Genetics and stem cells

Genetic link to lupus

Scientists have identified six or more “rogue genes” behind the disease lupus, reports the Daily Mail . Lupus affects nearly 50,000 women in Britain and it is a complex disease which “occurs when the immune system turns on the body”, the newspaper said.

The newspaper story is based on four studies published in scientific and medical journals that have looked at the association between variations in people’s genetic makeup and the likelihood they have lupus. These studies have found at least six different genetic variations associated with the disease, and this illustrates the complexity of the genetics of lupus. It is unlikely that these findings will be used to develop diagnostic tests for the general population in the near future. Further studies will be needed to confirm whether or not all these genetic variations are associated with the inheritance of lupus.

Where did the story come from?

This appraisal focuses on the study conducted by Prof Timothy Vyse, Dr Deborah Cunninghame Graham and colleagues at Imperial College London and other universities and academic institutions in the UK, America and Canada. The study was funded by the Wellcome Trust through a fellowship awarded to Prof Vyse. It was published in the peer-reviewed scientific journal: Nature Genetics .

What kind of scientific study was this?

This was a genetic case-control study, that included families with a member who has lupus and a sample of unrelated individuals with and without lupus. The study aimed to identify genetic variations associated with the disease.

The researchers were interested in a particular part of the DNA on chromosome 1 linked with lupus in previous studies. This region contained two genes, TNFSF4 and TNFRSF4 , which researchers think could both play a role in lupus as they affect the immune system. The researchers looked at whether they could identify any variations in the DNA of these genes (or the genes close to them on the DNA molecule)  that were more common or less common in people who had lupus.

First, the researchers looked at how 39 of these genetic variations (variants) were inherited in 472 UK families, all of whom had a family member with lupus. To confirm the findings in these families they repeated their experiments in 263 American families (using the DNA of the person affected by lupus and their parents) from Minnesota. Once they had identified the variants they were interested in, the researchers took 424 unrelated people from UK with lupus (cases) and 642 unrelated British people without lupus (controls) and looked for the same variants they had identified in the families. In addition, they pooled all their findings from the people with lupus in the UK family study with the unrelated UK cases.

Once they had identified the variants associated with lupus, they looked at their effect in human immune system cells grown in the laboratory (lymphoblastoid cells and peripheral blood lymphocytes).

What were the results of the study?

The researchers found an association between lupus and variants in and surrounding the TNFSF4 gene in the UK and US families, but no association between the TNFRSF4 gene and lupus. When they pooled the family data with data from unrelated UK cases and controls, the strongest association was seen with two groups of variants near the TNFSF4 gene. No one variant in these groups was responsible for the association.

The researchers thought that these variants might affect how active the gene was, so they identified human immune cells that had these variants and looked at TNFSF4 _ gene activity in the laboratory. They found that the _TNFSF4 gene was more active and produced more protein in cells if the variants identified as being common in people with lupus were more frequent, than in cells of the type that are more common in people without lupus. They found the same results in cells from eight individuals.

What interpretations did the researchers draw from these results?

The researchers concluded that a region of DNA close to the TNFSF4 gene contains variants associated with an increased risk of lupus. The variants affect how active the gene is in immune system cells and how much protein it produces. The researchers suggest that this may have an affect on how these cells interact in the body.

What does the NHS Knowledge Service make of this study?

This was a well-conducted study in which the researchers checked their results in different groups of individuals, and went on to show that the groups of variants that they identified could have an affect on how the gene was expressed. Finding an association between a genetic variant and a disease is the first step in a long process of investigation, and often later studies cannot repeat the initial findings. The fact that this research has gone on to show that the variants identified can actually have an effect on the function of the TNFSF4 gene in the laboratory increases the likelihood that these variants do play a role in the risk of developing lupus.

This paper is one of four papers on the genetic basis of lupus published this week. These papers have found associations between variants in at least six regions of the whole genome and the risk of developing lupus. These findings illustrate how complicated the genetic component of this disease is. It is also important to note that in this type of disease, there is a complex inheritance pattern with many genetic and environmental factors playing a part, and not all people who have the variants will develop lupus.

Because of this complicated situation, it seems unlikely that these findings will be used to develop diagnostic tests for the wider population in the near future. There will also need to be further studies to confirm whether the variants identified in these studies are associated with the inheritance of lupus. These studies do offer hope of further understanding the biological basis of lupus and this is a vital step towards developing new treatments.

NHS Attribution