Medical Genetics - V. M. Zaporozhan 2005

Multifactorial Diseases
Susceptibility to infectious diseases

Susceptibility to infectious diseases is determined by genetic polymorphisms of cellular receptors and genes involved in The formation of the Immune Response. For instance, the clinical picture of tuberculosis develops in fewer than 10% of infected immunocompetent individuals. Candidate genes whose polymorphism is associated with The Development of tuberculosis include the following:

1. NRAMP1 (natural resistance-associated macrophage protein Gene, 2q35) — a protein product of the gene associated with the phagosomal membrane that activates macrophages. The gene also determines resistance to Salmonella, Leishmania, and various species of mycobacteria.

2. MBL (10q11.2-q21) — mannose-binding serum lectin, participates in bacterial opsonization, initiates phagocytosis, and can activate Complement. High serum levels of MBL promote leprosy infection and the development of visceral leishmaniasis. Low or zero levels of serum MBL are associated with increased susceptibility to pneumococcal infection and a higher frequency of acute respiratory infections.

3. P-A (10q22.2-q23.1) and SP-B (2p 12-p 11.2) — surfactant Proteins.

4. VDR (12q12-q14) — vitamin D receptor, whose active metabolite can stimulate Cell-mediated Immunity.

5. Interleukins 1a and 1ß (2q 14). Disease development upon infection with non-pathogenic mycobacteria and BCG is associated with Mutations in the INF-y gene.

Another example is genetically determined resistance to HIV infection. The chemokine coreceptor CCR-5 On the surface of macrophages and T lymphocytes (3p21) plays a critical role in viral entry into lymphocytes. When a 32 bp region of the gene is deleted, a defective, non-functional protein is synthesized. Homozygotes for this mutation account for about 1% of Europeans and are characterized by resistance to HIV infection. In heterozygous carriers of the mutation, the disease occurs upon massive infection, but progresses more slowly (the number of receptors on The Cell surface is twice as low as in normal homozygotes).