Genes and infectious disease 27/8/02. By Richard Twyman Variations in the human genome are associated with differing susceptibilities to infectious diseases.

The role of genes in inherited disorders is well understood. For some diseases, one particular gene has such a major effect that mutations in it are said to 'cause' the disease. In most cases, however, there is no major single determinant. Instead, variations in many different genes contribute to disease susceptibility.

It is now recognised that the same principles apply to infectious diseases. Some rare mutations in specific genes 'cause' susceptibility to organisms that are normally repelled by healthy people. For example, certain mutations in a gene called IFNGR1 confer susceptibility to rare, opportunistic infections by Salmonella and non-tuberculosis mycobacteria. In other cases, variations have been identified that either increase or decrease our susceptibility to more common diseases.

Unsurprisingly, many of the genes that control our susceptibility to infectious diseases encode proteins that function in the immune system. Most of these genes are found on a stretch of DNA four million base pairs in length, known as the major histocompatibility complex (MHC), located on chromosome 6. The genes here are known as HLA (human leukocyte antigen) genes because most of the proteins they encode are either displayed on the surface of white blood cells or secreted from them.

Background: The major histocompatibility complex

HLA genes show a much greater frequency of single nucleotide polymorphisms than any other region of the genome, and many of these polymorphisms appear to be associated with either increased or decreased susceptibility to a range of diseases. Such diseases include malaria, tuberculosis, leprosy, typhoid fever, hepatitis and AIDS. Other susceptibility genes are located outside the HLA region and some examples are presented below:

Human immunodeficiency virus (HIV) and AIDS

Sequence variation around a gene called CCR5 may be involved in susceptibility to HIV infections and AIDS. The product of this gene is displayed on the surface of T-lymphocytes (the cells attacked by HIV) and probably acts as a receptor or co-receptor for the virus.

A polymorphic variant has been identified in the gene's promoter that protects against HIV infection. In homozygotes (people with two copies of this particular variant allele) HIV infection is restricted, while in heterozygotes (people with one copy of the variant allele and one copy of the normal allele) infection occurs as normal but there is a delay in the onset of AIDS.

The variant is present in about 10-20% of people in Caucasian populations but is a rare mutation in African and Asian populations. Other polymorphisms in the CCR5 promoter, and the gene itself, have also been studied.

Chronic hepatitis

Chronic hepatitis is caused by infections with hepatitis B virus (HBV) or hepatitis C virus (HCV). HCV infections are usually chronic, but only a minority of HBV infections progress this far. The tendency HBV infections to become persistent has long been known to run in families.

Recently, polymorphisms in the promoter of a gene called IL10 have been shown to be associated with the risk of HBV persistence. IL10 is another cell surface molecule that plays an important role in the running of our immune system.

Leprosy and tuberculosis

Leprosy and tuberculosis are both caused by bacteria of the mycobacterial family (Mycobacterium leprae and Mycobacterium tuberculosis respectively). However, susceptibility to each of these diseases shows such a strong tendency to run in families that until the bacteria were identified the diseases were widely believed to be inherited.

Two genes have been found that may be involved in susceptibility to both bacteria. SLC11A1 was the first infectious disease susceptibility gene to be cloned. This gene encodes a protein that transports ions across the cell membrane. VDR encodes the vitamin D receptor. One of the important roles of vitamin D is maintenance of the immune system, and vitamin D deficiency contributes to tuberculosis susceptibility. Polymorphisms in both genes have been linked to variations in susceptibility to leprosy and tuberculosis in different populations.

Other bacterial infections

The MBL2 gene encodes a lectin - a protein that binds to carbohydrate groups. The normal role of this protein is to stick to exposed sugars on the surface of invading bacteria so that cells of the immune system can recognise them.

Several polymorphic variants of this gene are known to result in the production of non-functional lectins, and about 5 per cent of people are homozygous for such alleles. Population studies have shown that homozygous individuals may be more at risk of respiratory infections and other bacterial diseases.