TOLLIP and MUC5B single nucleotide polymorphisms among interstitial lung disease patients from Western India

Genetic variants in TOLLIP and MUC5B influence innate immune signaling and mucosal defense and have been implicated in interstitial lung disease (ILD) susceptibility. However, data from Indian populations remain scarce. This study aimed to characterize single nucleotide polymorphisms (SNPs) in TOLLIP and MUC5B among patients with interstitial lung disease (ILD) and its subtypes. Additionally, it investigated the relationship between these genetic variants and inflammatory biomarkers, as well as the patterns of linkage disequilibrium (LD) in patients with ILD from Western India.

This cross-sectional study enrolled 200 patients with ILD and 104 healthy controls. Six SNPs, TOLLIP rs3750920, rs111521887, rs5743890, rs5743894, rs5743854, and MUC5B rs35705950, were genotyped using Sanger sequencing and PCR-RFLP. Serum cytokine levels (IL-1β, TNF-α, IFN-γ, and IL-6) were measured using a multiplex bead-based immunoassay. LD was assessed using Haploview software.

Connective tissue disease-related ILD (CTD-ILD) was the most common subtype (45%). The TOLLIP rs3750920_T allele was significantly more frequent in idiopathic pulmonary fibrosis (IPF) than in controls (66.1% vs. 50.5%; p = 0.038). The TOLLIP rs111521887_G allele was more frequent in CTD-ILD than controls (18.4% vs. 7.4%; p = 0.002). The TOLLIP rs5743890_C allele was more frequent in controls than ILD (7.5% vs. 2.9%; p = 0.016). The TOLLIP rs5743894_C allele was more frequent in all patients with ILD than in controls (14.5% vs. 8.1%; p = 0.03), and specifically in the IPF subtype (19.2% vs. 8.1%; p = 0.01). The TOLLIP rs5743854_G allele was found to be more frequent in the idiopathic NSIP subtype as compared to controls (41.2% vs. 23.2%; p = 0.033). The MUC5B rs35705950_T allele was significantly more frequent in ILD than controls (19.6% vs. 5.8%; p = 0.0008). Among cytokines, IFN-γ was significantly elevated in TOLLIP rs5743854 C/C and MUC5B rs35705950 G/G homozygous genotypes in patients with ILD. Furthermore, LD analysis revealed no significant haplotype blocks in this population.

This study provided the first population-specific data on TOLLIP and MUC5B genotypes in Indian patients with ILD, highlighting genotype-driven variation in IFN-γ and distinct allele-frequency patterns compared to Western cohorts. This study also indicated that one-third of the Indian patients with ILD, higher than the 6-7% from currently available Asian data, had genotypes that may benefit from NAC therapy.