Information on classical genetic diseases


It is becoming increasingly difficult to propose any disease that is wholly non-genetic. In addition to the 2–3% of pregnancies that result in the birth of a child with a condition that can be attributed to defective or absent genes, the frequency of adult diseases with a strong genetic component may be as high as 50%, and even infectious diseases such as HIV and toxin insults as in WernickeKorsakoff syndrome, are now known to be modified by host susceptibility factors.

To conclude the chapter, we would like to highlight genetic influences on two common disorders, asthma and diabetes. In these, as in other polygenic diseases, a number of genes provide the individual with an overall susceptibility to disease which may be unmasked by additional mutations in other genes, or environmental triggers. In each, genetic studies have identified a number of genes or chromosomal regions at which variants appear to provoke the disease in some (but not all) individuals. There are, however, many ways to recapitulate the disease phenotypes, and for both diseases studies have indicated key environmental precipitants which may be responsible for the increasing prevalence of these diseases in affluent societies.


The reversible bronchoconstriction which defines asthma is provoked by numerous inflammatory events, often occurring on a background of atopy . A number of candidate genes and regions identified as predisposing to an asthmatic phenotype have been identified.


The normal products of many genes are required to coordinate the exquisite regulation of insulin secretion within a few minutes of a hyperglycaemic stimulus. In insulin-dependent (type 1) diabetes mellitus, insulin secretion is impaired due to destruction of the islet beta cells; the major contributing gene is in the HLA complex, with sequence variations in HLA-DQB influencing both susceptibility and resistance to type 1 diabetes. Noninsulin-dependent (type 2) diabetes mellitus is a much more heterogeneous disease, resulting from numerous mechanisms of peripheral insulin resistance and beta cell dysfunction. Specific genetic defects are responsible for certain well-defined type 2 diabetes subtypes in which diabetes presents earlier in life than is usual for type 2 diabetes, e.g. maturity-onset diabetes in the young (MODY) and mitochondrial diabetes.

Genes currently implicated in asthma
Pathological process Candidate region Candidate gene(s) Normal function of gene product(s)
Atopic responses
IgE generation
  • 6p21
  • 12q14
  • 14q11
  • 16p12-p11
  • HLA complex
  • Interferonγ
  • TCR α/δ
  • IL-4 receptor
  • Antigen presentation
  • Inhibition of TH2 cells and IgE switching
  • T-cell activation
  • Regulates IgE production
Mast cell response
  • 11q13
  • 12q24
  • FCεRI-β
  • Mast cell growth factor
  • High-affinity IgE receptor
  • Mast cell growth
Eosinophil recruitment 5q31 IL-3, 4, 5, 9, 13 GM-CSF Cytokines up-regulating IgE responses
Inflammatory 6p21.3 TNFα Inflammatory cytokine
mediator release 12q Nitric oxide synthase 1 Inflammatory mediator
Bronchial hyper-responsiveness and bronchoconstriction
  • 5q31
  • 5q35
  • 5q32-q34
  • Corticosteroid receptor
  • Leucotriene C4 synthase
  • β2-adrenoceptor
  • Mediates inflammation
  • Inflammatory mediator
  • Bronchodilatation
  • ?
  • ?
  • Wheeze 1
  • Wheeze 2
  • Two asthma loci identified in Tristan da Cunha population, p < 0.0001: details not available (> 10 loci also identified for atopy)
Individual polymorphisms are not shown as it is not clear which, if any, are causative rather than merely in linkage disequilibrium with the disease-causing mutation.
Some of the genes currently implicated in diabetes mellitus (DM)
Mechanism of disease Chromosomal region Gene Proportion of cases of subset (it known)
Insulin-dependent DM (IDDM, type 1)
Reduced insulin production by islet cells, e.g. T cell-mediated destruction, detective synthesis
  • 6p21
  • 11p15
  • Numerous other regions including IDDM 4-10
  • IDDM 1(HLA)
  • IDDM 2(insulin gene)
  • -35%
  • Contribution probably differs between different populations leading to current discrepancies between genetic studies
Non-insulin-dependent DM (NIDDM, type 2)
A. Well-characterised genetic defects
  • 20q12
  • 7p15
  • 12q24
  • Mitochondrial
  • DNA
  • MODY1 (hepatocyte nuclear factor)
  • MODY2 (glucokinase)
  • MODY3 (hepatocyte nuclear factor ta)
  • tRNA-Leu
  • 40% of MODY,
  • 1% of type 2 diabetes
B. Other genes implicated
  • 1. Insulin secretion genes influencing
  • glucose sensing
  • glucose transport
  • intracellular signalling
  • insulin exocytosis
  • 11p15
  • 3q26
  • 5q15
  • 8p12
  • 19q13
  • 21q22
  • Insulin gene
  • Glut2 transporter
  • Proprotein convertase
  • β3 adrenoceptor
  • Glycogen synthase
  • ATP-dependent k+ channel
2. Insulin resistance genes
  • 2q36
  • 19p13
  • 17q25
  • 6q22-q23
  • 16q22
  • 17p13
  • Insulin receptor substrate-1
  • Insulin receptor
  • Glucagon receptor
  • PC-1 (phosphodiesterase-1)
  • Ras-related protein
  • Glut4 transporter
  • 15%, especially in Mexican Americas
  • 1%
  • 1-5%
3. HLA and cytokine genes 6p21
  • HLA-DR4
  • TNF-α (tumour necrosis factor-α)
4. Obesity genes 4q Intestinal fatty acid binding proteins
Evolutionarily, NIDDM genes would have been beneficial to store energy during periods of starvation, but no longer advantageous, are now deleterious in the sedentary, well-fed lifestyle of the Western world. In addition, numerous further genes influence susceptibility to complications such as retinopathy and nephropathy, and other well-characterised genetic diseases have a significant incidence of diabetes (e.g. cystic fibrosis).