence risk

MZ twins have a 90% risk

First-degree relatives have a 15% to 40% risk.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Positive family hx also major risk factor

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Multifactorial Disorders in the Adult Population (cont’d)

Type 2 diabetes (cont’d)

Genes

Variant of TCF7L2 is associated with a 50% increased risk.

Other genes: PPAR-γ and KCNJ11 are associated with increased risk.

Glucokinase gene is associated with maturity-onset diabetes of the young.

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Multifactorial Disorders in the Adult Population (cont’d) Question 4

Type 2 diabetes:

Is highly correlated with reduced body mass index (BMI).

Is caused by an absence of insulin.

Usually involves a gene identified as HLA.

Is often treated with lifestyle modification, including diet and exercise.

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Elsevier items and derived items © 2009, 2005, 2001 by Saunders, an imprint of Elsevier Inc.

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Multifactorial Disorders in the Adult Population (cont’d)

Obesity

Is a BMI greater than 30.

BMI = weight in kilograms (W) divided by height in meters squared (H2) (BMI = W/H2)

Presents a substantial risk factor for heart disease, stroke, hypertension, and type 2 diabetes.

Adoption studies

Body weights of adopted individuals correlated significantly with their natural parents’ body weights.

Twin studies

Genetics have an effect on body weight: most studies yielded heritability estimates between 0.60 and 0.80.

Gene for leptin and its receptors are related to obesity.

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-Major genetic component, linked to disease risks (cardiac, DM)

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Multifactorial Disorders in the Adult Population (cont’d)

Alzheimer disease (AD)

Results in progressive dementia and a loss of memory.

Produces amyloid plaques and neurofibrillary tangles.

Risk doubles if a first-degree relative has AD.

Mutations for early-onset affect amyloid-beta deposition.

Presenilin 1 (PS1), presenilin 2 (PS2), and amyloid-beta precursor protein (APP) gene, which is the primary cause of AD

Mutations for late-onset AD

Allelic variation (ε2, ε3, and ε4) in apolipoprotein E (APOE)

One copy of the ε4 allele: at least two to five times at greater risk

Two copies of the ε4 allele: at least five to ten times more likely to develop AD

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Risk doubles if first-degree relative is affected

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Multifactorial Disorders in the Adult Population (cont’d)

Alcoholism

Risk is three to five times higher in the individual with an alcoholic parent.

Adoption studies

Offspring of an alcoholic parent, even when raised by nonalcoholic parents, have a fourfold increased risk.

Offspring of nonalcoholic parents, when reared by alcoholic parents, did not have an increased risk.

Twin studies: MZ and DZ pairs have a >60% and <30%, respectively, increased risk.

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-Risk triples or more with alcoholic parent as seen in adoption studies

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Multifactorial Disorders in the Adult Population (cont’d)

Alcoholism (cont’d)

Genes

Individuals with ALDH2*2 allele are much less likely to become alcoholics.

Allelic variation of gamma-aminobutyric acid (GABA) receptors increase the risk.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

Multifactorial Disorders in the Adult Population (cont’d)

Schizophrenia

Recurrence risk among offspring of one affected parent is 10 times higher than the general population.

If an individual has an affected sibling and an affected parent, then the risk is approximately 17%.

If an individual has two affected parents, then the risk is 46%.

Twin and adoption studies

MZ and DZ pairs have a risk of 47% and 12%, respectively.

If the offspring of a schizophrenic parent are adopted by normal parents, then the risk is approximately the same as the risk when raised by a schizophrenic biologic parent.

Brain-expressed genes whose products interact with glutamate receptors have been implicated.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Major genetic component especially affecting first degree relatives (offspring and siblings) as seen in adoption studies.

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Multifactorial Disorders in the Adult Population (cont’d)

Bipolar affective disorder

Is also called manic depressive disorder.

Risk rises between 5% and 10% if an individual has an affected first-degree relative, as compared with the normal risk of 0.5%.

Concordance rates are 79% and 24% for MZ and DZ twins, respectively.

Genes that affect serotonin, dopamine, and noradrenaline systems have been implicated.

Schizophrenia and bipolar disorder

Both are heterogeneous—reflects the influence of numerous genetic and environmental factors, making the phenotype hard to identify and genetic analysis complicated.

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Multifactorial Disorders in the Adult Population (cont’d)

Other complex diseases

Many other multifactorial diseases are also being studied.

Some susceptibility genes have been identified.

General principles of complex diseases

The more strongly inherited forms of complex disorders generally have an earlier age of onset.

Often represent single-gene inheritance.

When laterality is a component, the bilateral forms are more likely to cluster strongly in families.

The sex-specific threshold model fits some of the disorders (pyloric stenosis, CL/P, autism, heart disease), but it can also fail to fit other disorders (type 1 diabetes).

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-The more strongly inherited forms of complex disorders generally have an earlier age of onset.

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Multifactorial Disorders in the Adult Population (cont’d)

General principles of complex diseases (cont’d)

The assumption that a genetic component means the course of a disease cannot be altered is incorrect; most diseases have both genetic and environmental aspects.

Lifestyle modification (diet, exercise, stress reduction) can often reduce the risk for diseases.

Identifying a specific genetic lesion can lead to more effective prevention and treatment of diseases.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Misconception that course of a disease cannot be altered when genetic component involved; most diseases have both genetic and environmental aspects. Lifestyle choices are extremely important

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Chapter 6

Epigenetics and Disease

Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

95

Epigenetics

Are chemical modifications of deoxyribonucleic acid (DNA) sequences that alter the expression of genes, resulting in disease and phenotypic variations (upon genetics).

Types of epigenetic modifications

DNA methylation

Histone modification

Microribonucleic acids (miRNAs) or mature miRNAs [miRs])

Specific environmental or nongenetic factors, such as diet and exposure to certain chemicals, can affect epigenetics.

‹#›

Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Study of heritable changes in gene expression or phenotype caused by mechanisms other than changes in DNA sequences

-Environmental factors such as diet and exposure to certain chemicals may cause epigenetic modifications

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Epigenetics Video Links

https://www.youtube.com/watch?v=JMT6oRYgkTk

Introduction to epigenetics

https://www.youtube.com/watch?v=SrqmuYvk3iQ

Epigenetics, our bodies way to change the destiny written in our DNA

https://www.youtube.com/watch?v=VaDlLD97CLM Plasticity

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Epigenetics (cont’d)

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

Three Major Types of Epigenetic Processes. Investigators are studying the following epigenetic mechanisms: (1) DNA methylation, (2) histone modifications, and (3) RNA based-mechanisms. See text for discussion.

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DNA Methylation

Is the attachment of a methyl group to a cytosine base that is followed by a guanine base; also known as CpG dinucleotide.

Causes a gene to become transcriptionally inactive or silent.

When DNA sequence in the promoter region of a gene becomes heavily methylated, DNA is less likely to be transcribed into messenger RNA (mRNA).

Aberrant methylation: Is the silencing of tumor suppressor genes in cancer development.

Is a key component of X-inactivation.

‹#›

Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Methylation occurs when a methyl group is attached to cytosine base and followed by a guanine base.

-Methylation causes a gene to become transcriptionally inactive or silent

-Aberrant methylation: Is the silencing of tumor suppressor genes in cancer development.

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DNA Methylation (cont’d)

Process

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100

Twin Studies Provide Insights on Epigenetic Modification (cont’d)

Twins with significant lifestyle differences (e.g., smoking versus non-smoking)

Accumulated larger numbers of differences in their methylation patterns.

Became more different as a result of epigenetic changes, which in turn affected the expression of genes.

These results, along with findings generated in animal studies, suggest that changes in epigenetic patterns may be an important part of the aging process.

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101

Epigenetics and Cancer

DNA methylation and cancer tumor cells

Exhibit hypomethylation (decreased methylation).

Increases activity of oncogenes.

Hypomethylation increases as tumors progress from benign neoplasms to malignancy.

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-Best evidence of epigenetics effects on disease risk comes from studies on human cancer

-Methylation densities decline as tumors progress which can increase activity of oncogenes causing tumors to progress from benign neoplasms to malignancies

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Epigenetics and Cancer (cont’d)

DNA methylation and cancer tumor cells (cont’d)

Exhibit hypermethylation in promoter regions of tumor-suppressor genes.

Ability to inhibit tumor formation: Decreases

Promoter region of the RB1: Can cause retinoblastoma

BRCA1: can lead to inherited breast cancer

VHL promoter region: associated with von Hippel-Lindau disease, in which renal cell carcinomas frequently occur

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Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

-Hypermethylation also occurs in microribonucleic acid (microRNA) genes and is associated with tumorigenesis

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Epigenetics and Cancer (cont’d)

DNA methylation and cancer tumor cells (cont’d)

Methylation of the promoter region of a gene: MLH1

When MLH1 becomes inactive, damaged DNA accumulates, eventually resulting in colon tumors.

Is the major cause of one form of inherited colon cancer—hereditary nonpolyposis colorectal cancer.

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104

Epigenetics and Cancer (cont’d)

Strategies for treating epigenetic disease

Epigenetic modifications can be reversed.

Demethylating agent: 5-azacytidine is used as the treatment of leukemia and myelodysplastic syndrome.

Histone deacetylase (HDAC) inhibitors: Counteracts the removal of acetyl groups from histone proteins, which can silence the activity of tumor-suppressor genes.

Are used in the treatment of T-cell lymphomas.

Major challenge: Is to develop drugs that target only the genes responsible for a specific cancer.

‹#›

Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc.

Unlike DNA sequence mutations, epigenetic modifications can be reversed through pharmaceutical intervention

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Epigenetics and Cancer (cont’d) Question

Which statement by the nurse indicates an accurate understanding of epigenetics and cancer?

“Hypomethylation of the promoter region of the RB1 gene is often observed in retinoblastoma.”

“Hypomethylation increases as tumors progress from benign neoplasms to malignancy.”

“Hypomethylation of specific subgroups of miRNAs is associated with tumorigenesis.”

“Hypomethylation occurs when HDAC inhibitors are administered for cancer.”

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