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A b s t r ac t Background The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk. Methods Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families. We then evaluated genetic variation in this region in gel-forming mucin genes expressed in the lung among 83 subjects with familial interstitial pneumonia, 492 subjects with idiopathic pulmonary fibrosis, and 322 controls. MUC5B expression was assessed in lung tissue. Results Linkage and fine mapping were used to identify a region of interest on the p-terminus of chromosome 11 that included gel-forming mucin genes. The minor-allele of the single-nucleotide polymorphism (SNP) rs35705950, located 3 kb upstream of the MUC5B transcription start site, was present at a frequency of 34% among subjects with familial interstitial pneumonia, 38% among subjects with idiopathic pulmonary fibrosis, and 9% among controls (allelic association with familial interstitial pneumonia, P = 1.2×10 − 15 ; allelic association with idiopathic pulmonary fibrosis, P = 2.5×10 − 37 ). The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP were 6.8 (95% confidence interval [CI], 3.9 to 12.0) and 20.8 (95% CI, 3.8 to 113.7), respectively, for familial interstitial pneumonia and 9.0 (95% CI, 6.2 to 13.1) and 21.8 (95% CI, 5.1 to 93.5), respectively, for idiopathic pulmonary fibrosis. MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P

Several lines of evidence suggest that genetic factors and environmental exposures play a role in the development of pulmonary fibrosis.We evaluated families with 2 or more cases of idiopathic interstitial pneumonia among first-degree family members (familial interstitial pneumonia, or FIP), and identified 111 families with FIP having 309 affected and 360 unaffected individuals.The presence of probable or definite FIP was based on medical record review in 28 cases (9.1%); clinical history, diffusing capacity of carbon monoxide (DL(CO)), and chest X-ray in 16 cases (5.2%); clinical history, DL(CO), and high-resolution computed tomography chest scan in 191 cases (61.8%); clinical history and surgical lung biopsy in 56 cases (18.1%); and clinical history and autopsy in 18 cases (5.8%).Older age (68.3 vs. 53.1; p0.0001), male sex (55.7 vs. 37.2%; p0.0001), and having ever smoked cigarettes (67.3 vs. 34.1%; p0.0001) were associated with the development of FIP. After controlling for age and sex, having ever smoked cigarettes remained strongly associated with the development of FIP (odds ratio(adj), 3.6; 95% confidence interval, 1.3-9.8). Evidence of aggregation of disease was highly significant (p0.001) among sibling pairs, and 20 pedigrees demonstrated vertical transmission, consistent with autosomal dominant inheritance. Forty-five percent of pedigrees demonstrated phenotypic heterogeneity, with some pedigrees demonstrating several subtypes of idiopathic interstitial pneumonia occurring within the same families.These findings suggest that FIP may be caused by an interaction between a specific environmental exposure and a gene (or genes) that predisposes to the development of several subtypes of idiopathic interstitial pneumonia.

Several lines of evidence suggest that genetic factors and environmental exposure play a role in the development of pulmonary fibrosis. The authors evaluated families with familial pulmonary fibrosis (FPF), defined as the presence of two or more cases of idiopathic interstitial pneumonia (IIP) in first degree family members. In total, 56 families with FPF were evaluated with 193 affected and 196 unaffected individuals. The presence of FPF was based on clinical history, DLCO, and CXR in 27 (14%); clinical history and HRCT scan in 102 (53%); clinical history and SLB in 55 (28%); and clinical history and autopsy in nine (5%). Older age (67.8 vs. 53.6; P