Cryptic haplotypes of SERPINA1 confer susceptibility to chronic obstructive pulmonary disease.
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.
Chappell
Sally
S
Division of Clinical Chemistry, Molecular Medical Sciences, Institute of Genetics, University Hospital, Queens Medical Centre, University of Nottingham, Nottingham, United Kingdom.
Daly
Leslie
L
Morgan
Kevin
K
Guetta Baranes
Tamar
T
Roca
Josep
J
Rabinovich
Roberto
R
Millar
Ann
A
Donnelly
Seamas C
SC
Keatings
Vera
V
MacNee
William
W
Stolk
Jan
J
Hiemstra
Pieter
P
Miniati
Massimo
M
Monti
Simonetta
S
O'Connor
Clare M
CM
Kalsheker
Noor
N
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*
C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin