Multistudy fine mapping of chromosome 2q identifies XRCC5 as a chronic obstructive pulmonary disease susceptibility gene.
BACKGROUND
Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q.


OBJECTIVE
We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q.


METHODS
Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study.


RESULTS
Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 x 10(-5) across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5.


CONCLUSIONS
By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.
Hersh
Craig P
CP
Channing Laboratory, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA. craig.hersh@channing.harvard.edu
Pillai
Sreekumar G
SG
Zhu
Guohua
G
Lomas
David A
DA
Bakke
Per
P
Gulsvik
Amund
A
DeMeo
Dawn L
DL
Klanderman
Barbara J
BJ
Lazarus
Ross
R
Litonjua
Augusto A
AA
Sparrow
David
D
Reilly
John J
JJ
Agusti
Alvar
A
Calverley
Peter M A
PM
Donner
Claudio F
CF
Levy
Robert D
RD
Make
Barry J
BJ
Paré
Peter D
PD
Rennard
Stephen I
SI
Vestbo
Jørgen
J
Wouters
Emiel F M
EF
Scholand
Mary Beth
MB
Coon
Hilary
H
Hoidal
John
J
Silverman
Edwin K
EK
D017668:Age of Onset; D000368:Aged; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D004265:DNA Helicases / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D000072200:Ku Autoantigen; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D058255:Protease Nexins; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics; D012907:Smoking / Q000009:adverse effects
D016564:Amyloid beta-Protein Precursor; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen
Am J Respir Crit Care Med. 2001 Apr;163(5):1256-76
11316667
Am J Respir Crit Care Med. 2006 Sep 1;174(5):490-1
16931642
Am J Hum Genet. 2004 Feb;74(2):367-9
14740322
Am J Respir Cell Mol Biol. 2000 Jan;22(1):26-33
10615062
Eur Respir J. 2001 Sep;18(3):482-90
11589345
BMC Genet. 2003 Dec 31;4 Suppl 1:S49
14975117
Nature. 2003 Dec 18;426(6968):789-96
14685227
Respir Med. 2008 Sep;102(9):1215-30
18617381
Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10770-5
10485901
N Engl J Med. 2003 May 22;348(21):2059-73
12759479
Am J Respir Crit Care Med. 2007 Jul 15;176(2):167-73
17446335
PLoS Genet. 2009 Mar;5(3):e1000421
19300482
Am J Respir Crit Care Med. 2004 Dec 15;170(12):1294-301
15347563
Proc Am Thorac Soc. 2006 Aug;3(6):486-7
16921121
Am J Hum Genet. 2008 Jul;83(1):112-9
18589396
N Engl J Med. 2008 Apr 17;358(16):1682-91
18403759
Am J Hum Genet. 2009 Nov;85(5):692-8
19853241
Am J Hum Genet. 2004 Jan;74(1):106-20
14681826
Nature. 1996 Aug 8;382(6591):551-5
8700231
Clin Exp Immunol. 1989 Jun;76(3):366-72
2665976
J Biol Chem. 2006 Apr 7;281(14):9600-6
16461352
Am J Respir Crit Care Med. 2008 Sep 1;178(5):500-5
18565956
Nat Med. 2007 May;13(5):567-9
17450149
Am J Hum Genet. 2006 Jul;79(1):184-6; author reply 186-7
16773582
Am J Hum Genet. 2002 May;70(5):1229-39
11914989
Dis Markers. 2002;18(3):129-36
12515908
Epidemiology. 2008 Sep;19(5):649-51; discussion 657-8
18703928
Nature. 2007 Jul 26;448(7152):470-3
17611496
Thorax. 2003 Oct;58(10):832-4
14514931
JAMA. 1994 Nov 16;272(19):1497-505
7966841
Am J Respir Cell Mol Biol. 2005 Jul;33(1):71-8
15817713
Am J Respir Crit Care Med. 2005 Aug 15;172(4):446-52
15901612
Am J Hum Genet. 2006 Feb;78(2):253-64
16358219
N Engl J Med. 2009 Jun 4;360(23):2445-54
19494220
Am J Respir Crit Care Med. 2003 Sep 1;168(5):556-61
12791583
Nat Genet. 2008 Feb;40(2):161-9
18193043
JAMA. 2007 Jul 11;298(2):218-21
17622604