Feb. 01, 2010

Twin Study Seeks to Unravel Genetic Clues to Lupus Development

Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus.
Authors: Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J, Berdasco M, Fraga MF, O'Hanlon TP, Rider LG, Jacinto FV, Lopez-Longo FJ, Dopazo J, Forn M, Peinado MA, Carreño L, Sawalha AH, Harley JB, Siebert R, Esteller M, Miller FW, and Ballestar E. (2009).
Genome Research, epub ahead of print December 22

What is the topic?
DNA contains the blueprints for all the proteins in the body. DNA is wound up in tight coils and when a cell wants to make a protein, these coils unravel to expose the instructions for making that protein. The degree to which DNA stays tightly coiled or loosens up is influenced by whether or not chemicals called "methyl groups" are attached to specific parts of the DNA.

This arrangement allows each type of cell in the body to make the kinds of proteins needed to do its particular job. However, changes to how DNA coils up or unravels may be influenced by the environment around a cell, including the diet that people eat and the environment in the womb while a baby is developing.

What did the researchers hope to learn?
The researchers hoped to find out if DNA methylation is different between twins when one twin has lupus and the other does not.

Who was studied?
Part of the study looked at five pairs of identical twins where only one had lupus and the results from these twins was compared to 10 healthy people who were matched to the twins by age, gender, and race.

Twelve additional pairs of siblings (not necessarily twins) where only one had lupus were also looked at and seven sets of identical twins who both had lupus were also studied.

How was the study conducted?
Blood samples were taken from each patient and white blood cells were analyzed for DNA methylation. The researchers studied methylation in regions of the DNA that contain blueprints (genes) that are already known to influence the development of lupus.

What did the researchers find?
In the five pairs of identical twins where only one had lupus, there were 49 genes that had different amounts of DNA methylation between the twins with lupus and those without lupus. These 49 genes were the blueprints for proteins that are known to affect the activity of the immune system. Some of them are involved with regulating how cells make little immune system regulators called "cytokines." However, this same set of 49 genes did not have different amounts of DNA methylation when people with lupus were compared to the healthy people. It may be that the differences in DNA methylation are only important against the background of the other genes specifically inherited and shared by these twins.

Seven of these 49 genes had decreased methylation in lupus patients when compared to their healthy siblings. For five of these seven genes, reduced methylation was associated with increased manufacture of the specific proteins that they control, which is thought to contribute to the development of lupus.

What were the limitations of the study?
The number of lupus patients studied here was small and for some of these genes it may not be clear yet what exactly is going on as a result of the changes in methylation, so more studies will be needed to sort through all of these differences. It is also not known how long the patients with lupus have had these changes in gene methylation, or whether this is a cause or result of lupus.

What do the results mean for you?
There are already several treatments known that can affect methylation of genes and cause lupus-like syndromes. By better understanding how that works, it is likely that new treatments could be invented to prevent those methylation changes that could put people at risk for lupus.

It is also possible that, in some cases, something in the environment affected DNA methylation in one identical twin but not the other. If so, it is possible that learning more information about this could help us learn how to avoid some of the triggers that could lead to lupus in genetically susceptible people.