Impact of the Human Leukocyte Antigen Complex on Idiopathic Pulmonary Fibrosis Development and Progression in the Sardinian Population

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by the disruption of the alveolar and interstitial architecture due to extracellular matrix deposition. Emerging evidence suggests that genetic susceptibility plays a crucial role in IPF development. This study explores the role of human leukocyte antigen (HLA) alleles and haplotypes in IPF susceptibility and progression within the genetically distinct Sardinian population. Genotypic data were analyzed for associations with disease onset and progression, focusing on allele and haplotype frequencies in patients exhibiting slow (S) or rapid (R) progression. While no significant differences in HLA allele frequencies were observed between IPF patients and controls, the HLA-DRB1*04:05 allele and the extended haplotype (HLA-A*30:02, B*18:01, C*05:01, DQA1*05:01, DQB1*02:01, DRB1*03:01) were associated with a slower disease progression and improved survival (log-rank = 0.032 and 0.01, respectively). At 36 months, carriers of these variants demonstrated significantly better pulmonary function, measured with single-breath carbon monoxide diffusing capacity (DLCO%p) (p = 0.005 and 0.02, respectively). Multivariate analysis confirmed these findings as being independent of confounding factors. These results highlight the impact of HLA alleles and haplotypes on IPF outcomes and underscore the potential of the Sardinian genetic landscape to illuminate immunological mechanisms, paving the way for predictive biomarkers and personalized therapies.

Keywords: HLA; ILDs; IPF; Sardinia; genetics; idiopathic pulmonary fibrosis.

Figure 1

IPF patient enrollment: A total of 136 ILD patients were recruited over a period of 54 months, from January 2020 to July 2024, and follow-up was conducted at the Department of Pneumology of Binaghi Hospital (ASL, Cagliari, Italy). IPF was diagnosed according to the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and the Asociación Latinoamericano de Tórax guidelines and recommendations [24,25]. The aim of the study was to evaluate the influence of HLA haplotypes on the onset and progression of IPF, and to investigate potential differences between two subgroups of patients: (i) the slow progression group (S), which consisted of 69 patients with a stable clinical condition or slow disease progression, and (ii) the rapid progression (R) group, which was represented by 34 patients who met the criteria for lung transplant listing. These criteria included rapid clinical deterioration with an annual decline of >10% in ventilatory indices (FVC%p and DLCO%p) and/or the need for oxygen therapy [25]. Patients with lung comorbidities were also excluded from the analysis (lung cancer, fibroelastosis, COPD, PPF). An additional two patients were excluded due to incomplete clinical and follow-up data. Abbreviations: COPD: chronic obstructive pulmonary disease; ILDs: interstitial lung diseases; IPF: idiopathic pulmonary fibrosis; and PPF: progressive pulmonary fibrosis.

Figure 2

IPF overall survival. The overall survival based on IPF-specific mortality is graphically presented for a cohort of 103 patients observed over a 60-month time frame. p values were calculated using the two-sided log-rank test.

Figure 3

IPF overall survival: HLA-DRB1*04:05 association. Presents the analysis of survival correlated with the pulmonary function in patients carrying the HLA-DRB1*04:05 allele. (A) The overall survival based on IPF-specific mortality is graphically presented for a cohort of 103 patients observed over a 60-month time frame. p values were calculated using the two-sided log-rank test. One hundred and three patients were categorized based on the presence or absence of HLA-DRB1*04:05 (orange presence, cyan other alleles). p values were calculated using the two-sided log-rank test. The figure shows that patients lacking the HLA-DRB1*04:05 allele exhibit lower survival rates than those who carry it. The log-rank test indicates a statistically significant difference between the two groups (X² = 4.57; p = 0.032), suggesting a potential protective effect of the allele. (B) Comparison of the % predicted (FVC%) forced vital capacity between HLA-DRB1*04:05 absence and presence. The FVC% at 36 months, depicted as a violin, is compared between the group of patients who are HLA-DRB1*04:05-negative and HLA-DRB1*04:05-positive. No significant difference is observed between the two groups (p = 0.723), indicating that the presence of the allele does not appear to influence this particular pulmonary function parameter. (C) Comparison of % predicted single breath diffusing capacity for carbon monoxide (DLco%) between the absence and presence of HLA-DRB1*04:05. The DLco% at 36 months, depicted as a violin, is compared between the group of patients who are HLA-DRB1*04:05-negative and HLA-DRB1*04:05-positive. In this case, patients carrying the HLA-DRB1*04:05 allele exhibit significantly higher DLco% values compared to those without the allele (p = 0.005).

Figure 4

IPF overall survival: association with the extended haplotype HLA-A*30:02, -B*18:01, -C*05:01, -DQA1*05:01, -DQB1*02:01, -DRB1*03:01. This figure presents the analysis of the survival rate correlated with the pulmonary function in patients carrying the Sardinian HLA extended haplotype (HLA-A*30:02, -B*18:01, -C*05:01, -DQA1*05:01, -DQB1*02:01, -DRB1*03:01). (A) The overall survival of IPF-specific mortality is graphically presented for a cohort of 103 patients observed over a 60-month time frame. p values were calculated using the two-sided log-rank test. One hundred and three patients were categorized based on the presence (orange line) or absence of the extended haplotype HLA-A*30:02, B*18:01, C*05:01, DQA1*05:01, DQB1*02:01, DRB1*03:01 (cyan line). p values were calculated using the two-sided log-rank test. Panel A shows the difference in the terms of OS between these two groups of patients. Patients lacking the haplotype (cyan line) exhibit a lower survival probability over time. The log-rank test indicates a statistically significant difference (p = 0.011). (B) Comparison of % predicted forced vital capacity (FVC%) between the absence and presence of the extended haplotype HLA-A*30:02, -B*18:01, -C*05:01, -DQA1*05:01, -DQB1*02:01, -DRB1*03:01. The FVC% at 36 months, represented as a violin, shows no significant difference between these two groups (p = 0.272), indicating that the presence of the haplotype does not seem to influence this pulmonary function parameter. (C) Comparison of % predicted single breath diffusing capacity for carbon monoxide (DLco%) between the presence and absence of the extended haplotype HLA-A*30:02, -B*18:01, -C*05:01, -DQA1*05:01, -DQB1*02:01, -DRB1*03:01. Haplotype-positive patients show significantly higher DLCO% values compared to haplotype-negative individuals (p = 0.02), suggesting better lung function.