title: A common MUC5B promoter polymorphism and pulmonary fibrosis.
abstract: 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.).
authors.affiliation: National Jewish Health, Denver, USA.
authors.forename: Max A
authors.initials: MA
authors.lastname: Seibold
authors.forename: Anastasia L
authors.initials: AL
authors.lastname: Wise
authors.forename: Marcy C
authors.initials: MC
authors.lastname: Speer
authors.forename: Mark P
authors.initials: MP
authors.lastname: Steele
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Brown
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
authors.forename: Tasha E
authors.initials: TE
authors.lastname: Fingerlin
authors.forename: Weiming
authors.initials: W
authors.lastname: Zhang
authors.forename: Gunnar
authors.initials: G
authors.lastname: Gudmundsson
authors.forename: Steve D
authors.initials: SD
authors.lastname: Groshong
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Evans
authors.forename: Stavros
authors.initials: S
authors.lastname: Garantziotis
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Adler
authors.forename: Burton F
authors.initials: BF
authors.lastname: Dickey
authors.forename: Roland M
authors.initials: RM
authors.lastname: du Bois
authors.forename: Ivana V
authors.initials: IV
authors.lastname: Yang
authors.forename: Aretha
authors.initials: A
authors.lastname: Herron
authors.forename: Dolly
authors.initials: D
authors.lastname: Kervitsky
authors.forename: Janet L
authors.initials: JL
authors.lastname: Talbert
authors.forename: Cheryl
authors.initials: C
authors.lastname: Markin
authors.forename: Joungjoa
authors.initials: J
authors.lastname: Park
authors.forename: Anne L
authors.initials: AL
authors.lastname: Crews
authors.forename: Susan H
authors.initials: SH
authors.lastname: Slifer
authors.forename: Scott
authors.initials: S
authors.lastname: Auerbach
authors.forename: Michelle G
authors.initials: MG
authors.lastname: Roy
authors.forename: Jia
authors.initials: J
authors.lastname: Lin
authors.forename: Corinne E
authors.initials: CE
authors.lastname: Hennessy
authors.forename: Marvin I
authors.initials: MI
authors.lastname: Schwarz
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D002880:Chromosomes, Human, Pair 11; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics*; D015810:Linkage Disequilibrium; D008168:Lung / Q000378:metabolism; D017563:Lung Diseases, Interstitial / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D055257:Mucin-5B / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
chemical_list: C524578:MUC5B protein, human; D055257:Mucin-5B