TOLLIP and MUC5B Genetic Variants Influence the Circulating KL6, SPD, and HE4 Levels in Interstitial Lung Abnormalities

Background: Interstitial lung abnormalities (ILAs) are alterations of lung parenchyma found in approximately 5% of individuals older than 60 years. There is growing interest in identifying early biomarkers that may facilitate diagnosis and predict disease progression. Given ILA’s biological complexity, a multidimensional approach integrating genetic susceptibility and immune dysregulation is warranted. Methods: We studied 87 ILA subjects and 74 subjects without changes on high-resolution computed tomography and without respiratory symptoms. We also classified ILA subjects by progression status during 5 years of follow-up: 20 progressed, and 67 did not. This study evaluated demographic characteristics, circulating soluble proteins (KL6, SPD, and HE4), T cell polarization (Th1/Th2 balance), and selected gene polymorphisms (TERT, MUC5B, FAM13A, TOLLIP, and DSP). Results: Patients with ILA were predominantly male and showed significant abnormalities in pulmonary function tests; they had higher circulating SP-D levels (78 ± 44 versus 43 ± 31 ng/mL, p < 0.0001). Genetic variants significantly influence circulating levels; the median KL6 levels were higher in patients and controls carrying the TOLLIP rs5743890 TT genotype (0.27 ng/mL [0.01–0.71 ng/mL]) than in those with the TC genotype (0.01 ng/mL [0.00–0.19 ng/mL]). The SPD levels according to the MUC5B rs35705950 genotypes were lower in controls and patients carrying the common genotype GG (48.66 ng/mL [27.49–80.40 ng/mL] and 56.91 ng/mL [32.23–90.22 ng/mL]) than subjects with GT + TT genotypes (83.09 ng/mL [56.52–139.72 ng/mL], and 93.70 ng/mL [57.77–154.38 ng/mL]) and HE4 levels were different when the patients and controls carrying the MUC5B rs35705950 GG (2.43 pmol/mL [1.56–3.22 pmol/mL], and 2.43 pmol/mL [1.65–3.29 pmol/mL]) were compared to those with the GT genotype (1.56 pmol/mL [1.21–1.97 pmol/mL], and 1.48 pmol/mL [1.08–2.09 pmol/mL]). No difference emerged when we divided ILAs by progression. The Th1/Th2 ratio does not differ between ILAs and controls, even after polyclonal stimulation. Conclusions: Our findings provide relevant insight into the relationship between genetic background and circulating levels.