TY - JOUR
T1 - A common MUC5B promoter polymorphism and pulmonary fibrosis
AU - Seibold, Max A.
AU - Wise, Anastasia L.
AU - Speer, Marcy C.
AU - Steele, Mark P.
AU - Brown, Kevin K.
AU - Loyd, James E.
AU - Fingerlin, Tasha E.
AU - Zhang, Weiming
AU - Gudmundsson, Gunnar
AU - Groshong, Steve D.
AU - Evans, Christopher M.
AU - Garantziotis, Stavros
AU - Adler, Kenneth B.
AU - Dickey, Burton F.
AU - Du Bois, Roland M.
AU - Yang, Ivana V.
AU - Herron, Aretha
AU - Kervitsky, Dolly
AU - Talbert, Janet L.
AU - Markin, Cheryl
AU - Park, Joungjoa
AU - Crews, Anne L.
AU - Slifer, Susan H.
AU - Auerbach, Scott
AU - Roy, Michelle G.
AU - Lin, Jia
AU - Hennessy, Corinne E.
AU - Schwarz, Marvin I.
AU - Schwartz, David A.
PY - 2011/4/21
Y1 - 2011/4/21
N2 - 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<0.001). The variant allele of rs35705950 was associated with up-regulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wild-type allele, P<0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis. Conclusions: A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis. Our findings suggest that dysregulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
AB - 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<0.001). The variant allele of rs35705950 was associated with up-regulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wild-type allele, P<0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis. Conclusions: A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis. Our findings suggest that dysregulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
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U2 - 10.1056/NEJMoa1013660
DO - 10.1056/NEJMoa1013660
M3 - Article
C2 - 21506741
AN - SCOPUS:79955146233
SN - 0028-4793
VL - 364
SP - 1503
EP - 1512
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 16
ER -