Identification of FGF7 as a novel susceptibility locus for chronic obstructive pulmonary disease

被引:28
作者
Brehm, John M. [1 ]
Hagiwara, Koichi [2 ]
Tesfaigzi, Yohannes [3 ]
Bruse, Shannon [3 ]
Mariani, Thomas J. [4 ]
Bhattacharya, Soumyaroop [4 ]
Boutaoui, Nadia [1 ]
Ziniti, John P. [5 ]
Soto-Quiros, Manuel E. [6 ]
Avila, Lydiana [6 ]
Cho, Michael H. [5 ,7 ,8 ]
Himes, Blanca [5 ]
Litonjua, Augusto A. [5 ,7 ,8 ,9 ]
Jacobson, Francine [10 ]
Bakke, Per [11 ,12 ]
Gulsvik, Amund [11 ,12 ]
Anderson, Wayne H. [13 ]
Lomas, David A. [14 ]
Forno, Erick [15 ]
Datta, Soma [5 ]
Silverman, Edwin K. [5 ,7 ,8 ,16 ]
Celedon, Juan C. [1 ]
机构
[1] Childrens Hosp Pittsburgh UPMC, Div Pediat Pulm Med Allergy & Immunol, Pittsburgh, PA 15224 USA
[2] Saitama Med Univ Hosp & Inst, Saitama, Japan
[3] Lovelace Resp Res Inst, Albuquerque, NM USA
[4] Univ Rochester, Med Ctr, Rochester, NY 14642 USA
[5] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA
[6] Hosp Nacl Ninos Dr Carlos Saenz Herrera, Div Pediat Pulmonol, San Jose, Costa Rica
[7] Brigham & Womens Hosp, Div Pulm Crit Care Med, Boston, MA 02115 USA
[8] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[9] Harvard Univ, Sch Med, Dept Med, Boston, MA USA
[10] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA
[11] Univ Bergen, Inst Med, Bergen, Norway
[12] Univ Bergen, Haukeland Univ Hosp, Bergen, Norway
[13] GlaxoSmithKline Res & Dev Ltd, Res Triangle Pk, NC USA
[14] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England
[15] Univ Miami, Dept Pediat, Div Pediat Pulmonol, Miami, FL 33152 USA
[16] Brigham & Womens Hosp, Ctr Genom Med, Boston, MA 02115 USA
基金
英国惠康基金; 美国医疗保健研究与质量局; 英国医学研究理事会;
关键词
GENE; ASSOCIATION; ADMIXTURE; KGF;
D O I
10.1136/thoraxjnl-2011-200017
中图分类号
R56 [呼吸系及胸部疾病];
学科分类号
摘要
Rationale Traditional genome-wide association studies (GWASs) of large cohorts of subjects with chronic obstructive pulmonary disease (COPD) have successfully identified novel candidate genes, but several other plausible loci do not meet strict criteria for genome-wide significance after correction for multiple testing. Objectives The authors hypothesise that by applying unbiased weights derived from unique populations we can identify additional COPD susceptibility loci. Methods The authors performed a homozygosity haplotype analysis on a group of subjects with and without COPD to identify regions of conserved homozygosity haplotype (RCHHs). Weights were constructed based on the frequency of these RCHHs in case versus controls, and used to adjust the p values from a large collaborative GWAS of COPD. Results The authors identified 2318 RCHHs, of which 576 were significantly (p<0.05) over-represented in cases. After applying the weights constructed from these regions to a collaborative GWAS of COPD, the authors identified two single nucleotide polymorphisms (SNPs) in a novel gene (fibroblast growth factor-7 (FGF7)) that gained genome-wide significance by the false discovery rate method. In a follow-up analysis, both SNPs (rs12591300 and rs4480740) were significantly associated with COPD in an independent population (combined p values of 7.9E-7 and 2.8E-6, respectively). In another independent population, increased lung tissue FGF7 expression was associated with worse measures of lung function. Conclusion Weights constructed from a homozygosity haplotype analysis of an isolated population successfully identify novel genetic associations from a GWAS on a separate population. This method can be used to identify promising candidate genes that fail to meet strict correction for multiple testing.
引用
收藏
页码:1085 / 1090
页数:6
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