Untangling TNF Trouble

Lurking within the human genome lies a single genetic letter that might reveal why an autoimmune disease therapy can worsen multiple sclerosis (MS). New research reveals that this small variation, associated with a tiny increase in MS risk, impedes the activity of tumor necrosis factor-α (TNFα), a crucial immune system regulator. The finding could explain how drugs that interfere with this protein exacerbate MS, say the study’s authors. 

Inhibitors of TNFα often feature in treatments for autoimmune disorders such as rheumatoid arthritis. But when researchers tried anti-TNFα therapy in people with MS, the drugs intensified disease activity in some individuals. Now a team led by Lars Fugger, a neuroimmunologist at Oxford University in the U.K., reports that an MS-linked variation in the gene sequence for a TNFα receptor might help explain—and perhaps could have predicted—the negative TNFα-blocker treatment response in MS patients. It’s also an example of how such seemingly small genetic signals could be put to clinical use, he adds. The study appeared online 8 July in Nature.

Trevor Kilpatrick, a neurologist at the Florey Neuroscience Institutes at the University of Melbourne in Parkville, calls the work “important” and says it “provides an interesting bridge” between small differences in a gene sequence and the function of the resulting proteins. The investigators also provide evidence for “disease-specific nuances” in how autoimmunity is regulated, he adds, underscoring the importance of these single-unit sequence swaps in evaluating susceptibility to complex diseases such as MS.

The observation emerged from a genome-wide association study (GWAS) that identified one-letter substitutions—known as single-nucleotide polymorphisms (SNPs)—linked statistically to an elevated risk for MS (see “Genetic Associations”). This particular SNP was associated with MS but not with autoimmune-related disorders such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Of special interest, the SNP sits in the gene for a TNFα receptor. The combined connection to MS and TNFα led the authors to explore the fate of the protein that results from the potentially troublesome SNP.

The single nucleotide, they found, yields a shortened version of the receptor. Although the stumpy molecule still binds TNFα, its missing segments prevent it from embedding in the plasma membrane. Instead, the alternative form loiters around outside the cell, binding TNFα and hindering its activity—the opposite behavior of the full-length form. In grabbing and silencing TNFα, the undersized receptor also keeps TNFα away from its normal partner on the cell surface. The authors suggest that this TNFα-blocking behavior mirrors the clinical activity of TNFα antagonists that can exacerbate MS. The discovery “indicates that TNF blockade promotes MS risk,” Fugger says, and shows that “the modest effect you can get from a genetic risk factor [could] be amplified by a drug.”

Furthermore, understanding the behavior of this abbreviated, MS-linked receptor “could have predicted the side effects of these drugs in MS patients” in clinical trials, Fugger says. If researchers had known about the connection between the disease and a genetic signature that interferes with TNFα activity, they might have foreseen that thwarting TNFα with drugs could cause trouble. More broadly, he adds, the study spans a gap between GWAS results and clinical application. As with most complex diseases, almost all MS-associated SNPs identified so far—including this one—contribute only modestly to disease risk, leading to suggestions that they lack clinical value, although some are beginning to wend their way toward clinical relevance (see “MS Gene Tests Inch Toward the Clinic”). But the current results could serve as a prototype for how other GWAS findings might facilitate patient profiling for risk of drug response, Fugger says. Insights into how particular SNPs confer disease risk could yield ways to counteract—or enhance—their effects and “allow for more appropriate drug administration,” he says.

Kilpatrick agrees that “the genotype might be a foot in the door” to understanding why some drugs work better or worse in different people. However, the suggested parallel between adverse clinical outcomes and the actions of this undersized protein relies on correlative evidence, he says. Rogier Hintzen, a neuroimmunologist at Erasmus MC University Medical Center in Rotterdam, the Netherlands, agrees: “It’s an elegant biological study, [but] the comparisons between the … therapy effects and the natural variant are highly speculative.” Pinpointing the genetic status of MS patients who responded negatively to anti-TNFα drugs might firm up the link, he adds.

Nevertheless, Hintzen says, “to understand disease mechanisms, we need to have functional studies of why these SNPs are related to disease, and this is a very nice example.” Still unknown is how exactly TNFα blockade promotes MS. Numerous pathways—“both the immunological and neurological arms of the disease”—might be involved, Fugger says. It’s an active area of research, he adds, “so hopefully the medical and scientific community will be able to provide some answers in the near future.”

Key open questions

• What is the relevance to clinical practice of the TNFα SNP identified in this study? 
• How does TNFα inhibition trigger or exacerbate MS?
• Can other risk alleles help identify which MS patients might respond to—or be harmed by—particular treatments?

Image credit

Thumbnail image on landing page. "DNA structure," Elapied, 2007. Single nucleotide variations in the DNA sequence of a gene can change the function of a resulting protein. Released under a Creative Commons Attribution-Share Alike 2.0 France license.