| Inflammation is a major factor in the pathophysiology of many different pulmonary diseases. However, phenotypic presentation, such as severity of disease and organ involvement, can be variable. In this study, we will look at inflammatory mediators thought to be involved with two primarily pulmonary diseases: sarcoidosis and cystic fibrosis. Sarcoidosis is a complex inflammatory disorder in which 90% of the patients have pulmonary involvement; however, virtually any organ can be affected. We evaluated whether 25 variants distributed in 19 genes with a known role in inflammation were associated with sarcoidosis disease and/or erythema nodosum status in 659 sarcoidosis patients and 658 controls from "A Case Control Etiologic Study of Sarcoidosis" (ACCESS). We found no association with affectation status itself; however, a variant in the promoter of tumor necrosis factor (TNF) at position -308 was found to be associated with erythema nodosum in Caucasian sarcoidosis patients (study-wide p=0.027). When stratified by sex, a variant in intron 1 of lymphotoxin alpha (LTA), a gene adjacent to TNF, was associated with erythema nodosum in female Caucasian sarcoidosis patients (study-wide p=0.027). Cystic fibrosis (CF) is a single-gene pulmonary disorder influenced by multiple components, including CFTR genotype, Pseudomonas aeruginosa (Pa) infection and conversion to mucoid Pa , and patient age. Evidence that lung function is heritable independently of CFTR genotype indicates modifier genes may play an important role. Further, pulmonary disease in CF is exacerbated by dysregulation of the nuclear factor kappa-B (NFkB) pathway. To assess contribution of MBL2 diplotype, IL10-571, IL6-174, CCR5 de132, and IL1B-511 in components of CF pulmonary disease, we proposed a modeling framework relating key variables to each other and to lung function using 788 CF patients from the CF Twin and Sibling Study. We then used this framework to evaluate a possible modifier role for MBL2, IL10, IL6, CCR5, and IL1B in Pa infection, mucoid Pa conversion, and lung function. In this manner, we showed patients with MBL2 diplotypes corresponding to low levels of MBL acquired Pseudomonas aeruginosa ( Pa) infection 1.94 years earlier on average than did patients with MBL2 diplotypes corresponding to high levels of MBL (p=0.0034). Additionally, Pa-infected CF patients with MBL2 diplotypes corresponding to low levels of MBL underwent conversion to mucoid Pa 2.72 years earlier (p=0.0003). IL1B-511 was associated with Pa infection status, with homozygotes for the major allele at greatest risk for infection (p=0.0015; odds ratio 2.22 (1.35, 3.64)). Additionally, if a patient is both a CFTR delF508 homozygote and is homozygous for the IL1B-551 major allele, they were 4.9 times more likely to be infected with Pa (p≤0.0001). Among patients infected with Pa, CCR5 major allele homozygotes had a 1.84 times greater risk of converting to mucoid Pa (p=0.0086). IL6-174 was correlated with FEV1 % predicted, with an increase in 4.11 units FEV1 % predicted for each copy of the minor allele (p=0.0085; Figure 4.1). These results show that genetic variation in inflammatory mediators modify both cystic fibrosis and sarcoidosis. |
