IPF Risk Genes Linked to AAV in Study, But Not to AAV-associated Lung Disease

Genetic variations in the TERT and DSP genes, previously associated with an increased risk of idiopathic pulmonary fibrosis (IPF), are also tied to a greater likelihood of ANCA-associated vasculitis (AAV), a study in Japan found.

However, these gene variants are not associated with a risk of interstitial lung disease (ILD; a group of lung diseases that includes IPF) among people with AAV, its findings suggest.

The study, “Association of TERT and DSP variants with microscopic polyangiitis and myeloperoxidase-ANCA positive vasculitis in a Japanese population: a genetic association study,” was published in Arthritis Research & Therapy.

AAV, an autoimmune disease, is characterized by blood vessel inflammation and swelling. The disease has multiple subtypes, and noteworthy differences are evident in how AAV tends to manifest in various groups of people.

In East Asian populations, for example, the most common types of AAV are microscopic polyangiitis (MPA) and myeloperoxidase (MPO)-ANCA positive AAV (MPO-AAV), whereas other types are more common in European populations.

AAV-associated ILD, a serious complication of AAV, is also more common in Japanese people with AAV than in Europeans, even among those with the same type of AAV. This distinction could be the result of genetic differences between Japanese and European populations.

Previous research indicated a link between a variant in the MUC5B gene, a known risk factor for IPF, and ILD-associated AAV. However, the MUC5B variant is not very common in Japanese populations, so it alone could not account for the increased ILD frequency among Japanese people with AAV.

This led the researchers to suspect other genetic factors may be at play. Specifically, they focused on variants in two other genes, TERT and DSP, which also have established links to IPF.

“We had previously reported that a MUC5B gene variant linked to IPF was increased only in AAV patients with ILD. However, its rarity among Japanese made us suspect other IPF susceptibility alleles in TERT and DSP genes,” Aya Kawasaki, a professor at the University of Tsukuba and study co-author, said in a press release.

To test this idea, the researchers examined these genes in 544 AAV patients and 785 healthy people serving as controls, all of whom were Japanese. Among the AAV patients, 432 were positive for MPO-ANCA and 315 had MPA.

Using statistical models, the researchers determined that the TERT variant was associated with a 38% increased likelihood of MPA, and a 33% increased likelihood of MPO-AAV, both of which were statistically significant. Similarly, the DSP variant was associated with a significant 32% and 26% increased likelihood of MPA and MPO-AAV, respectively.

“Here, we report that TERT rs2736100A and DSP rs2076295G, both of which are the risk alleles for IPF, are associated with susceptibility to MPA and MPO-AAV in a Japanese population,” the researchers wrote.

Associations between these genetic variants and other types of AAV were also detected, but they failed to reach statistical significance (meaning that, mathematically, there is a substantial likelihood the difference was due to random chance).

In additional analyses segregated by sex, the researchers determined that the TERT variant was significantly associated with MPA and MPO-AAV in both males and females, whereas the DSP variant was significantly linked with these conditions in males, but not females.

“Although the reason of such difference remains unclear, sex hormone or genes located in sex chromosomes might affect the association of DSP,” the researchers wrote.

Among individuals with MPO-AAV, who have a greater incidence of ILD compared with people whose ANCA antibodies target the proteinase 3 protein (PR3-ANCA), 176 had ILD and 216 did not, as determined by CT scans. In these patients, neither the TERT nor the DSP variants were significantly associated with ILD risk.

“Unexpectedly, association of these alleles with occurrence of ILD among the patients with MPO-AAV was not detected,” the researchers wrote.

These findings, they said, support the idea that IPF and AAV may share common disease-driving mechanisms, which studies have previously suggested.

“These results might suggest a possibility that some IPF associated genes (e.g., MUC5B) may play a role in the process of lung disease, and others (e.g., TERT and DSP) may be involved in the shared molecular background between [AAV] and IPF. Further studies are required to validate this hypothesis,” the researchers concluded.

“Factoring these epidemiological and genetic differences between European and East Asian populations will broaden our knowledge base of rare diseases such as AAV,” said Naoyuki Tsuchiya, a study co-author and Tsukuba university professor.

“Pinpointing the risk alleles [genetic variants] and elucidating the underlying molecular mechanisms would not only lead to better understanding of the [cause] of these conditions, but also help identify new molecular targets for treatment of related autoimmune diseases,” Tsuchiya added.