Gene variant linked to greater relapse risk in PR3-associated AAV

Risk of severe relapse 5 times higher for these patients: Study

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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A specific variant in both copies of the gene that codes for proteinase 3 (PR3) — one of the most common targets of ANCA-associated vasculitis (AAV)-driving antibodies — is linked to a nearly five times higher risk of severe relapse in people with PR3-associated AAV, a study found.

While this variant, called PR3-Ile119, was found to be the strongest predictor of severe relapse in PR3-AAV patients, it showed no link to the frequency or risk of severe relapse among AAV patients with antibodies against the other common target, myeloperoxidase (MPO).

“We identified a genetic association that has potential prognostic relevance for the relapse risk stratification and management of PR3-AAV,” the researchers wrote.

Further studies are needed to understand the link between this gene variant and the risk of relapse, and also its underlying molecular mechanisms, they added.

The study, “Risk of relapse of ANCA-associated vasculitis among patients homozygous for the proteinase 3 gene Val119Ile polymorphism,” was published in the journal RMD Open.

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Investigating the PR3-Ile119 gene variant in PR3-AAV

In AAV, self-reactive antibodies called anti-neutrophil cytoplasmic autoantibodies (ANCAs) target one of two enzymes —PR3 or MPO — within neutrophils, a type of immune cell. This overly activates neutrophils, causing inflammation and damage to small blood vessels.

In PR3-related AAV, studies examining genetic changes within PRTN3, the gene that provides instruction to produce PR3, have identified eight single nucleotide polymorphisms (SNPs), or single changes in the gene’s DNA code. However, the impact of these SNPs on AAV outcomes has yet to be thoroughly investigated.

One SNP, called rs351111, switches one of PR3’s amino acids, or a protein’s building blocks, from valine to isoleucine — from the original PR3-Val119 form to the PR3-Ile119 variant.

Because this change may alter how PR3-targeting ANCAs interact with the target enzyme, researchers based at the Mayo Foundation for Medical Education and Research, in Minnesota, wondered whether the rs351111 SNP might impact AAV outcomes.

To find out, they analyzed blood samples collected from 188 severe AAV patients who participated in the Phase 2/3 RAVE trial (NCT00104299). Completed in 2010, the study compared the efficacy of two therapies, cyclophosphamide and rituximab — sold as Rituxan in the U.S. and MabThera in Europe, with available biosimilars.

Next-generation DNA sequencing detected the rs351111 variant in 115 AAV patients (61.1%) and 75 patients with PR3-targeting ANCAs (39.9%).

From the 125 PR3-AAV patients evaluated, 50 (40%) carried the original PR3-Val119 form in both copies of the PRTN3 gene (homozygous), 62 (49.6%) had one copy of the PR3-Ile119 variant (heterozygous), and 13 (10.4%) carried the variant in both PRTN3 copies.

The team then compared the clinical features and outcomes of 51 patients homozygous for PR3-Val119 and 13 patients homozygous with PR3-Ile119.

Disease activity was assessed by the Birmingham Vasculitis Activity Score for Wegener Granulomatosis (BVAS/WG). Remission was defined as a score of 0, and a relapse as a score greater than one point or more. Severe relapse, meanwhile, was described as an increase of three or more BVAS/WG points.

While there were no differences in treatment and clinical presentation between the two groups, more than twice as many patients homozygous for PR3-Ile119 experienced severe relapses by 18 months compared with those homozygous for PR3-Val119 (46.2% vs. 19.6%).

The time to severe relapse also was significantly shorter in the PR3-Ile119 group versus the PR3-Val119 group (424 vs. 489 days).

After adjusting for potentially influencing factors, such as demographics, clinical characteristics, and remission-induction treatment, being homozygous for the PR3-Ile119 variant was found to be the strongest predictor of severe relapse at 18 months — increasing the risk by 4.67 times.

By contrast, any degree of kidney involvement was protective in these patients, being linked to an 85% lower risk of severe relapse.

We identified a genetic association that has potential prognostic relevance for the relapse risk stratification and management of PR3-AAV.

Similar findings were obtained after making further adjustments, such as the presence of any small blood vessel inflammation, lung bleeding, BVAS/WG scores at study’s start, relapsing activity, and remission-induction treatment with rituximab.

Lastly, among AAV patients who tested positive for anti-MPO ANCAs, there were no differences in the frequency or risk of severe relapses between those homozygous for PR3-Ile119 and those homozygous for PR3-Val119 (14.3% vs. 17.4%).

“The findings in this [group] of patients with PR3-AAV suggest an association of homozygosity for the PRTN3-Ile119 [variant] with higher frequency of severe relapse,” the team wrote.

“Consequently, homozygosity for this [variant], which is the only one resulting in a change of the amino acid sequence of PR3, may represent an additional identifiable risk factor for severe relapsed,” they added.