A single-nucleotide polymorphism (SNP) in the gene that encodes the major histocompatability complex (MHC) class II transactivator (MHC2TA) affects the expression of human leukocyte antigen (HLA) molecules, and may confer an increased risk for a number of diseases mediated by inflammation, according to a study published in the May issue of Nature Genetics.¹

Up to a quarter of the population could be affected, indicate researchers from the Karolinska Institutet and the Centre for Molecular Medicine, both in Stockholm, Sweden. People carrying the polymorphism may have a greater risk of developing rheumatoid arthritis (RA) or of suffering a myocardial infarction (MI), the study showed.

"The gene variant we report regulated the expression of HLA molecules, meaning that it could potentially be of relevance for all diseases linked to HLA," author Fredrik Piehl, MD, PhD, groupleader at the Karolinska Institutet, tells CIAOMed. "It can therefore be one of the single largest genetic causes of complex diseases with inflammatory components."

"[MHC2TA] is smack in the middle of regulating inflammation and the immune response, so that makes it compelling," Peter K. Gregersen, MD, director of Robert S. Boas Center for Genomic and Human Genetics at North Shore/Long Island Jewish Research Institute in Manhasset, New York, tells CIAOMed. "Variations in this gene may interact with variations in HLA genes and other genes to put people at higher risk for these diseases," he suggests.

After establishing a genetic correlation between variability in MHC2TA and production of MHC class II molecules in rats, the authors analyzed genotypes at three SNPs in human MHC2TA in case-controlled populations of 387 MI patients, 1288 RA patients, and 548 MS patients. They found that a -168 A to G polymorphism in the promoter of MHC2TA was significantly associated with an increased susceptibility to RA (OR 1.29), and MI (OR 1.39), though there was no association of the genotype with MS when compared to corresponding controls. The study furthermore demonstrated that cultured peripheral blood cells from patients carrying the G/G or G/A variants generated comparatively lower levels of MHC class II molecules when stimulated with IFN-γ than A/A homozygotes.

 

A potentially important contributing factor

"You can have the disease without the gene variant and vice versa, however, it can be an important cause for morbidity on the population level," Dr. Piehl says. "It is an important piece of the puzzle for chronic inflammatory disease. Other genes as well as environmental factors have to be identified to provide the full understanding of the causes and mechanisms," he tells CIAOMed. "However, in the not-so-far-away future, I think it will be possible to include genetic testing together with assessing environmental risk factors, ie, smoking, to be able to give qualified health counseling and perhaps even prescribe tailor-made preventive treatments."

The discovery may also reveal a valuable pharmacogenetic correlation for statins. "Statins have an effect on this gene, and we're now trying to look into genotyping individuals participating in a clinical trial of statins to see if the gene variant predicts treatment effect," Dr. Piehl remarks. "It is too early to speculate on which way this will come out, but one possibility is that gene testing can be of relevance for identifying individuals that will benefit from [statin] treatment."

 

Results requires replication

Calling the new study "very compelling and intriguing," Dr. Gregersen nonetheless cautions that it is crucial that the results be replicated by other investigators. "It's a great piece of work from an animal perspective, and the data associated with human diseases is extremely provocative, but it needs to be replicated," he says.

For instance, he points out, a great deal of enthusiasm was generated about the initial observation of a correlation between the incidence of RA and variability in peptidyl arginine deiminase 4 (PADI4), which converts arginine to citrulline. "This was very compelling because antibodies to citrulline appear to be quite specific to RA," he adds. The first attempt to replicate it has failed, however.

Because MHC2TA controls HLA expression, it regulates one of the mechanisms by which interferon upregulates HLA genes. "It's intriguing because it suggests a pathway of genes," Dr. Gregersen says. "In a sense, [MHC2TA] is a master regulator [and] we know that if it's knocked out and kids are born without it, they don't have HLA genes, and are very immunocompromised," he explains.

In sum, "it's really nice work, very stimulating, a great candidate gene, and will provoke a lot of people to look [for the genotype] in a lot of diseases."

Reference:

Swanberg M, Lidman O, Padyukov L, et al. MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat Genet. 2005;37:486-494.