Power Point: Genes and Genetic Diseases , AND Genes, Environment–Lifestyle, and Common Diseases

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Chapter 5

Genes, Environment–Lifestyle, and

Common Diseases

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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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Analysis of Risk Factors

Relative risk

Is the increased 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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Analysis of Risk Factors 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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ANS: 3

Relative risk is the ratio of the incidence a disease in those exposed to a risk factor to the incidence of the disease in those not exposed to the risk factor. This is a common indicator of the effects of specific risk factors.

1. The number of new cases of a disease in a specific time period is the incidence.

2. The proportion of a population with the disease at one time point is the prevalence.

4. Pathogenicity describes the ability of a particular disease agent to produce a disease.

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

Environmental factors cause the variations in traits.

Quantitative traits

Are measured on a continuous numeric scale.

Follow a normal bell curve for distribution.

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Principles of Multifactorial Inheritance (Cont.)

Threshold model

Liability distribution

Does not follow the bell-shaped distribution.

Appears to be either present or absent in individuals.

Does not follow the inheritance patterns expected of single-gene diseases.

Has a low end of getting the disease, compared with a high end of getting disease.

Threshold of liability

Below the threshold, an individual appears normal; above the threshold, the disease affects the person.

Examples: Pyloric stenosis, neural tube defects, cleft lip with or without cleft palate (CL/P), club foot, and some forms of congenital heart disease

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Principles of Multifactorial Inheritance (Cont.)

Liability distribution shows the threshold for males and females.

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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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Recurrence Risks (Cont.)

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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Recurrence Risks 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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ANS: 1

First, the recurrence risk becomes higher if more than one family member is affected. For example, the sibling recurrence risk for a ventricular septal defect (VSD), a type of congenital heart defect) is 3% if one sibling has had a VSD but increases to approximately 10% if two siblings have had VSDs.

2. Second, if the expression of the disease in the proband is more severe, the recurrence risk is higher. This is again consistent with the liability model because a more severe expression indicates that the affected individual is at the extreme tail end of the liability distribution (see Figure 5-2). His or her relatives are thus at a higher risk for inheriting disease genes.

3. Third, the recurrence risk is higher if the proband is of the less commonly affected sex. This is because an affected individual of the less susceptible gender is usually at a more extreme position on the liability distribution.

4. Fourth, the recurrence risk for the disease usually decreases rapidly in more remotely related relatives (Table 5-2). Whereas the recurrence risk for single-gene diseases decreases by 50% with each degree of relationship (e.g., an autosomal dominant disease has a 50% recurrence risk for siblings, 25% for uncle–nephew relationships, 12.5% for first cousins), it decreases much more quickly for multifactorial diseases.

Nature and Nurture: Disentangling the Effects of Genes and Environment

Nature

Genetics

Nurture

Environment

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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Nature and Nurture: Disentangling the Effects of Genes and Environment (Cont.)

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.

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Nature and Nurture: Disentangling the Effects of Genes and Environment (Cont.)

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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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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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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Multifactorial Disorders in the Adult Population (Cont.)

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 includes the renin-angiotensin system, nitric oxide, and kallikrein–kinin system.

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Multifactorial Disorders in the Adult Population (Cont.)

Cancer

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

Many major cancers occur in families.

Environmental and lifestyle choices affect the risk for cancer.

Tobacco use accounts for one-third of all cancers.

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Multifactorial Disorders in the Adult Population (Cont.)

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% to 10%) 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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Multifactorial Disorders in the Adult Population 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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ANS: 4

Genes responsible for this form of breast cancer have been mapped to chromosomes 17 (BRCA1) and 13 (BRCA2). It is possible to test each of these genes for inherited cancer-causing mutations. Women who inherit a mutation in BRCA1 or BRCA2 experience a 50% to 80% lifetime risk of developing breast cancer.

1. BRCA1 is on chromosome 17. Genes responsible for this form of breast cancer have been mapped to chromosomes 17 (BRCA1) and 13 (BRCA2).

2. If a woman has one affected first-degree relative, her risk of developing breast cancer doubles.

3. Kallikrein–kinin system is involved with blood pressure, not breast cancer.

Multifactorial Disorders in the Adult Population

Colorectal cancer

Is second only to lung cancer in the number of deaths 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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Prostate Cancer

Second most commonly diagnosed cancer in men (after skin cancer)

Second only to lung cancer as a cause of cancer death in men

Loss of heterozygosity in some regions

Several dozen polymorphisms associated with prostate cancer risk

High-fat diet is risk factor.

Detected by digital examination and prostate specific antigen (PSA) test

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Cancer Gene Identification

Large-scale DNA sequencing

Indentified hundreds of genes that are mutated in various cancers; some are considered primary causes of cancer.

Driver genes

Passenger genes

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Multifactorial Disorders in the Adult Population

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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Multifactorial Disorders in the Adult Population (Cont.)

Type 1 diabetes

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

T-cell infiltration

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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Multifactorial Disorders in the Adult Population (Cont.)

Type 1 diabetes (cont.)

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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Multifactorial Disorders in the Adult Population (Cont.)

Type 2 diabetes

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

Neither HMC associations 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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Multifactorial Disorders in the Adult Population (Cont.)

Type 2 diabetes (cont.)

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 Question 4

Type 2 diabetes

is caused by an absence of insulin.

usually involves a gene identified as HLA.

is commonly associated with HLA associations or autoantibodies.

is often treated with lifestyle modification including diet and exercise.

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ANS: 4

This type of diabetes is highly associated with increased BMI and obesity, thus weight loss is one goal of therapy. Dietary modifications can aid weight loss and reduce total glucose load.

1. Type 2 diabetes is highly associated with obesity and an increase in BMI. Obesity is most commonly defined as a body mass index (BMI) greater than 30. Obesity increases insulin resistance.

Type 2 diabetes produces insulin resistance; cells have difficulty using the insulin that is produced. Type 1 diabetes is characterized by destruction of pancreatic beta cells and reduction/absence of insulin.

3. The most significant gene identified thus far is TCF7L2, which encodes a transcription factor involved in the secretion of insulin. A variant of TCF7L2 is associated with a 50% increased risk of developing type 2 diabetes. Neither HLA associations nor autoantibodies are seen commonly in this form of diabetes.

Multifactorial Disorders in the Adult Population

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, cancer (prostate, breast, colon), 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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Multifactorial Disorders in the Adult Population (Cont.)

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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Multifactorial Disorders in the Adult Population (Cont.)

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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Multifactorial Disorders in the Adult Population (Cont.)

Alcoholism (cont.)

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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Multifactorial Disorders in the Adult Population (Cont.)

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 20%.

If an individual has two affected parents, then the risk is 50%.

Twin and adoption studies

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

If the offspring of a schizophrenic parent is 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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Multifactorial Disorders in the Adult Population (Cont.)

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%.

Twin and family studies show 60% or bipolar risk is due to genetic factors; 30% of the risk for unipolar disorder (major depression) is due to genetics.

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

Schizophrenia and bipolar disorder

Both are heterogeneous—reflect 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.)

Other complex disorders

Many other multifactorial diseases are also being studied.

Some susceptibility genes have been identified.

General principles of complex disorders

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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Multifactorial Disorders in the Adult Population (Cont.)

General principles of complex disorders (cont.)

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.

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

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