新的基因變異與慢性阻塞性肺病有關
作者：Jacquelyn K. Beals, PhD
出處：WebMD醫學新聞
February 24, 2010 — 一項全基因組關聯研究合併來自幾個較早期肺功能研究，已經確認第四對染色體長臂一個區域與慢性阻塞性肺病（COPD）感受性增加有關。這個位置是基因FAM13A，這個基因變異過去被認為與肺功能有關。儘管FAM13A變異與較高的COPD風險有關，但吸菸的影響遠大於基因。
這項研究於2月21日線上發表於自然基因學期刊，起源於COPD盛行率在過去與目前吸菸者之間有相當變異，代表基因成分是COPD感受性差異的原因之一。
來自麻州波士頓哈佛醫學院布萊根婦女醫院錢尼實驗室、與胸腔及重症部門的第一作者Michael H. Cho醫師在一封電子郵件中向Medscape胸腔醫學表示，基因變異與其他常見變異可能影響COPD感受性，因吸菸對COPD風險的影響而變得渺小。
在這項起始研究中，所有病患都罹患COPD（共2940位），控制組病患（共1380位），這些受試者們目前或之前曾吸菸。一組是來自於挪威一項病例控制全基因組關聯研究，另一組來自國家肺氣腫治療研究（COPD患者）以及標準老化研究（Normative Aging Study；NAS）（控制組病患），第三組是來自於ECLIPSE研究。所有病例都已經被診斷罹患中重度COPD；控制組病患肺功能正常。分析校正了病患與控制組的年齡與每年吸菸包數，發現兩個群體之間仍然有些許分層。
起始研究確認了兩個單一核苷酸多型性（SNPs）高度與COPD有關（P= 7.18 × 10-8與P= 8.59 × 10-8），這兩個都在FAM13A中。次高度相關的第三個SNP也是在這個區域中（P= 1.48 × 10-6）。從COPD基因研究族群重複這項研究發現（502位病患罹患COPD，504位病患控制組）顯示這三個SNPs都與COPD顯著有關，但第三個SNP的關連性仍然最弱。
在獨立的家族為基礎的群體確認頭兩個SNPs的影響發現，一項研究中並沒有這樣的關連性存在，或許是因為年齡對COPD發作與更嚴重的疾病，但在另外一個以家族為基礎的群體卻是高度顯著相關的（P= 1.29 × 10-3與P= 5.15 × 10-4）。合併這六個群體（起始研究的三個群體、重複進行組、以及這兩個以家族為基礎的研究）發現整體的相關性是高度顯著的（P= 9.47 × 10-11與P= 1.22 × 10-11）。
目前我們對於FAM13A的功能了解得不多，雖然非肺組織的細胞培養已經證實缺氧會增加FAM13A的表現。在正常FAM13A的表現方面，相較於輕微的肺囊性纖維化病患，嚴重者的肺細胞表現是有差異的。
沒有參與這項研究的麻州波士頓哈佛公共衛生學院錢尼實驗，環境健康部門教授，同時也是副主任醫師的哈佛醫學院醫學教授Scott T. Weiss醫師評論，吸菸會造成缺氧，這可以解釋。
Weiss醫師透過電子郵件向Medscpe胸腔醫學表示，但是也有其他可能性。或許這些基因牽涉到肺臟發育、或許有獨立於缺氧以外的發炎反應差異。
Cho醫師承認這個變異如何造成COPD，目前我們仍然沒有頭緒。Cho醫師表示，一個更基本的問題是，超過特定變異對COPD的效應是這個基因的主要功能是什麼？之前的研究顯示，對缺氧的反應差異應該給了我們與其他研究者們一個研究的起點。
雖然基因變異在COPD風險扮演部分角色，且找出這些變異增加了我們對這個疾病科學背景的了解，吸菸仍然是最大的危險因子。舉例來說，每年抽10包以上增加COPD風險達10%（勝算比1.5；P= 9.3 × 10-95）。
Cho醫師表示，病患們不應該因為他們可以根據這些研究結果而免於罹患COPD，所有病患都應該妥善地接受戒菸諮詢以及接受適當的藥物輔助戒菸。當我們相信基因變異對了解COPD病理生理學具潛在重要性時，我們目前並未期待任何立即受益於這項發現的臨床介入。
Cho醫師與Weiss醫師表示已無相關資金上的往來。
New Gene Variants Associated With Chronic Obstructive Pulmonary Disease
By Jacquelyn K. Beals, PhD
Medscape Medical News
February 24, 2010 — A genomewide association study combining populations from several earlier studies of pulmonary function has identified a locus on the long arm of chromosome 4 associated with increased susceptibility to chronic obstructive pulmonary disease (COPD). The site is in gene FAM13A, whose variants have been previously linked to pulmonary function. Despite this evidence that greater COPD risk is associated with FAM13A variants, the effects of cigarette smoking far outweigh the genetic influences.
Published online February 21 in Nature Genetics, the study stemmed from observations that COPD prevalence is quite variable among former and current smokers, suggesting that genetic components contribute to COPD susceptibility.
"The effect of this genetic variant and other common variants likely to influence COPD susceptibility are dwarfed by the effect of cigarette smoking on COPD risk," first author Michael H. Cho, MD, MPH, from the Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, told Medscape Pulmonary Medicine in an email.
All patients with COPD (n = 2940) and control patients (n = 1380) in the initial study were current or former smokers. One group was from a case-control genomewide association study investigation in Norway, another from the National Emphysema Treatment Trial (patients with COPD) and the Normative Aging Study (control patients), and a third group from the ECLIPSE Study. All case patients had been diagnosed with moderate to very severe COPD; control patients had normal lung function. Analyses adjusted the case and control groups for age and pack-years of cigarette smoking and found little remaining stratification between the 2 cohorts.
Initial results identified 2 single nucleotide polymorphisms (SNPs) highly associated with COPD (P = 7.18 × 10?8 and P = 8.59 × 10?8), both within FAM13A. The next highest association was for a third SNP within this locus (P = 1.48 × 10?6). Replication in a population from the COPD Gene Study (502 patients with COPD, 504 control patients) demonstrated significant association with COPD for all 3 SNPs, although the third SNP was again the weakest association.
Checking the 2 front-runners in independent family-based cohorts found a lack of association in 1 study, perhaps the result of age at COPD onset and more severe disease, but highly significant association in the other family-based cohort (P = 1.29 × 10?3 and P = 5.15 × 10?4). Combining analysis across all 6 cohorts (3 groups in the initial analysis, the replication group, and both family-based studies) found highly significant association overall (P = 9.47 × 10?11 and P = 1.22 × 10?11).
Not much is known about the function of FAM13A, although cell cultures of nonlung tissues have shown that FAM13A expression increases in hypoxia. Expression of normal FAM13A has also been found to differ in pulmonary cells from patients with severe, as compared with mild, cystic fibrosis.
"Cigarette smoking induces hypoxia, so that fits," commented Scott T. Weiss, MD, professor of medicine, Harvard Medical School; associate physician, Brigham Women's Hospital; and a professor in the Department of Environmental Health, Channing Laboratory, Harvard School of Public Health, Boston, Massachusetts, who was not involved in this study.
"But there are other possibilities as well. Perhaps the gene is involved in lung development, or perhaps there is a differential effect on inflammatory response that is not dependent on hypoxia," Dr. Weiss suggested via email to Medscape Pulmonary Medicine.
Dr. Cho acknowledged that "we don't have any indication yet on how this variant contributes to COPD. A more fundamental question, however, than the effect of the specific variant...on COPD is the primary function of the gene," said Dr. Cho. "The prior studies showing differences in response to hypoxia should give us and others a starting point for investigation."
Although genetic variants play a part in COPD risk, and identifying the variants adds to science'sunderstanding of the disease, cigarette smoking is still the greatest risk factor. For example, every 10 pack-years of smoking increases COPD risk by 50% (odds ratio, 1.5; P = 9.3 × 10?95).
"Patients should not in any way be reassured that they could be protected from the development of COPD based on our results, and all patients should be properly counseled against smoking and receive proper medical assistance to quit smoking. While we believe that this genetic variant is potentially important to understand the pathophysiology of COPD, we do not currently anticipate any clinical interventions to immediately result from this discovery," said Dr. Cho.
Dr. Cho and Dr. Weiss have disclosed no relevant financial relationships.
Nat Genet. Published online February 21, 2010.
