Scientists Discover A Genetic Cause For Severe Complication Of The Autoimmune Disease Lupus

The findings appear in the March issue of the journal Arthritis and Rheumatism, published March 13, 2001.

Like most autoimmune diseases, lupus affects far more women than men - in the case of lupus, 10 times more women. In addition, ethnicity affects disease vulnerability, with about one in 250 African-American women contracting lupus compared to one in 1,000 Caucasian women. The condition can cause arthritis, as well as heart and lung inflammation, and leads to kidney failure in about 10 percent of patients.

There appears to be no single genetic cause for lupus, but recent research has focused on failures in the immune system's normal ability to rid the body of rogue antibodies. When the immune army is not appropriately held in check, it may start attacking the body's own cells and tissues, causing rampant inflammation and other ailments.

The new research examined naturally occurring variants of two genes for receptors in the immune system that bind to antibodies and normally clear them out of the system. The variants, or alleles, were already known to code for receptors that differed in their ability to bind to antibodies. The researchers wanted to determine if there was an association between having the weak-binding allele and suffering from kidney complications, or nephritis.

They found that allele differences in one gene had no effect on kidney disease. But for the other gene, which codes for a receptor known as Fc gamma receptor IIIA, the results were dramatic. Lupus patients possessing the weaker-binding allele had twice the risk of developing nephritis, and more than four times the risk of developing severe nephritis - but only if they were Caucasians. Non-Caucasians were at no greater risk if they possessed this variant of the gene.

"The fact that lupus does not appear to be caused by a single gene prepares us to expect a complex genetic contribution to the disease," says Lindsey A. Criswell, MD, MPH, UCSF associate professor of medicine and senior author on the research paper.

"We suspect that the increased risk among Caucasians results from the combined effect of this allele and others that are all inherited as a unit. Ancestry or ethnic background determine the specific sequence of alleles that we inherit."

"We expect to find many more genetically based differences in disease susceptibility as we probe further with the tools of genetics and epidemiology," she added.

Criswell and lead author Victoria Seligman, MD, UCSF senior rheumatology fellow, stress that while this study found greater susceptibility to nephritis among Caucasians, it is non-Caucasians overall who are more likely to get lupus and more likely to suffer from the more severe complications, such as nephritis.

"We expect to find other genetic variants that explain this greater overall susceptibility," Seligman said. "And we hope that increased genetic understanding will lead to both better treatments and new genetic tests to identify someone's predisposition to disease, and to more severe forms of disease."

The researchers also expect the findings will ultimately help clinicians refine treatment options, for example, focusing the most potent but also most toxic treatment on those at highest risk of developing the most severe forms of the disease.

The scientists were able to identify the ethnic difference in genetic susceptibility to kidney disease because they designed their study with a large, multi-ethnic patient population. The study focused on 587 lupus patients, including 235 whose disease had progressed to include nephritis and a control group of 352 lupus patients who showed no signs of kidney disease.

The research was supported by the NIH, the Arthritis Foundation, and UCSF's Rosalind Russell Medical Research Center for Arthritis.

Co-authors on the research paper, along with Criswell and Seligman include UC Davis scientists Michael F. Seldin, MD, PhD, chair, Rowe Program in Genetics; Hongzhe Li, PhD, assistant professor of medicine; Charlyn Suarez, BS, and Sven Inda, BS, postgraduate researchers in genetics.

Also: Jean L. Olson, MD, UCSF professor of clinical pathology; Raymond Lum, MPH, statistician in the UCSF division of rheumatology; and Doris Lin, BS, UCSF medical student.