LUPUS and the Genome

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LUPUS and the Genome

Nipurna Jina,
Department of Clinical Biochemistry,
University of Leicester

LUPUS is a complex disease now where have we heard that before?

The statement above tends to be used in the opening paragraph by authors who go on to describe exactly how complex lupus is. Whether you examine SLE and the immune system or the genetic influence in SLE, it is complex! Having read around the subject I will attempt to give you an insight into how scientists are unravelling the disease from where it stems - the genes.

Susceptibility to Lupus
Lupus occurs in individuals who are genetically susceptible or prone to developing the disease depending on their genetic makeup. We inherit our genes from both parents and the combination of genes differs in everyone except identical twins.

Since the 1950s, doctors have been aware that SLE and other autoimmune diseases, such as rheumatoid arthritis, run in families and that the disease may be influenced by genes as well as the environment. Findings from studies of twins with lupus support this view; there is a greater chance of both identical twins developing lupus than non-identical twins. The probability that both twins will express lupus (termed the concordance rate) for identical and non-identical twins is 24% and 2% respectively. This shows that an individuals genes influence lupus, however, concordance rates for identical twins is not 100% suggesting that environmental factors are involved e.g. exposure to UV light.

The familial tendency is also supported in studies of siblings who develop SLE. Siblings predisposed to lupus tend to develop lupus at about the same age and within a few years of each other. Another feature of familial lupus is that family members share similar pathologies or symptoms. In fact research has shown that some unaffected first-degree relatives (immediate family members e.g. sister) may also exhibit one or more of the clinical symptoms e.g. high antibody titre.

Genetic associations in Lupus
Studies were conducted to investigate which genes are commonly found in SLE patients that are different to genes found in healthy people. As SLE is an autoimmune disease, investigators began by looking at genes involved in directing the immune response. These genes include the Human Leucocyte Antigen (HLA):

The HLA are a group of genes found on chromosome 6, which regulates the immune system. The HLA contains 3 subsets of genes, class I, II and III. There are several gene variations present on the HLA class II and III that have been linked to different pathologies of lupus. For example HLA-DR2 and DR3 variants increase the risk of developing lupus by 2-3 fold in Caucasians whilst HLA-DR2 and DR7 variants are associated with the development of lupus in African-American people. These findings suggest that ethnicity may ascertain which clinical symptoms an individual develops.
The gene C4A, involved in clearing immune complexes, is found within the HLA region. An unresponsive or null C4A gene has been linked quite strongly to people with lupus. However, this does not mean that this gene is necessary to cause lupus or that anyone with this gene variation will develop lupus.
Other genes may also be associated in the development of lupus, for example a receptor found on some immune cells required to help clear immune complexes can be defective resulting in the presence of immune complexes in the circulation for longer.

Research has shown that a combination of genes with low penetrance i.e. little effect alone, act together to trigger lupus and contribute to disease progression. These first genes recognised to be associated with SLE have since been found to influence clinical symptoms rather than contribute to the predisposition to lupus.

Search for susceptibility genes
The completion of the human genome project (analysis of all 23 chromosomes) and development of newer genetic techniques paved the way for research groups to scan the entire genome for genes that are linked to lupus. Five studies have so far been completed involving families with one or more affected individuals, including families from various ethnic backgrounds.

Collectively these studies have pointed to regions on chromosomes 1, 2, 4, 6 and 16 which may contain genes that contribute to a susceptibility to lupus. This information considered with other evidence highlights certain hotspots of interest, for example the potential susceptibility regions identified on chromosome 1 have been linked to similar regions found on mouse models of lupus which cause lupus in mice. Also those regions identified on chromosome 6 lie close to or encompass some HLA genes. As these regions help control the immune system this may be a feature in all autoimmune diseases.

Researchers discovered that when these findings were further divided, certain regions were more common to specific racial groups. This may help explain why people from different ethnic backgrounds tend to be susceptible to a separate set of pathologies.

It must be stressed that these regions identified so far give an indication into the area of the genome on which scientists can now focus their research. With the information being gathered from all corners of the globe, scientists are getting closer to understanding the complex disease that is SLE. This will inevitably facilitate improved diagnostic treatments and maybe even tailor them to treat various groups depending on varying disease expression.

Summary

SLE is multigenic and a number of genes are associated in the progression of lupus.
No specific gene is either necessary or likely to cause SLE and many genes tend to contribute to susceptibility.
Regions on chromosomes 1, 2, 4, 6 and 16 may be associated with lupus susceptibility and are candidates for further research.
Racial origin is likely to influence specific genetic involvement. Background information.
DNA holds the blueprint for life. Every cell in the body contains DNA, which is necessary for cells and organs to grow and function.
A gene is a stretch of DNA that holds one piece of information and each piece of DNA contains many genes.
DNA containing these genes is organised and packed tightly to form chromosomes so that masses of information can be packaged neatly into a cell.

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