General aspects - genetics and medicine, personalised medicine, rare diseases, Human Genome Project

• Medical genetics studies how inherited variation in the genome causes, modifies and predicts disease, and how that knowledge is used in diagnosis, treatment and prevention.
• The human genome has about 3 billion base pairs. Only about 2 per cent codes for protein; the rest regulates gene expression and maintains genomic stability.
• Personalised medicine chooses prevention, diagnosis and treatment on the basis of each patient's genetic and non-genetic profile.
• A rare disease affects a small proportion of the population. Rare diseases are collectively common: there are more than 6,000 known, and together they affect a large number of people.
• The Human Genome Project, completed in the early 2000s, sequenced the human genome and set the basis for genomic medicine: predicting drug response, improving diagnosis and detecting predisposition early.
• Pharmacogenetics studies variation in a single gene that alters drug response; pharmacogenomics studies variation across many genes or the whole genome.

Exam tip: be ready to define medical genetics, pharmacogenetics versus pharmacogenomics, a mutation versus a polymorphism, and the aims of the Human Genome Project.

Medical genetics is the branch of medicine concerned with inherited disorders. Its scope runs from the basic biology of genes and chromosomes, through the mechanisms by which a change in the DNA produces disease, to the clinical care of patients and families.

Genetic information is held in DNA. A gene is a segment of DNA that carries the information for a protein or a functional RNA molecule. The expression of that information is controlled at several levels, and changes in the sequence or in regulation can alter the phenotype.

Genetic factors contribute to disease in several ways. Some disorders are caused by a single gene (monogenic disorders). Others result from changes in many genes together with environmental factors (multifactorial disorders). Some are caused by abnormal numbers or structures of whole chromosomes.

Why medicine needs genetics

• Many common diseases have a genetic component: heart disease, diabetes, cancer and psychiatric disorders all show familial clustering.
• Knowing the genetic cause allows an accurate diagnosis, a prognosis, an estimate of recurrence risk and, increasingly, a targeted treatment.

• Mutation: a variation in the DNA sequence that is found in less than 1 per cent of the population. Mutations are often associated with rare diseases, for example cystic fibrosis, sickle cell anaemia and Huntington disease.
• Polymorphism: a variation in the DNA that is found in more than 1 per cent of the population. A single polymorphism is unlikely to be a major cause of illness, and most polymorphisms have no apparent clinical effect.
• Pharmacogenetics: the study of how variation in a single gene influences the response to a drug, both its efficacy and its toxicity.
• Pharmacogenomics: the study of how genetic (genomic) variation across multiple genes influences the response to a drug.
• Pharmacokinetics is affected by genetic variation through changes in plasma clearance, transport of the drug or its metabolites to target cells, and metabolism.
• Pharmacodynamics is affected by genetic variation through changes in the relationship between drug concentration and the therapeutic effect.

Personalised medicine means choosing the prevention, diagnosis and treatment that suit the individual. The aim is to match the right drug at the right dose to the right patient.

The response of two patients to the same drug at the same dose can differ widely. Variability in response is explained by several factors, which act together:

• Genetic factors: polymorphisms in drug-metabolising enzymes, transporters and drug targets.
• Age
• Race and ethnicity
• Body weight
• Sex
• Accompanying diseases
• Accompanying drugs, which can cause interactions.
• Social factors, including diet and lifestyle.

Examples of poor response show the scale of the problem. In asthma, beta-agonists give a poor response in 40 to 75 per cent of patients. In depression, SSRIs and tricyclic antidepressants give a poor response in 20 to 40 per cent. In arthritis, NSAIDs and COX-2 inhibitors give a poor response in 30 to 60 per cent. In solid tumours, a standard treatment gives a poor response in about 70 per cent.

The aims of pharmacogenetics in practice

• Improve drug selection by predicting whether a patient will respond positively or negatively to a drug.
• Select the optimal dose for each individual.
• Help the pharmaceutical industry predict the effectiveness of new drugs in different populations.
• Reduce health care costs by avoiding deaths and hospitalisations from atypical drug effects, and by not prescribing drugs that the patient's genotype makes ineffective.

Challenges

• Many studies exist, but the literature is not definitive in some cases.
• Genetics explains only a small percentage of the variation in drug response.
• It is clear that genotype-based therapy is better than the usual common approach, but only a small number of tests are in routine use for determining genetic variants or protein expression.

A rare disease is a condition that affects a small number of people in the population. The thresholds differ by region:

• World Health Organizationa disease affecting fewer than 65 per 100,000 people.
• United Statesa condition affecting fewer than 200,000 people in the country.
• European Uniona life-threatening or chronically debilitating condition affecting not more than 5 in 10,000 people.

Each individual rare disease is uncommon, but rare diseases together form a large group. The group encompasses more than 50 different rare diseases in one category alone, for example the mucopolysaccharidoses, and thousands of rare diseases are described in total. Most are genetic, and many begin in childhood.

Rare diseases pose particular problems:

• Diagnosis is delayed because few clinicians have seen a given condition.
• Patient populations are very small, so developing a drug is commercially difficult.
• Specialised, expensive treatments may be needed for life.

Orphan drugs

An orphan drug is a medicine developed to diagnose, prevent or treat a rare disease. Because the patient population is small, such drugs are commercially unattractive without government incentives. Examples in genetic disease include:

• Ivacaftor and lumacaftor (CFTR modulators) for specific CFTR mutations in cystic fibrosis.
• Nusinersen (Spinraza) and onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy. Zolgensma is a gene therapy.
• Alglucosidase alfa (Myozyme), an enzyme replacement for Pompe disease (glycogen storage disease type II).
• Idursulfase (Elaprase), an enzyme replacement for Hunter syndrome.
• Elosulfase alfa (Vimizim) for Morquio A syndrome.
• Luxturna, a gene therapy for Leber congenital amaurosis.
• Ataluren (Translarna) for Duchenne muscular dystrophy caused by specific mutations in the dystrophin gene.
• Eculizumab (Soliris) for paroxysmal nocturnal haemoglobinuria.

The Human Genome Project aimed to:

1. Determine the sequence of the roughly 3 billion nucleotides that make up human DNA.
2. Characterise the variability of the genome.
3. Identify all the genes in human DNA.

The project opened an era of genomic medicine. Its main promises for healthcare were to predict drug efficacy and toxicity, to improve the diagnosis of disease, and to detect genetic predisposition to disease early.

What the genome contains

• The human genome has about 3 billion base pairs, organised into 22 pairs of autosomes and the sex chromosomes (XX in females, XY in males).
• About 2 per cent of the genome codes for protein. The remaining 98 per cent regulates gene expression and maintains genomic stability.
• Estimates of the number of protein-coding genes have changed over time. Current analyses suggest about 20,000 to 25,000 protein-coding genes, and thousands of non-coding RNA genes.
• The mitochondrial genome is a separate circular DNA molecule of about 16,569 base pairs, which encodes 37 genes and is inherited through the maternal line.
• Individual variation comes mainly from single nucleotide polymorphisms (SNPs), of which there are about 3 million in a person's genome.

Uses of genomic information in healthcare

• Diagnosissequencing identifies the cause of rare and unexplained disorders.
• Predictiongenotype can estimate a person's risk of disease and the likely response to a drug.
• Treatmentgenotype guides the choice and dose of drugs, and targeted and gene therapies are designed around the genetic lesion.
• Researchdatabases such as PharmGKB store primary genetic data, link genetic variants with drug responses, and summarise published findings.

The future direction is a whole-genome approach in place of the older candidate-gene approach, with thousands of single nucleotide polymorphisms studied in thousands of patients, and drug and dose selection based on a combination of genetic and non-genetic information.

Clinical link: a genotype-based test before prescribing, for example a test for a specific enzyme variant before a drug is given, is the practical form of personalised medicine.