Chapter 5, Genes, Environment-Lifestyle, and Common Diseases Understanding Genetics of Common Diseases
What are the prevalence and causes of congenital malformations?
Some common multifactorial disorders, the congenital malformations, are present at birth. Others, including heart disease, cancer, diabetes, and most psychiatric disorders, are seen primarily in adolescents and adults.
These disorders are complex, and unraveling their genetics is a daunting task but significant progress is being made.
2% of newborns present with a congenital malformation; most of these are multifactorial in etiology.
Sibling recurrence risks for these disorders range from 1% to 5%.
Table 5.4 lists some more common congenital malformations.
Table 5.4 Prevalence Rates of Common Congenital Malformations in Whites
Disorder
Prevalence Per 1000 Births (Approximate)
Cleft lip/palate
1
Clubfoot
1
Congenital heart defects
4–8
Hydrocephaly
0.5–2.5
Isolated cleft palate
0.4
Neural tube defects
1–3
Pyloric stenosis
3
Some common congenital malformations are:
CL/P and pyloric stenosis are relatively easy to repair and are not considered to be serious problems.
Neural tube defects, have more severe consequences.
Some cases occur in the absence of any other problems, but they could be associated with other disorders. For example:
Hydrocephaly and clubfoot are often seen secondary to spina bifida
CL/P is often seen in babies with trisomy 13
Congenital heart defects are seen in children with many other disorders, including Down syndrome (Fig. 5.4)
Fig. 5.4 Spina Bifida and Anencephaly
.
(A)
Spina bifida in a newborn.
(B)
Anencephaly, showing the absence of the cranial vault. (From Jones KL, Smith DM.
Smith’s recognizable patterns of human malformation
, 6th edition. Philadelphia: Saunders; 2006:705).
Environmental factors also cause some congenital malformations.
An example is thalidomide, a sedative used during pregnancy in the early 1960s.
When ingested during early pregnancy, this drug often caused phocomelia (severely shortened limbs) in babies.
Maternal exposure to retinoic acid, used to treat acne, can cause congenital defects of the heart, ear, and central nervous system.
Maternal rubella infection can cause congenital heart defects.
How does genetics affect coronary heart disease?
With more powerful laboratory and analytic techniques available much is known about the specific genes responsible for common adult diseases.
Coronary Heart Disease (CHD) is the leading killer of Americans, accounting for approximately 25% of all deaths in the United States. The table lists the causes and the risk factors of the CHD.
Causes
Risk factorss
Caused by
atherosclerosis
(narrowing because of the formation of lipid-laden lesions) of the coronary arteries.
This narrowing impedes blood flow to the heart and can eventually result in a
myocardial infarction
(destruction of heart tissue caused by an inadequate supply of oxygen).
When atherosclerosis occurs in arteries supplying blood to the brain, a
stroke
can result.
Chapter 5, Genes, Environment-Lifestyle, and Common Diseases Understanding Genetics of Common Diseases
Obesity
Cigarette smoking
Hypertension
Elevated cholesterol level
Positive family history (usually defined as having one or more affected first-degree relatives)
The person is two to seven times more likely to have heart disease than is an individual with no family history (this would be the relative risk of heart disease because of a positive family history)
The risk increases if:
There are more affected relatives
The affected relative or relatives are female (the less commonly affected sex) rather than male
The age of onset in the affected relative is early (before 55 years)
For example, one study showed that men between the ages of 20 and 39 years had a relative risk of 3 for CHD if they had one affected first-degree relative.
The relative risk increased to 13 if two first-degree relatives were affected with CHD before 55 years of age.
What part do genes play in the familial clustering of heart disease?
Due to the lipids in atherosclerosis that play a key role, focus is on the genetic determination of various lipoproteins.
Important advance in this area is the identification of several genes that encode the processing of low-density lipoproteins and that, when mutated, can cause
familial hypercholesterolemia
. (Box 5.3)
Box 5.3 Familial Hypercholesterolemia
Box. 5.3
Data from Brautbar A, Leary E, Rasmussen K, et al. Genetics of familial hypercholesterolemia.
Current Atherosclerosis Reports
, 2015;17:491; Roberts R, Davidson MH, Hirsh BJ, et al. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease.
Journal of the American College of Cardiology
, 2014;64(23):2525–2540; Varret MM, Abifadel M, Rabès JP, et al. Genetic heterogeneity of autosomal dominant hypercholesterolemia.
Clinical Genetics
, 2008; 73(1): 1–13.
Autosomal dominant familial hypercholesterolemia (FH) is an important cause of heart disease, accounting for approximately 5% of myocardial infarctions in individuals younger than 60 years of age. FH is one of the most common autosomal dominant disorders: in most populations surveyed to date, approximately 1 in 500 people is a heterozygote. Plasma cholesterol levels are approximately twice as high as normal (i.e., approximately 300–400 mg/dL), resulting in substantially accelerated atherosclerosis and distinctive cholesterol deposits in skin and tendons (
xanthomas
[see Fig. 5.6]). Data compiled from five studies showed that approximately 75% of men with FH developed coronary disease, and 50% had a fatal myocardial infarction by 60 years. The corresponding percentages for women were lower (45% and 15%) because women generally develop heart disease at a later age than men.
Consistent with Hardy-Weinberg predictions, approximately 1 in 1 million births is homozygous for the FH gene. Homozygotes are much more severely affected, with cholesterol levels ranging from 600 to 1200 mg/dL. Most experience myocardial infarctions before 20 years of age, and a myocardial infarction at 18 months of age has been reported. If untreated, most FH homozygotes die before 30 years of age.
All cells require cholesterol as a component of their plasma membrane. They can either synthesize their own cholesterol or, preferably, obtain it from the extracellular environment, where it is carried primarily by low-density lipoprotein (LDL). In a process known as
endocytosis
, LDL-bound cholesterol is taken into the cell via LDL receptors on the cell’s surface (see Fig. 5.5). FH is most caused by a reduction in the number of functional LDL receptors on cell surfaces. Lacking the normal number of LDL receptors, cellular cholesterol uptake is reduced and circulating cholesterol levels increase.
Much of what we know about endocytosis has been learned through the study of LDL receptors. The process of endocytosis and the processing of LDL in the cell are described in detail in Fig. 5.5 (endocytosis is discussed in Chapter 1). These processes result in a fine-tuned regulation of cholesterol levels within cells, and they influence the level of circulating cholesterol as well.
The identification of the LDL receptor gene in 1984 was critical in understanding exactly how LDL receptor defects cause FH. More than 1000 different mutations, including missense and nonsense substitutions as well as insertions and deletions, have been identified in the LDL receptor gene. These can be grouped into five broad classes according to their effects on the activity of the receptor. Class 1 mutations result in no detectable protein product. Thus, heterozygotes would produce only half the normal number of LDL receptors. Class 2 mutations in the LDL receptor gene result in production of the LDL receptor, but it is altered such that it cannot leave the endoplasmic reticulum. It is eventually degraded. Class 3 mutations produce an LDL receptor that can migrate to the cell surface but incapable of normal binding to LDL. Class 4 mutations, which are comparatively rare, produce receptors that are normal except that they do not migrate specifically to coated pits and thus cannot carry LDL into the cell. The final group of mutations, class 5, produces an LDL receptor that cannot dissociate from the LDL particle after entry into the cell. The receptor cannot return to the cell surface and is degraded. Each class of mutations reduces the number of effective LDL receptors, resulting in decreased LDL uptake and hence elevated levels of circulating cholesterol. The number of effective receptors is reduced by approximately half in FH heterozygotes, and homozygotes have virtually no functional LDL receptors. LDL receptor that can migrate to the cell surface but incapable of normal binding to LDL. Class 4 mutations, which are comparatively rare, produce receptors that are normal except that they do not migrate specifically to coated pits and thus cannot carry LDL into the cell. The final group of mutations, class 5, produces an LDL receptor that cannot dissociate from the LDL particle after entry into the cell. The receptor cannot return to the cell surface and is degraded. Each class of mutations reduces the number of effective LDL receptors, resulting in decreased LDL uptake and hence elevated levels of circulating cholesterol. The number of effective receptors is reduced by approximately half in FH heterozygotes, and homozygotes have virtually no functional LDL receptors.
Understanding the defects that lead to FH has helped to develop effective therapies for the disorder. Dietary reduction of cholesterol (primarily through the reduced intake of saturated fats) has only modest effects on cholesterol levels in FH heterozygotes. Because cholesterol is reabsorbed into the gut and then recycled through the liver (where most cholesterol synthesis takes place), serum cholesterol levels can be reduced by the administration of bile acid–absorbing resins, such as cholestyramine. The absorbed cholesterol is then excreted. It is interesting that reduced recirculation from the gut causes the liver cells to form additional LDL receptors, lowering circulating cholesterol levels. However, the decrease in the concentration of intracellular cholesterol also stimulates cholesterol synthesis by liver cells, so the overall reduction in plasma LDL level is only approximately 15% to 20%. This treatment is much more effective when combined with agents that reduce cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (the “statin” class of drugs). Decreased synthesis leads to further production of LDL receptors. When these therapies are used in combination, serum cholesterol levels in FH heterozygotes can be reduced to approximately normal levels.
The picture is less encouraging for FH homozygotes.
The therapies just discussed can enhance cholesterol elimination and reduce its synthesis, but they are largely ineffective because homozygotes have few or no LDL receptors. Liver transplants, which provide hepatocytes that have normal LDL receptors, have been successful in some cases, but this option is often limited by a lack of donors.
Plasma exchange carried out every 1–2 weeks, in combination with drug therapy, can reduce cholesterol levels by approximately 50%.
However, this therapy is difficult to continue for long periods. Somatic cell gene therapy, in which hepatocytes carrying normal LDL receptor genes are introduced into the portal circulation, is now being tested. It may eventually prove to be an effective treatment for FH homozygotes.
FH also can be caused by inherited mutations in the gene that encodes apolipoprotein B. In addition, a small number of FH cases are caused by mutations in the gene that encodes PCSK9 (proprotein convertase subtilisin/kexin type 9), an enzyme that plays a key role in degrading LDL receptors. Gain-of-function mutations in the
PCSK9
gene reduce the number of LDL receptors, causing FH. Loss-of-function mutations in this gene can increase the number of LDL receptors, resulting in exceptionally low circulating LDL levels. These findings have led to the development of drugs that inhibit PCSK9 activity, thus lowering LDL cholesterol levels. These drugs, which have been approved for clinical use, can reduce LDL cholesterol levels by approximately 50% in the general population of persons with hypercholesterolemia and produce significant effects even in those who are using statin drugs.
The FH story illustrates how medical research has made important contributions both to our understanding of basic cell biology and to our advances in clinical therapy. The process of receptor-mediated endocytosis, elucidated largely by research on the LDL receptor defects, is of fundamental significance for cellular processes throughout the body. Equally important is that this research, by clarifying how cholesterol synthesis and uptake can be modified, has led to significant improvements in therapy for this important cause of heart disease. The discovery of rare mutations in PCSK9 has led to PCSK9 inhibitor drugs that may benefit millions of persons with high cholesterol levels.
Data from Brautbar A, Leary E, Rasmussen K, et al. Genetics of familial hypercholesterolemia.
Current Atherosclerosis Reports
, 2015; 17: 491; Roberts R, Davidson MH, Hirsh BJ, et al. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease.
Journal of the American College of Cardiology
, 2014; 64(23): 2525–2540; Varret MM, Abifadel M, Rabès JP, et al. Genetic heterogeneity of autosomal dominant hypercholesterolemia.
Clinical Genetics
, 2008; 73(1): 1–13.
Many other genes involved in lipid variation, coagulation, and hypertension have been identified, including several genes encoding apolipoproteins (the protein components of lipoproteins) (Fig. 5.5).
Fig. 5.5 Process of Receptor-Mediated Endocytosis.
1, The low-density lipoprotein (LDL) receptors, which are glycoproteins, are synthesized in the endoplasmic reticulum of the cell. 2, From here, they pass through the Golgi apparatus to the cell surface, where part of the receptor protrudes outside the cell. 3, The circulating LDL particle is bound by the LDL receptor and localized in cell surface depressions called coated pits (so named because they are coated with a protein called clathrin). 4, The coated pit invaginates, bringing the LDL particle inside the cell. 5, Once inside the cell, the LDL particle is separated from the receptor, taken into a lysosome, and broken down into its constituents by lysosomal enzymes. 6, The LDL receptor is recirculated to the cell surface to bind another LDL particle (each LDL receptor goes through this cycle approximately once every 10minutes even if it is not occupied by an LDL particle). 7, Free cholesterol is released from the lysosome for incorporation into cell membranes or metabolism into bile acids or steroids. Excess cholesterol can be stored in the cell as a cholesterol ester or removed from the cell by associating with high-density lipoprotein (HDL). 8, As cholesterol levels in the cell rise, cellular cholesterol synthesis is reduced by inhibition of the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. 9, Rising cholesterol levels also increase the activity of acyl coenzyme A (acyl CoA):cholesterol acyltransferase (ACAT), an enzyme that modifies cholesterol for storage as cholesterol esters. 10, In addition, the number of LDL receptors is decreased by lowering the transcription rate of the LDL receptor gene itself. This decreases cholesterol uptake. (From Jorde LB, Carey JC, Bamshad MJ.
Medical genetics
, 6th edition. Philadelphia: Elsevier; 2020).
Functional analysis of these genes is leading to an increased understanding and eventually more effective treatment of CHD. Xanthomas, which are fatty deposits, are often noted in individuals with familial hypercholesterolemia (Fig. 5.6).
Fig. 5.6 Xanthoma.
Fatty deposits, referred to as xanthomas as seen here on the knuckles, are often noted in individuals with familial hypercholesterolemia. (From Jorde LB, Carey JC, Bamshad MJ.
Medical genetics
, 6th edition. Philadelphia: Elsevier; 2020).
How do genetic and environmental factors affect blood pressure?
Key Points
Some common multifactorial disorders, the congenital malformations, are present at birth. Others, including heart disease, cancer, diabetes, and most psychiatric disorders, are seen primarily in adolescents and adults.
Due to the lipids in atherosclerosis that play a key role, focus is on the genetic determination of various lipoproteins. Important advance in this area is the identification of several genes that encode the processing of low-density lipoproteins and that, when mutated, can cause
familial hypercholesterolemia
.
Systemic hypertension has a worldwide prevalence of approximately 25% to 30%. It is a key risk factor for heart disease, stroke, and kidney disease.
Women who inherit a mutation in
BRCA1
or
BRCA2
experience a 50% to 80% lifetime risk of developing breast cancer.
Prostate cancer is second only to lung cancer as a cause of cancer death in men, causing more than 30,000 deaths each year.
How do genes correlate with cancer?
Question 1 of 3
Which statement would accurately describe the source of a congenital malformation?
Exactly!
Heart defects may occur from only environmental factors.
Club foot is an isolated condition related to birth trauma.
Spina bifida results exclusively from genetic causes.
Heart disease in adolescents is not genetically based.
Heart defects may occur from only environmental factors.
Congenital heart defects are seen in children with genetic disorders; however, there is evidence that maternal rubella infection and exposure to retinoic acid alone can cause environmental congenital defects of the heart. Chapter 5, Genes, Environment-Lifestyle, and Common Diseases Understanding Genetics of Common Diseases
Club foot is an isolated condition related to birth trauma.
Club foot is associated with multifactorial etiology that includes a genetic component. It is often seen secondary to spina bifida.
Spina bifida results exclusively from genetic causes.
Multifactorial etiology with a genetic component and environmental component is associated with spina bifida.
Heart disease in adolescents is not genetically based.
Some common multifactorial disorders that include heart disease and cancer are seen primarily in adolescents and adults.
Question 2 of 3
Which therapy would be most effective for a patient who is homozygous for the familial hypercholesterolemia (FH) gene?
Exactly!
Bile acid–absorbing resins
Plasma exchange with drug therapy
Dietary reduction of cholesterol
Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
Bile acid–absorbing resins
Combination therapies reduce serum cholesterol levels for patients that are FH heterozygotes rather than homozygous patient because homozygotes have few or no LDL receptors for the uptake of LDL cholesterol.
Plasma exchange with drug therapy
Plasma exchange, in combination with drug therapy, is the most effective to reduce cholesterol levels by approximately 50% for patient that are FH homozygous since medication alone is not effective.
Dietary reduction of cholesterol
Dietary reduction of cholesterol without medication has only modest effects on cholesterol levels in FH heterozygotes and basically no effect with homozygous patients.
Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
HMG-CoA reductase inhibitors are largely ineffective for FH homozygotes since LDL receptors are minimal to absent to respond to drug therapy to reduce LDL cholesterol.
Question 3 of 3
When a patient reports that a sister has breast cancer, which statement would indicate that the patient correctly understands the assessment of breast cancer risk?
Exactly!
“Genetic testing is limited to research studies.”
“Breast cancer risks are about the same in all women.”
“Two genes create the risk for the most breast cancer cases.”
“Breast cancer risk increases with early onset in a relative.”
“Genetic testing is limited to research studies.”
Genetic testing for inherited cancer-causing mutations is used to identify risk in clinical practice and provide targeted treatment. Examples include the BRCA1 and BRCA2 genes.
“Breast cancer risks are about the same in all women.”
Women who inherit a mutation in BRCA1 or BRCA2 experience a 50% to 80% lifetime risk of developing breast cancer compared to a 1 in 8 risk for all women.
“Two genes create the risk for the most breast cancer cases.”
An autosomal dominant form of breast cancer accounts for approximately 5% to 10% of breast cancer cases that includes the BRCA1 and BRCA2 genes; however, this is not the major risk factor. Ninety percent of breast cancer cases are not inherited as this type of mendelian disease.
“Breast cancer risk increases with early onset in a relative.”
If a woman has one affected first-degree relative, her risk of developing breast cancer doubles and it increases further if the age of onset in the affected relative is early and if the cancer is bilateral.
How does genetics affect type 1 diabetes?
What is the pathophysiology of type 2 diabetes?
How do environmental and genetic factors contribute to obesity?
Obesity is defined as a body mass index (BMI) greater than 30 (BMI is defined as W/H2, in which W is weight in kilograms and H, is height in meters.).
Using this criterion, more than one-third of American adults are obese, and an additional one third are overweight (BMI greater than 25 but less than 30).
The proportion of obese adults and children continues to increase rapidly.
Obesity itself is not a “disease,” but it is an important risk factor for several common diseases, including heart disease, stroke, type 2 diabetes, and cancers of the prostate, breast, and colon.
There is a strong correlation between obesity in parents and their children. This could be ascribed to common environmental effects.
Parents and children usually share similar dietary and exercise habits.
There is good evidence for genetic components as well.
Body weights of adopted individuals correlated significantly with their natural parents’ body weights but not with those of their adoptive parents.
Twin studies also provide evidence for a genetic effect on body weight, with most studies yielding heritability estimates between 0.60 and 0.80.
Research, aided substantially by mouse models, shows that many genes each play a role in human obesity. Important among these are the genes that encode leptin and its receptor.
The leptin hormone is secreted by adipocytes (fat storage cells) and binds to receptors in the hypothalamus, the site of the body’s appetite control center.
Cloning of the human leptin gene and its receptor led to optimistic predictions that leptin could be a key to weight loss in humans (without the perceived unpleasantness of dieting and exercise).
Mutations in the human leptin gene and its receptor have been identified in a few humans with severe obesity (BMI >40), but they both appear to be extremely rare.
Clinical trials using recombinant leptin have demonstrated moderate weight loss in a subset of obese individuals.
Leptin participates in important interactions with other components of appetite control, like neuropeptide Y and α-melanocyte–stimulating hormone and its receptor, the melanocortin-4 receptor (MC4R).
Mutations in the gene that encodes MC4R have been found in 3% to 5% of severely obese individuals.
Homozygosity for a DNA variant in the
FTO
gene (which is seen in 16% of Whites) has been associated with 40% and 70% increases in the risks of overweight and obesity, respectively.
Recent evidence shows that the
FTO
variant is part of an enhancer that binds to the
IRX
gene, which is located 2 million base pairs away from
FTO
and is involved in regulation of fat mass.
Identification of these human genes is leading to a better understanding of natural weight control in the human, and it could eventually lead to effective treatments for some cases of obesity.
How are genes associated with susceptibility to alcohol addiction?
Key Points
The genes that affect type 1 diabetes are alleles, insulin gene, cytotoxic T-lymphocyte,
PTPN22
, systemic lupus erythematosus (SLE), rheumatoid arthritis and autoimmune thyroid disease.
The associations between diabetes susceptibility and each of these genes have been widely replicated in multiple populations. These genes include
TCFL2
, allele, and
KCNJ11
.
Mutations in the human leptin gene and its receptor have been identified in a few humans with severe obesity (BMI >40), but they both appear to be extremely rare.
An allele of the
ALDH2
gene
(ALDH2*2)
results in excessive accumulation of acetaldehyde and thus in facial flushing, nausea, palpitations, and lightheadedness.
Question 1 of 3
Which statement would accurately describe the pathology of type 1 diabetes?
Exactly!
Genetic factors alone are responsible.
Infection contributes to a genetic immune response.
A homozygous genetic disorder alters blood glucose levels.
An altered insulin gene occurs from an infection response.
Genetic factors alone are responsible.
Type 1 diabetes is not 100% concordant among identical twins indicating that genetic factors are not solely responsible for the pathology of the disorder.
Infection contributes to a genetic immune response.
There is evidence that specific viral infections contribute to the causation of type 1 diabetes, possibly by activating an autoimmune response that corresponds to genetic factors.
A homozygous genetic disorder alters blood glucose levels.
Diabetes is a heterogeneous group of disorders characterized by elevated blood glucose levels. Multiple genetic factors with additional environmental factors are considered to be present.
An altered insulin gene occurs from an infection response.
More than 50 additional genes have been shown to be associated with susceptibility to type 1 diabetes. The altered genetics contributes to an altered response to infection and immune response rather than an infection altering the gene.
Question 2 of 3
Which information would accurately describe a feature for type 2 diabetes?
Exactly!
Identical twin risk is low
Obesity occurrence is high
Insulin is required for treatment
Evidence of autoimmune disease
Identical twin risk is low
Identical twin risk is 0.35 to 0.60 for type 2 diabetes, which is similar to the risk for type 1 diabetes (0.30 to 0.70).
Obesity occurrence is high
Obesity is a feature of type 2 diabetes rather than of type 1 diabetes. This is considered both genetic and environmental factor for the disease.
Insulin is required for treatment
Individuals with type 2 diabetes may receive exogenous insulin or other treatments to lower blood glucose.
Evidence of autoimmune disease
Variation in genes associated with type 1 diabetes, not type 2 diabetes, is found with several other autoimmune diseases.
Question 3 of 3
Which person would have the lowest risk for alcohol use disorder?
Exactly!
Monozygotic twin with alcohol use disorder
Parent treated successfully for an alcohol use disorder
Offspring of alcoholic parent raised by nonalcoholic parents
Adopted by alcoholic parent without alcoholic birth parent
Monozygotic twin with alcohol use disorder
Twin studies have yielded concordance rates for DZ twins less than 30% and concordance rates for MZ twins more than 60%.
Parent treated successfully for an alcohol use disorder
With one affected parent the risk is three to five times higher than for those with unaffected parents.
Offspring of alcoholic parent raised by nonalcoholic parents
Adoption studies show that the offspring of an alcoholic parent, even when raised by nonalcoholic parents, have a fourfold increased risk of developing the disorder.
Adopted by alcoholic parent without alcoholic birth parent
One study showed that the offspring of nonalcoholic parents, when reared by alcoholics, did not have an increased risk of developing alcoholism.
How are genes associated with Alzheimer disease?
What principles and conclusions result from studies on the genetics of complex disorders?
The disorders represent some of the most common multifactorial disorders and for which significant progress has been made in identifying genes.
Many other multifactorial disorders are being studied as well, and in some cases specific susceptibility genes have been identified.
These include Parkinson disease, hearing loss, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, asthma, inflammatory bowel disease, and some forms of blindness.
Some general principles can be drawn from the results obtained thus far on the genetics of complex disorders.
First, the more strongly inherited forms of complex disorders generally have an earlier age of onset.
For example, breast cancer, AD, heart disease
Often these represent subsets of cases in which there is single-gene inheritance.
Second, when laterality is a component, the bilateral forms are more likely to cluster strongly in families.
For example, breast cancer
Third, although the sex-specific threshold model fits some of the complex disorders (e.g., pyloric stenosis, CL/P, autism, heart disease), it fails to fit others (e.g., type 1 diabetes).
A tendency exists, particularly among the lay public, to assume that the presence of a genetic component means that the course of a disease cannot be altered which is incorrect.
Most of the diseases have both genetic and environmental components.
Lifestyle modification (e.g., diet, exercise, stress reduction) often can reduce risk significantly.
Such modification may be especially important for individuals with a family history of a disease because they are likely to develop the disease earlier in life.
For example, those with a family history of heart disease can often add many years of productive living with relatively minor lifestyle alterations.
By targeting those who can benefit most from intervention, genetics helps to serve the goal of preventive medicine.
It should be stressed that the identification of a specific genetic lesion can lead to more effective prevention and treatment of the disease.
Identification of mutations that cause autosomal dominant breast cancer may enable early screening and prevention of metastasis.
Pinpointing a gene responsible for a neurotransmitter defect in a behavioral disorder such as schizophrenia could lead to the development of more effective drug treatments.
In cases, such as those with familial hypercholesterolemia, targeted drug therapy or gene therapy may prove to be useful in treating the disease.
It is important for health care practitioners to help individuals to understand these facts.
Genetics of common disorders is complex and often confusing, but the community health effect of these diseases, together with the evidence for hereditary factors in their etiology, demands that genetic studies be pursued.
Substantial progress is already being made. The next decade will undoubtedly witness many further advances in the understanding and treatment of these disorders.
How are schizophrenia and bipolar disorder affected by genetic factors?
Key Points
Despite the strong association between
ε4
and AD, approximately half of individuals who develop late-onset AD do not have a copy of the
ε4
allele, and many who are homozygous for
ε4
remain free of AD even at advanced age.
The proportion of schizophrenic probands who have a schizophrenic parent is only approximately 5%, which is substantially lower than the risk for other first-degree relatives (e.g., siblings, affected parents and their offspring).
Twin and family studies show that approximately 60% of the risk for bipolar disorder is attributable to genetic factors, whereas approximately 30% of the risk for unipolar disorder (major depression) is because of genetic factors.
Lifestyle modification (e.g., diet, exercise, stress reduction) often can reduce risk significantly. Such modification may be especially important for individuals with a family history of a disease because they are likely to develop the disease earlier in life. For example, those with a family history of heart disease can often add many years of productive living with relatively minor lifestyle alterations.
Question 1 of 3
Which finding would be associated with early onset of Alzheimer disease?
Exactly!
Homozygous gene mutations
Absent copy of the ε4 allele
Allelic variation in the apolipoprotein E (APOE) locus
Mutations in presenilin (
PSEN1
or
PSEN2
) Chapter 5, Genes, Environment-Lifestyle, and Common Diseases Understanding Genetics of Common Diseases
Homozygous gene mutations
AD is a genetically heterogeneous disorder. Approximately 5% of AD cases are considered early onset before age 65 that are considered autosomal dominant inheritance.
Absent copy of the ε4 allele
There is an association between absent ε4 and late-onset AD instead of early-onset AD.
Allelic variation in the apolipoprotein E (APOE) locus
An important risk factor for the more common late-onset form of AD is allelic variation in the apolipoprotein E (APOE) locus, which has three major alleles: ε2, ε3, and ε4.
Mutations in presenilin (
PSEN1
or
PSEN2
)
Mutations in PSEN1 typically result in early-onset AD, with the first occurrence of symptoms in the fifth decade of life.
Question 2 of 3
Which condition would
most
likely be attributed to heredity of a patient who has family history of mental health conditions?
Exactly!
Any psychiatric disorder
Schizophrenia
Bipolar disorder
Depression
Any psychiatric disorder
Any psychiatric disorder includes some conditions with lower risk for hereditary factors.
Schizophrenia
Estimated heritability of schizophrenia is up to 85% making this the most likely condition attributed to hereditary factors.
Bipolar disorder
Approximately 60% of the risk for bipolar disorder is attributable to genetic factors.
Depression
Genetic factors are related to approximately 30% of the risk for unipolar disorder or major depression.
Question 3 of 3
Which benefit from genetic studies would be important to include in patient teaching?
Select all that apply. One, some, or all responses may be correct.
Exactly!
Identification of illness prevention
Provision of early screening for disease
Realistic expectations for life expectancy
Development of gene therapy treatment
Classification of diseases as genetic or environmental
Unnecessary use of lifestyle treatment plans
Identification of illness prevention
Genetic studies support effective prevention and treatment of the disease.
Provision of early screening for disease
Early screening for disease is supported when genetic risks are identified through genetic studies. Chapter 5, Genes, Environment-Lifestyle, and Common Diseases Understanding Genetics of Common Diseases
Realistic expectations for life expectancy
Early treatment and appropriate lifestyle modifications from genetic studies may result in extended lifetime.
Development of gene therapy treatment
Genetic studies may contribute to gene therapy useful in treating disease with a genetic component.
Classification of diseases as genetic or environmental
Many diseases have both genetic and environmental components. Genetic studies support recognition of multifactorial components of disease.
Unnecessary use of lifestyle treatment plans
Lifestyle modifications are often recognized by genetic studies to reduce the risk of disorders with genetic components. It is incorrect to assume that disease with a genetic component may not benefit from lifestyle modifications.
Key Points
Some common multifactorial disorders, the congenital malformations, are present at birth. Others, including heart disease, cancer, diabetes, and most psychiatric disorders, are seen primarily in adolescents and adults.
Due to the lipids in atherosclerosis that play a key role, focus is on the genetic determination of various lipoproteins. Important advance in this area is the identification of several genes that encode the processing of low-density lipoproteins and that, when mutated, can cause
familial hypercholesterolemia
.
Systemic hypertension has a worldwide prevalence of approximately 25% to 30%. It is a key risk factor for heart disease, stroke, and kidney disease.
Women who inherit a mutation in
BRCA1
or
BRCA2
experience a 50% to 80% lifetime risk of developing breast cancer.
Prostate cancer is second only to lung cancer as a cause of cancer death in men, causing more than 30,000 deaths each year.
The genes that affect type 1 diabetes are alleles, insulin gene, cytotoxic T-lymphocyte,
PTPN22
, systemic lupus erythematosus (SLE), rheumatoid arthritis and autoimmune thyroid disease.
The associations between diabetes susceptibility and each of these genes have been widely replicated in multiple populations. These genes include
TCFL2
, allele, and
KCNJ11
.
Mutations in the human leptin gene and its receptor have been identified in a few humans with severe obesity (BMI >40), but they both appear to be extremely rare.
An allele of the
ALDH2
gene
(ALDH2*2)
results in excessive accumulation of acetaldehyde and thus in facial flushing, nausea, palpitations, and lightheadedness.
Despite the strong association between
ε4
and AD, approximately half of individuals who develop late-onset AD do not have a copy of the
ε4
allele, and many who are homozygous for
ε4
remain free of AD even at advanced age.
The proportion of schizophrenic probands who have a schizophrenic parent is only approximately 5%, which is substantially lower than the risk for other first-degree relatives (e.g., siblings, affected parents and their offspring).
Twin and family studies show that approximately 60% of the risk for bipolar disorder is attributable to genetic factors, whereas approximately 30% of the risk for unipolar disorder (major depression) is because of genetic factors.
Lifestyle modification (e.g., diet, exercise, stress reduction) often can reduce risk significantly. Such modification may be especially important for individuals with a family history of a disease because they are likely to develop the disease earlier in life. For example, those with a family history of heart disease can often add many years of productive living with relatively minor lifestyle alterations.
Chapter 5, Genes, Environment-Lifestyle, and Common Diseases Understanding Genetics of Common Diseases