Mapping Why Lupus Discriminates

The protein structure of human interferon-alpha

The protein structure of human interferon-alpha

As discussed yesterday, lupus is not an equal-opportunity disease. Ninety percent of lupus cases occur in women, the disease is three times more likely to affect African-American women than Caucasian women, and lupus is more common and severe in other minority populations as well. Given that the general cause of lupus remains unknown, the reason for these discrepancies is also mysterious. But a grant from the Lupus Research Institute recently awarded to Timothy Niewold, assistant professor of rheumatology at the University of Chicago Medical Center, hopes to turn the focus of science to this issue, looking for genetic factors that may explain why minority women are more seriously afflicted by lupus.

One of the few things that is clear about lupus is that it must have a strong genetic component. The disease is strongly inherited – if someone has a close relative with lupus, their own chances of having the disease are increased twenty-fold. Genetic linkage studies have found a number of promising genes and clusters of genes that are associated with an increased risk of contracting lupus. But while such results are promising, they also contain a couple of problems. 1) The genes don’t account for everything, suggesting an environmental role in triggering the disease. 2) The multiple linkages indicate that lupus cannot be traced back to just one gene, backing theories that the complexity of the disease is due to multiple genetic factors. 3) The linkage studies were conducted in patient populations that were predominantly Caucasian, obfuscating any genetic differences that could account for the increased incidence of lupus in minorities.

“We are excited that we are mapping a bunch of different genes, but it is kind of like we’re sketching some of the first maps of the continent,” Niewold said. “We’re getting something here, something there, and not everything is connected. It’s kind of a vague diagram.”

If all those caveats and complexities are giving you a headache, you’re not alone. But Niewold’s approach is to focus on particular portions of the map that look like they may be relevant to at least a large portion of lupus patients, while expanding genetic studies to start filling in some of the blank parts on the map.

One part of that effort is to focus on a likely suspect in lupus – cytokines. Small signaling molecules that play a role in the immune system, cytokines are normally responsible for helping marshal immune defenses to fight off infections. But one particular cytokine, called interferon-alpha, or IFN-α, may go awry in lupus patients, with elevated levels of the cytokine producing the disease’s characteristic overactive immune response. The theory is backed by both genetic linkage data (where several genes associated with the IFN-α pathway pop up) and acute measurements revealing high levels of IFN-α in lupus patients.

“One of the most common and consistent pathways dysregulated in lupus is type I interferon,” Niewold said. “It doesn’t give us a complete answer, but the data suggests that it’s an important pathway in lupus.”

Why not a complete answer? IFN-α is not elevated in all lupus patients, suggesting that it may only explain the cause of the disease in a sub-population of those patients. And as mentioned before, lupus is unlikely to result from just one faulty gene, and elevation of IFN-α alone may not be sufficient to trigger the disease. But combine high IFN-α levels with another genetic risk factor for lupus or a particular antibody that attacks normal tissue, and it could be a “one-two punch,” Niewold said.

IFN-α also figures into the other branch of Niewold’s research, and the one for which he received the $300,000 award from the Lupus Research Institute last year – levels of the cytokine are elevated in the African-American population. But beyond that, information about what genetic factors could raise the susceptibility of minority populations to lupus is scarce, due to most large-scale genetic studies using predominantly subjects of European ancestry. The limitations of that approach were emphasized by a recent experiment performed by Niewold: when African-American lupus patients with high IFN-α were compared to those with low IFN-α, a genetic study turned up five novel genetic variants that could be involved in IFN-α-related lupus.

The LRI grant will allow Niewold to replicate and expand upon those results, running more genetic comparisons and testing out how those promising genetic variants affect the interferon pathway. Such studies could help delineate the different paths to lupus that may have arisen over the course of human evolution, as populations isolated to different areas of the world developed different means of fighting off disease and infection.

“I think nature is very clever,” Niewold said. “It’s very likely that in populations that are separated for a long time on different continents, you would probably find gene variants that modulate the same pathway with a similar end result.”

But that’s not to say that future treatments for lupus will differ across racial lines. Patients with abnormally high IFN-α may be treated the same way, black or white – and clinical trials are already underway to see whether IFN-α is a valid target for lupus therapy. But with a disease as complex as lupus, there won’t be one magic cure, so understanding the different flavors of the disease and how they cause such dramatic gender and racial discrepancies will remain an important pursuit.

“We’re hoping that we may map some of these multiple roads to lupus and then that hopefully will translate into thinking about the disease or therapies in a different way,” Niewold said.

Niewold, T., Hua, J., Lehman, T., Harley, J., & Crow, M. (2007). High serum IFN-α activity is a heritable risk factor for systemic lupus erythematosus Genes and Immunity, 8 (6), 492-502 DOI: 10.1038/sj.gene.6364408

About Rob Mitchum (525 Articles)
Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.
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