Using a genomewide linkage scan, Seibold et al. (2011) detected linkage between idiopathic interstitial pneumonia (178500) and a 3.4-Mb region of chromosome 11p15 in 82 families. They 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. The minor allele (T) of 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 x 10(-15); allelic association with idiopathic pulmonary fibrosis, p = 2.5 x 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% 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 less than 0.001). The variant allele of rs35705950 was associated with upregulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wildtype allele, p less than 0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis.
Zhang et al. (2011) confirmed the findings of Seibold et al. (2011). They studied 341 cases with idiopathic pulmonary fibrosis from the University of Pittsburgh, University of Chicago, and 802 controls from the same 2 centers and found a strong association of the minor allele at rs35705950 with pulmonary fibrosis, with a P value of 7.6 x 10(-40). The odds ratios for idiopathic pulmonary fibrosis in subjects who were heterozygous or homozygous for the minor allele of rs35705950 were 5.9 (95% CI, 4.4 to 7.8) and 9.7 (95% CI, 4.7 to 19.9), respectively.
Hunninghake et al. (2013) performed a blinded assessment of interstitial lung abnormalities in 2,633 participants in the Framingham Heart Study by means of volumetric chest computed tomography (CT). One hundred seventy-seven of these individuals (7%) had interstitial lung abnormalities. Those individuals were more likely to have shortness of breath, chronic cough, and reduced measures of total lung and diffusion capacity. After adjustment for covariates, for each copy of the minor rs35705950 allele, the odds of interstitial lung abnormalities were 2.8 times greater (95% CI, 2.0 to 3.9; p less than 0.001), and the odds of definite CT evidence of pulmonary fibrosis were 6.3 times greater (95% CI, 3.1 to 12.7; p less than 0.001). Although the evidence of an association between the MUC5B genotype and interstitial lung abnormalities was greater among participants who were older than 50 years of age, a history of cigarette smoking did not appear to influence the association.
Using a discovery population and multiple validation populations, Juge et al. (2018) tested the association of the MUC5B promoter variant rs35705950 in 620 patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD), 614 patients with RA without ILD, and 5448 unaffected controls. Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% CI, 2.8 to 5.2; p = 9.7 x 10(-17)). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; p = 4.7 x 10(-35)) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; p = 1.3 x 10(-49)). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; p = 7.4 x 10(-5)), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography. However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. Juge et al. (2018) concluded that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging.
