Multistudy Fine Mapping of Chromosome 2q Identifies XRCC5 as a Chronic Obstructive Pulmonary Disease Susceptibility Gene

Craig P. Hersh, Sreekumar G. Pillai, Guohua Zhu, David A. Lomas, Per Bakke, Amund Gulsvik, Dawn L. DeMeo, Barbara J. Klanderman, Ross Lazarus, Augusto A. Litonjua, David Sparrow, John J. Reilly, Alvar Agusti, Peter M A Calverley, Claudio F. Donner, Robert D. Levy, Barry J. Make, Peter D. Paré, Stephen I. Rennard, Jørgen VestboEmiel F M Wouters, Mary Beth Scholand, Hilary Coon, John Hoidal, Edwin K. Silverman

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstrakt

Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q. Objectives: 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. Measurements and Main 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 × 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.
OriginalsprogEngelsk
TidsskriftAmerican Journal of Respiratory and Critical Care Medicine
Vol/bind182
Udgave nummer5
Sider (fra-til)605-613
Antal sider9
ISSN1073-449X
DOI
StatusUdgivet - 1. sep. 2010
Udgivet eksterntJa

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Bibliografisk note

HL075478, NHLBI NIH HHS, United StatesHL080242, NHLBI NIH HHS, United StatesHL084323, NHLBI NIH HHS, United StatesHL094635, NHLBI NIH HHS, United StatesN01HR76101, NHLBI NIH HHS, United StatesN01HR76102, NHLBI NIH HHS, United StatesN01HR76103, NHLBI NIH HHS, United StatesN01HR76104, NHLBI NIH HHS, United StatesN01HR76105, NHLBI NIH HHS, United StatesN01HR76106, NHLBI NIH HHS, United StatesN01HR76107, NHLBI NIH HHS, United StatesN01HR76108, NHLBI NIH HHS, United StatesN01HR76109, NHLBI NIH HHS, United StatesN01HR76110, NHLBI NIH HHS, United StatesN01HR76111, NHLBI NIH HHS, United StatesN01HR76112, NHLBI NIH HHS, United StatesN01HR76113, NHLBI NIH HHS, United StatesN01HR76114, NHLBI NIH HHS, United StatesN01HR76115, NHLBI NIH HHS, United StatesN01HR76116, NHLBI NIH HHS, United StatesN01HR76118, NHLBI NIH HHS, United StatesN01HR76119, NHLBI NIH HHS, United StatesP01 HL072903, NHLBI NIH HHS, United StatesP01 HL083069, NHLBI NIH HHS, United StatesU01 HL065899, NHLBI NIH HHS, United States

Emneord

  • Emphysema
  • Genetic linkage
  • Metaanalysis
  • Single nucleotide polymorphism

Citationsformater

Hersh, C. P., Pillai, S. G., Zhu, G., Lomas, D. A., Bakke, P., Gulsvik, A., DeMeo, D. L., Klanderman, B. J., Lazarus, R., Litonjua, A. A., Sparrow, D., Reilly, J. J., Agusti, A., Calverley, P. M. A., Donner, C. F., Levy, R. D., Make, B. J., Paré, P. D., Rennard, S. I., ... Silverman, E. K. (2010). Multistudy Fine Mapping of Chromosome 2q Identifies XRCC5 as a Chronic Obstructive Pulmonary Disease Susceptibility Gene. American Journal of Respiratory and Critical Care Medicine, 182(5), 605-613. https://doi.org/10.1164/rccm.200910-1586OC