Genetics of common diseases

INTRODUCTION

 The study of medical genetics mainly involves the study of chromosomal and single gene disorders that are rare, when compared to other more common diseases occurring in population, which also have a genetic component. For example, diabetes mellitus, cancer, and cardiovascular diseases not only have a have high degree of morbidity and mortality, but the number of individuals suffering from them far out number those affected by classical genetic diseases. There are chances that a percentage of these diseases will increase due to an increased life span of humans. These diseases are characterized by not having a known pattern of inheritance. Multiple genetic factors interact with each other and get enhanced or triggered by environmental factors.

GENETIC SUSCEPTIBILITY

These common diseases, which occur due to interaction of gene and environment are said to have polygenic inheritance. In familial hypercholesteremia, the FH gene is mutated and the development of coronary artery disease is triggered off by conditions like obesity, smoking and lack of physical exercise. Similarly, smoking or exposure to dust, very often an occupational hazard, is responsible for pulmonary emphysema. Patients with α-1 antitrypsin deficiency manifest with a severe form of emphysema, which gets worse on smoking. Such

examples suggest that a single gene mutation couples with the environment contributes to these disorders. The mechanism of genetic susceptibility may not be always clear, as genetic polymorphism leads to variation in the susceptibility of a disease. An example of this is the correlation between alcoholism and acetaldehyde dehydrogenase enzyme activity. In order to demonstrate that a particular disease has a genetic susceptibility different approaches are can be used. Some of these are: Family studies, twin studies, study of adopted children, and population studies.

Aproaches for study

Family Studies

If a disease shows a higher frequency in a particular family as compared to the general population, it can be assumed as being of familial origin. Familial aggregation may not necessarily prove genetic susceptibility, especially if the environmental circumstances are similar. A control study could examine the respective spouses. If they too have a similar problem the condition has more of an environmental factor than genetic, as both the partners will have different genetic make-ups.

Study of Twins

Identical twins showing similar traits could be explained by heredity, but the fact that identical twins may share the same environment needs to be considered. Members of a pair of twins are called concordant when either both are affected or not affected. They are termed discordant when only one member is affected. If a disease is purely environmental, identical and non-identical twins will have the same concordance. Non­identical twins sharing a similar environment but not sharing the same genes will not be similarly affected unless it is a single gene disorder or a chromosomal translocation. The ideal way to study this is the study of identical twins brought up in different environments. In such cases, if a similar disease exists in them one can assume a genetic component in the disorder.

Adoption Studies

Studying adopted children can be a different approach in studying genetic and environmental factors. Adopted individuals will have their genes from their biological parents, thus predisposition to some disease - if a disease is more similar to that in adopted parents the environmental factors are more likely the cause of disease.

Population Studies

A majority of genetic diseases in a population occur irrespective of race and social status of an individual. However, differences in the incidence of some diseases in some specific populations are known. For example, there is a high incidence of thalassaemia in the Mediterranean region. Specific mutations occur in a particular community, for example in India, Kachhi lohanas, Punjabis, Bhatias have a high incidence thalassaemia.

There are situations where an incidence of a particular genetic disease with low occurrence increases in an immigrant population, suggesting the influence of environmental factors. If a low incidence of disease is maintained in the immigrant population, genetic factors would play a role.

The genetic components of some commonly seen diseases

Diabetes Mellitus

Diabetes mellitus is a syndrome characterized by elevated levels of glucose in the serum. The criteria for the diagnosis of diabetes according to the American Diabetes Association are:

1- A fasting plasma glucose level of greater than 126 mg/dl or,

2- A random plasma glucose level of greater than 200 mg/dl or,

3- A plasma glucose level greater than 200 mg/dl at 2 hours after the ingestion of oral glucose (75 g).

Diabetes is a heterogeneous clinical syndrome with multiple etiologies.

Type I Diabetes

The frequency in the Caucasian population is estimated to be 1 in 400. The mode of inheritance is polygenic. Type I diabetes (also known as insulin dependent diabetes mellitus, or IDDM) is caused by destruction of pancreatic beta cells, most often by autoimmune mechanisms. IDDM is associated with specific HLA antigens, where over 95% of the individuals with IDDM have HLA DR3 or DR4 or both antigens, and these persons develop pancreatic islet cell antibodies. Infections like occurrence of mumps, cytomegalovirus or Coxsackie B in autumn or winter with autoimmune disorders are common in IDDM persons, suggesting a possible viral etiology. The immune mediated form of type-I diabetes (IMD) is present when autoantibodies to islet cells and or insulin are detected in the presence of diabetes. The pathogenesis involves multiple genetic lesions affecting immunoregulation against self, coupled with strong influences from the environment affecting penetrance. There is increased propensity to develop multiple organ-specific autoimmune diseases such as Addison disease, Hashimoto’s thyroiditis pernicious anemia, vitiligo and celiac disease. The long natural history and relatively low concordance of IMD in twin pairs affected by the disease provides an opportunity for disease prevention. The mutant gene product is the HLADQP1 on 6p21.3, the most common being a substitution at codon 57. The mutant gene product is presumed to predispose to autoimmunity directed against pancreatic P cells.

Type II Diabetes

Type II diabetes which is the most common form of diabetes accounting for greater than 90% of patients is caused by two defects: a resistance to the action of insulin combined with a deficiency in insulin secretion. Although the primary causes of insulin resistance have not yet been elucidated in most patients with type 2 diabetes, mutations in the insulin receptor gene have been demonstrated to cause several rare syndromes associated with insulin resistance. Some factors are known to contribute to the pathogenesis of insulin resistance. Most patients with type 2 diabetes are obese, and the increase in adiposity is believed to be an important causal factor in the development of insulin resistance. Obesity is the major factor that unmasks                           diabetes. First-degree relatives of a patient with NIDDM are at risk for diabetes and prevention is to be attempted by keeping optimal body weight. The role of genetic factors in NIDDM is suggested, and preservation of beta islet function, resistance to insulin, lipid abnormalities, obesity and maternal transmission support this.

MODY (Maturity Onset Diabetes of the Young)

The incidence of MODY is 1 in 400. It is inherited in an autosomal dominant fashion. In 60% of cases have mutations in the glucokinase gene on chromosome 7p13. Other families have been mapped to a locus on chromosome 20. Mutations in the glucokinase gene predispose to impaired glucose sensors in pancreatic P cells leading to decreased insulin secretion.

Gestational Diabetes

Diabetes is also seen in pregnant women. It is called gestational diabetes and occurs in 1-3% of all pregnant women. Their abnormal glucose tolerance returns to normal after pregnancy; however half of them develop diabetes in later life. Gestational diabetes was once thought to be type 2 or NIDDM, but it is genetically heterogeneous, as it shows association with HLA antigens DR3 and DR4, pancreatic islet cell antibodies and autoimmune diseases.

Diabetes can also be due to other genetic syndromes and non-genetic diseases. In myotonic dystrophy, diabetes is inherited in an autosomal dominant manner. Various studies on animal models and twin studies have shown enough evidence to suggest that in identical twins 96% of them are concordant while only 3 to 37% of non-identical are concordant. Family studies show about 25 to 50% diabetics have family history of diabetes as compared to 15% in general population. Various family studies have shown that incidence of diabetes in other family members of diabetics is higher up to 30% while in non-diabetics up to 6%.

Genetic Basis for Predisposition to Diabetes and its Complications

Common complications of diabetes are renal, retinal, coronary artery disease and peripheral vascular disease. It was once believed that, complications of diabetes are related to the control and duration of diabetes. However, it is now believed that this too has a genetic predisposition. Individuals with IDDM homozygous for the I (insertion) allele in angiotensin I converting enzyme (ACE) are at a lower risk of developing renal complications, while presence of the D (deletion) allele in persons with NIDDM have a high risk for coronary disease.

Hypertension

Introduction

Determinants of blood pressure variation include genetics and environmental factors as well as factors such as age, gender and ethnicity. Monozygotic twins who share 100% of their genes show significantly greater concordance in blood pressure than do dizygotic twins who only share 50% of their genes.

The incidence of hypertension in the general population is as high as 10 to 25%. By convention, any young adult with a persistently high blood pressure of 140/190 is to be considered hypertensive. Systolic blood pressure tends to increase with age but is medically significant. The main complications of hypertension are stroke, coronary artery disease and renal disease. They can be prevented by therapy.

Hypertensive patients fall into two groups the first one where onset is usually in early adult life and is secondary to renal disease or endocrine and the second one beginning at a later age with no apparent cause. This group is called essential hypertension.

Environmental factors responsible for developing hypertension are a high salt intake, reduced physical exercise, obesity and alcohol consumption. The role of environment has been studied in surveys of migrant populations. Moving from a low prevalence group to a high prevalence group shows that a migrant population suffers from hypertension with an increase in incidence in 1-2 generations, thus supporting the idea that environmental factors play a role in the aetiology of hypertension.

Genetic factors are important and biochemical studies indicate there is a possibility of an autosomal dominant gene responsible for hypertension. In some hypertensives, an extrusion of sodium from the red cells because of abnormal enzymatic controlled sodium potassium co-transport in the cell membrane has been detected. This leads to an increase in intra cellular sodium. Twin and family studies support that genes are also important for deciding the choice of hypertensive therapy for example, African races respond better to beta- blockers than Caucasians.

Regulation of blood pressure is a highly complex process and depends on many physiological factors. These include kidney and heart function, cellular ion transport. Components which influence blood pressure variation are angiotensin, angiotensinogen, urinary kallikerin, sodium and lithium counter transport. These factors appear to be under control of few genes. Studies have implicated gene for angiotensinogen in developing hypertension and preeclmpsia.

Genetic studies confirm that mutations underlying all mendelian forms of high and low blood pressure converge on a final common pathway: Mutations that cause an increase in salt reabsorption result in hypertension, whereas mutations that cause salt wasting produce hypotension.

Mendelian forms of hypertension include glucocorticoid remediable aldosteronism, Liddle syndrome, and hypertensive forms of congenital adrenal hyperplasia due to deficiencies in the steroid synthesis pathways.

Efforts to identify genetic variants that underlie blood pressure variation in the general population have revealed an interval on human chromosome 17, which is a blood pressure locus in rat, and shows evidence for linkage in both Mendelian and essential hypertension in humans.

Coronary artery disease

The main cause of coronary artery disease is atherosclerosis, in which lipid is deposited in the intima of the arteries resulting in narrowing of the coronary arteries. The constituents of the blood attack the endothelial surface of the arteries that are lined with lipid deposits, where after entering they proliferate and differentiate into macrophages. These macrophages engulf the lipids and produce fatty acid streaks. They are responsible for proliferation of smooth muscles and for atherosclerotic plaques. The plaques rupture and lead to the occurrence of thrombotic events resulting in myocardial ischemia and infarction. Coronary artery disease can occur secondary to other diseases like diabetes mellitus and hypertension. The sex ratio tends to be predominantly male, while females after menopauses have an increased risk due to hormonal charges. Familial and twin studies have confirmed the genetic background and the risk is about 7 times more for a person with family history.

Although coronary heart disease is of multifactorial etiology, about 5% of subjects with premature myocardial infarctions are heterozygotes for familial hypercholesterolemia, a single gene disorder that produces atherosclerosis in the absence of an extraordinary environmental factor. However even in this disorder, other loci such as genes for apolipoprotein B, apolipoprotein (a) lipoprotein lipase, and apolipoprotein E could influence the phenotype, and non-genetic factors such as diet and smoking can modify the risk. Therefore it is clear that numerous interrelated biochemical, genetic and non-genetic factors modify the risk for coronary artery disease.

Epilepsy

Epilepsies are a heterogeneous set of neurologic disorders defined by repeated clinical seizure episodes due to aberrant electrical synchronization of the brain. Epilepsy affects approximately 1% of the population. Heredity represents the single largest aetiology of the epilepsies. Genetic transmission patterns of epilepsy are both Mendelian and complex. Over 180 known

Mendelian variants share epilepsy as one expression of the inherited gene error. Most cases are sporadic. Currently recognized monogenic syndromes represent a small subset of all epilepsies. Twelve forms of epilepsy have been demonstrated to possess some genetic basis. Epileptic seizures are categorized by the extent of their cerebral involvement (partial or generalized), by the sparing or impairment of consciousness (simple or complex) and by the pattern of associated motor activity (tonic, clonic, atonic, arrest). Clinical epilepsy syndromes are defined by the seizure type, natural history, precipitating factors, drug sensitivity, and presence of associated neurological deficits. In benign epilepsy syndromes, seizures resolve over time. Benign or familial convulsions are inherited as an autosomal dominant trait. They begin during first neonatal week of life and resolve by 6 months of age. Grand mal epilepsy has a 1 in 25 recurrence risk to first-degree relatives, rising to 1 in 10 if two relatives are affected. Petit mal epilepsy has 7% recurrence in siblings. Numerous gene loci have been identified for common seizure patterns and syndromes. The genes involved include a broad range of molecules regulating brain assembly, activity and cell death.

ALZHEIMER DISEASE

Alzheimer disease (AD) is an adult onset neurodegenerative dementia characterized by the intracellular and extracellular accumulation of proteins, which assemble into P-pleated sheet fibrils. Alzheimer disease is a common cause of dementia in persons of less than 55 years (early onset) or more than 55 years (late onset). The disease presents with a constellation of symptoms that reflect dysfunction and degeneration of neural cells in the cerebral cortex and other selected brain regions. The dementia in AD is irreversible and progressive. The characteristics are impaired memory, intelligence, social skills and loss of control over emotions. Risk to the first-degree relatives, of an affected individual is approximately 10%, and variation is likely because of age dependence and heterogeneity.

Missense mutations in the P amyloid precursor protein (PAPP) gene on chromosome 21, in the presenillin 1 gene (PS1) on chromosome 14, and the presenillin 2 (PS2) gene on chromosome 1 are associated with early-onset forms of familial Alzheimer disease.

The late onset form may be linked to chromosome 19, which has a gene for apolipoprotein E (APOE). The e4 (Cys112Arg) variant of apolipoprotein E (APOE) is associated in a dose-dependant fashion with increased risk for late-onset Alzheimer disease (after age 55). The inheritance of one or more APOE e4 alleles is not deterministic for AD, and the mechanism by which inheritance of one or more e4 alleles causes AD is unclear.

Obesity

Obesity is the presence of an excess amount of adipose tissue. The excessive adipose tissue causes increased blood pressure, hepatic lipid synthesis, insulin resistance and susceptibility to certain cancers. Studies of concordance rates for adiposity among mono and dizygotic twins and among adoptive children and their family members, and segregation and linkage analysis point to a contribution of genes to the determination of body composition in humans. Human obesity is complex and multigenic, with the penetrance of responsible genes showing strong dependence on environmental circumstance. More recently rare mutations of human orthologs of some of the rodent single gene obesity mutations have been identified (LEP, LEPR), as well as in other genes that play a role in the control of body fat. The hormone leptin produced by adipocytes was initially discovered in mice. Leptin is a 146 amino acid peptide and has structural homology to the cytokine family. Deficiency of leptin action, due either to an absence of the peptide (as in the ob mutation), or inability to detect the signal (as in the db mutation of the receptor), results in extreme obesity and infertility.

Asthma

Asthma is a chronic inflammatory disorder of the airways characterized by coughing, shortness of breath and chest tightness, caused by narrowing of the airways due to edema and an influx of inflammatory cells. A variety of triggers may initiate or worsen an asthma attack, including viral respiratory infections, exercise and exposure to irritants such as tobacco smoke. There are a number of genes that contribute toward a person’s susceptibility to asthma, and genes on chromosomes

6, 11, 14, and 12 have been implicated. The region on chromosome 5 is rich in genes coding for key molecules in the inflammatory response seen in asthma, including cytokines, growth factors, and growth factor receptors.

References

Purandarey, H. (2009). Essentials of Human Genetics. Second Edition. Jaypee Brothers Medical Publishers (P) Ltd.