Genetic variant linked to worsening lung disease in sarcoidosis: Study
It could help with early identification of at-risk populations, tailored treatrment
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A common genetic variant in the TNFR1 gene, which encodes a protein involved in regulating inflammation, may help identify people with sarcoidosis who are at higher risk of worsening lung function, a new study suggests.
Researchers found that patients carrying two copies of the more common form of the genetic variant, rs1800693, showed poorer lung function and a greater decline over time than those carrying at least one copy of the alternative form of the variant.
“TNFR1 rs1800693 might be associated with lung function impairment and decline in … sarcoidosis patients,” researchers wrote, adding that genetic markers such as this one may “provide opportunities for the early identification of at-risk populations and tailored treatment.”
The study, “Association of the TNFRSF1A genotype with lung function impairment in patients with sarcoidosis,” was published in Scientific Reports.
Pulmonary sarcoidosis lung damage driven in part by TNF-alpha
In sarcoidosis, an overly active immune system causes clusters of inflammatory cells called granulomas to form in organs throughout the body, leading to symptoms.
Some people develop Löfgren syndrome, a milder form of sarcoidosis that usually resolves on its own within months to a year.
“The other [clinical profile], non-Lofgren syndrome, has a variable presentation where the disease burden and prognosis are related to organ involvement and damage,” the researchers wrote.
In people with non-Löfgren sarcoidosis, pulmonary sarcoidosis, a form of the disease that mainly affects the lungs, occurs in more than 90% of cases and can lead to impaired lung function, irreversible lung damage, and an increased risk of death.
This lung damage is driven in part by TNF-alpha, a signaling molecule that helps activate inflammatory cells by binding to one of its main receptor proteins, called TNFR1. Excessive TNF-alpha signaling can contribute to persistent inflammation and tissue damage.
Previous research showed that one small variation in the TNFR1 gene, rs1800693, can lead to production of a shortened, soluble version of TNFR1 that can bind and neutralize TNF-alpha, potentially reducing TNF-alpha-driven inflammation.
Known as a single-nucleotide polymorphism, this type of variation is marked by a change in a single building block of the DNA sequence; in this case, adenine (A) is swapped for a guanine (G). The G form is associated with the production of the altered receptor.
Researchers analyzed genetic and lung function data
In this study, a team of researchers investigated the frequency of these rs1800693 variants and whether they were associated with disease progression in people with non-Löfgren sarcoidosis.
They retrospectively analyzed genetic and lung function data from two independent groups of non-Löfgren sarcoidosis patients — 108 in Germany and 393 in Norway— and two control groups — people with chronic obstructive pulmonary disease, an inflammatory lung disease, and those without lung disease.
Participants in Germany were followed for an average of 6.5 years, while those in Norway were followed for an average of 7.9 years. Overall, the proportions of the A and G forms of the rs1800693 genetic variant were similar across all four groups.
Compared with Norwegian patients, German patients were younger, had poorer lung function, and were more likely to receive immunosuppressive treatments. The Norwegian group also included a higher proportion of people with earlier-stage sarcoidosis.
At the start of follow-up, Norwegian patients carrying two copies of the G form had significantly higher forced vital capacity (FVC) values, a measure of how much air a person can forcibly exhale after taking a deep breath, than those carrying two copies of the A form. In German patients, FVC was similar across genotypes.
Variant’s effects tied to inflammatory processes underlying sarcoidosis
Researchers then examined how lung function changed over time according to genetic profile.
German patients carrying two A form copies showed significantly lower FVC than those carrying at least one G form, and experienced pronounced declines in both FVC and diffusing capacity for carbon monoxide (DLCO) over follow-up. DLCO reflects how efficiently gases move from the lungs into the bloodstream.
German patients with two G forms showed stabilization of FVC and improvements in DLCO over time. Norwegian patients carrying two copies of the G form generally showed stable FVC and DLCO values over time.
No associations between genetic variation and lung function were detected among the control groups, suggesting that rs1800693’s effects may be more specifically linked to inflammatory processes underlying sarcoidosis rather than lung disease in general, the researchers noted.
After adjusting for factors including smoking and treatment use, significant differences in lung function decline according to genetic profile were observed in the German group alone. Specifically, patients carrying two copies of the A form showed a greater decline in FVC over time than those carrying G forms of the variant.
Overall, these findings suggest the rs1800693 variation may “provide opportunities for the early identification” of people with non-Löfgren sarcoidosis who are at higher risk of lung disease progression and who might benefit from closer monitoring or tailored treatment, the team wrote.
