title: Cryptic haplotypes of SERPINA1 confer susceptibility to chronic obstructive pulmonary disease.
abstract: Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity worldwide. While cigarette smoking is a major cause of COPD, only 15% of smokers develop the disease, indicating major genetic influences. The most widely recognized candidate gene in COPD is SERPINA1, although it has been suggested that SERPINA3 may also play a role. To detect cryptic genetic variants that might contribute to disease, we identified 15 SNP haplotype tags from high-density SNP maps of the two genes and evaluated these SNPs in the largest case-control genetic study of COPD conducted so far. For SERPINA1, six newly identified haplotypes with a common backbone of five SNPs were found to increase the risk of disease by six- to 50-fold, the highest risk of COPD reported to date. In contrast, no haplotype associations for SERPINA3 were identified.
authors.affiliation: Division of Clinical Chemistry, Molecular Medical Sciences, Institute of Genetics, University Hospital, Queens Medical Centre, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Sally
authors.initials: S
authors.lastname: Chappell
authors.forename: Leslie
authors.initials: L
authors.lastname: Daly
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.forename: Tamar
authors.initials: T
authors.lastname: Guetta Baranes
authors.forename: Josep
authors.initials: J
authors.lastname: Roca
authors.forename: Roberto
authors.initials: R
authors.lastname: Rabinovich
authors.forename: Ann
authors.initials: A
authors.lastname: Millar
authors.forename: Seamas C
authors.initials: SC
authors.lastname: Donnelly
authors.forename: Vera
authors.initials: V
authors.lastname: Keatings
authors.forename: William
authors.initials: W
authors.lastname: MacNee
authors.forename: Jan
authors.initials: J
authors.lastname: Stolk
authors.forename: Pieter
authors.initials: P
authors.lastname: Hiemstra
authors.forename: Massimo
authors.initials: M
authors.lastname: Miniati
authors.forename: Simonetta
authors.initials: S
authors.lastname: Monti
authors.forename: Clare M
authors.initials: CM
authors.lastname: O'Connor
authors.forename: Noor
authors.initials: N
authors.lastname: Kalsheker
mesh_terms: D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D012307:Risk Factors; D000515:alpha 1-Antitrypsin / Q000235:genetics*
chemical_list: C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin