It is common knowledge that lupus runs in families. In fact, primary relatives (siblings, parents, children) of a person with the condition have a three- to five-fold increased risk of developing the disease compared with the average person on the street. But until just the last decade, we haven’t known how increased risk of lupus could be inherited.
Figuring out how lupus runs in families has been complicated. Lupus is not like some genetic diseases carrying a high profile in the popular press. The phrase “genetic disease” might bring to mind hemophilia among the royal families of Europe, or the “boy in the bubble” with immune deficiency, or cystic fibrosis. In each of these cases, mutation of one or a few genes is the illness driver.
In contrast, for most cases in which lupus runs in families, alteration in more than one gene is likely behind the increased disease risk. Lupus is thus said to be “polygenic.” In fact, if risk of being diagnosed with lupus could be represented by a jigsaw puzzle, it’s likely that dozens of individual genes serve as pieces in that puzzle. As with a puzzle, each lupus gene plays a minor, but required role, in generating the final lupus disease picture.
Despite the subtlety and complexity of lupus genetics, progress has been tremendous in the past decade. Lupus “gene hunter” researchers (Tim Behrens, Patrick Gaffney, Kathy Moser) at the University of Minnesota helped to form an international consortium called “Genetics in Systemic Lupus Erythematosus” or SLEGEN in 2004. SLEGEN members searched for new genes using pooled samples from collections of lupus patient DNA samples from all over the globe. This effort brought into the light of day, for the first time, the identity of real live “lupus genes.” The scale of the research is truly amazing.
One of the key SLEGEN scientific papers in 2008 utilized samples from 720 women with lupus and 2,337 controls (women not suffering from lupus). These numbers are impressive, in part, because SLE is an uncommon condition (~ 1 in 1,000 women are affected), and it is therefore hard for any one center or researcher to collect enough samples to make real headway. To be absolutely certain about the genes they found with those huge sample collections, the SLEGEN investigators studied DNA from an additional 1,846 SLE patients and a similar number of controls. This research thus identified, beyond the shadow of a doubt, 13 genes that increase risk of lupus.
The bottom line after a decade of high-powered genetic research: the gene hunt has been a smashing success. Many more lupus genes (a total of 47 as of October 2012) have been reported since 2008.
The next great goal in lupus research must be to connect lupus genes to the causes of inflammatory tissue injury in the disease. Intriguingly, more than half of the lupus genes have been implicated in the controls of the powerful natural chemical type 1 Interferon. In the next post, I will describe the relationship between lupus genes and the lupus “interferon signature,” discussed in a previous blog post.