與兒童時期氣喘有關的全新基因
作者：Fran Lowry
出處：WebMD醫學新聞
December 23, 2009 — 根據一項線上發表於12月23日新英格蘭醫學期刊的研究結果，一個與中重度兒童時期氣喘有關的全新基因可能代表新的治療標的。
這個稱為DENND1B的基因，位於第一對染色體上，影響細胞與訊息傳遞，這被認為在氣喘免疫系統過度反應扮演部分角色。
資深作者、賓州費城兒童醫院應用基因體中心的Hakon Hakonarson醫師在新聞稿中表示，透過分析罹患中重度氣喘兒童族群，這些病患都需要常規使用控制藥物，我們加強這項研究的基因訊號、以及達到足夠的統計力量來揭開及複製一個全新的氣喘基因。
我們現在知道DENND1B基因及其蛋白質牽涉到細胞激素的釋放，這些都是在這個情況下告訴身體如何回應外在物質的訊息傳遞分子。這些物質許多都是廣為人知的誘發氣喘物質。
基因學家相信，許多基因大部分仍然是未被發現的，與其他及環境因子作用造成氣管過度敏感性與發炎，造成與氣喘有關的哮喘、咳嗽、呼吸急促。氣喘的異質性在不同病患身上造成不同的表徵，且在兒童與成人時期發作的氣喘有不同的病徵。
Hakonarson醫師表示，DENND1B基因突變顯然造成細胞激素過度產生，且接著驅使氣喘患者的過度敏感反應。
基因組關連研究（GWAS）使用自動化基因比對工具掃描整個人類基因體，並找出與疾病風險有關的基因變異，過去曾經確認出一個與氣喘感受性有關的基因，ORMDL3，位於第17對染色體。
目前這項研究針對793位罹患持續性氣喘、需要每天使用吸入性類固醇的北美兒童，以及1988位沒有氣喘的控制組兒童，比較這兩組的GWAS發現。研究者們在另外2,400位白人兒童，其中917位罹患氣喘，1,546位為控制組，還有第三組3,700位黑人兒童重複確認他們的發現。
除了確認有關於第17對染色體上ORMDL3的發現之外，研究者們還另外找出了8個單一核苷酸位於染色體1q31新位置強烈地與氣喘有關。黑人與白人兒童試驗樣本都具有相同氣喘敏感性基因。
這項研究的限制包括無法區分DENND1B發生年齡與對嚴重度影響之間的關係。
DENND1B基因位於染色體1q31，現在被確認為氣喘的基因危險因子，過去被認為與免疫反應有關，因為DENND1B蛋白在特定樹突細胞與T淋巴球，包括自然殺手細胞中是有活性的。
透過抗原表現突觸，這些調控免疫反應對於外來物質，例如病毒、細菌以及過敏原的免疫細胞亞型。與腫瘤壞死因子阿法受體作用的DENND1B蛋白因而是影響這個訊息傳遞路徑，治療氣喘新藥的一個潛在治療標的。
Hakonarson醫師的結論是，因為這些基因看起來調控許多不同的細胞激素，介入這個路徑對於治療氣喘有很大的潛力。其他與氣喘有關的基因仍需要進一步釐清，但是發現一條以這個常見基因變異為標的的方法將可以使許多兒童受益。
賓州費城兒童醫院、Cotswold基金會、Lundbeck基金會、國家衛生研究院贊助這項研究。試驗作者們表示已無相關資金上的往來。
Novel Gene Linked to Childhood-Onset Asthma
By Fran Lowry
Medscape Medical News
December 23, 2009 — A novel gene linked to moderate-to-severe childhood-onset asthma may suggest new therapeutic targets, according to the results of a study reported online December 23 in the New England Journal of Medicine.
The DENND1B gene, located on chromosome 1, affects cells and signaling molecules thought to play a key role in immune system hyperactivity seen in asthma.
"By analyzing a large cohort of children with moderate to severe asthma, all of whom require controller medications on a regular basis, we managed to enrich our study for genetic signals and achieve sufficient statistical power to uncover and replicate a novel asthma gene," senior author Hakon Hakonarson, MD, PhD, from the Center for Applied Genomics at the Children's Hospital of Philadelphia, Pennsylvania, said in a news release.
"We now know that the DENND1B gene and its protein are involved in the release of cytokines, which are signaling molecules that in this case tell the body how it should respond to foreign particles. Many of these particles are well-known triggers of asthma."
Geneticists believe that a large number of genes, most of which are still undiscovered, interact with each other and with environmental factors to produce airway hyperresponsiveness and inflammation, resulting in wheezing, coughing, and shortness of breath associated with asthma. The heterogeneity of asthma results in different presentations in different patients and in different manifestations in childhood-onset vs adult-onset asthma.
"The gene mutations in DENND1B appear to lead to overproduction of cytokines that subsequently drive this oversensitive response in asthma patients," Dr. Hakonarson said.
Genomewide association study (GWAS), which uses automated genotyping tools to scan the entire human genome and to identify gene variants contributing to disease risk, previously identified only 1 other asthma-susceptibility gene, ORMDL3, located on chromosome 17.
The present study compared GWAS findings in 793 white North American children with persistent asthma requiring daily inhaled glucocorticoid therapy with those in a control group of 1988 children without asthma. The investigators replicated their findings in a separate group of 2400 white children with asthma (n = 917) and controls (n = 1546), as well as in a third group of 3700 black children.
In addition to confirming findings regarding ORMDL3 on chromosome 17, the investigators identified 8 single nucleotide polymorphisms associating robustly with asthma in a new location on chromosome 1q31. The same gene for asthma susceptibility was present in study samples from both white and black children.
Limitations of this study include the inability to differentiate a genetic effect of DENND1B on age of onset from an effect on severity.
The DENND1B gene on chromosome 1q31, now identified as a genetic risk factor for asthma, was previously implicated in the immune response because the DENND1B protein is active in specific dendritic cells and T lymphocytes, including natural killer cells.
Via the antigen-presenting synapse, cross-talks between these immune cell subtypes regulate immune response to foreign particles including viruses, bacteria, and allergens. DENND1B protein, which interacts with the tumor necrosis factor alpha receptor, is therefore a potential therapeutic target for development of new asthma drugs affecting this signaling pathway.
"Because this gene seems to regulate many different cytokines, intervening in this pathway has great potential for treating asthma," Dr. Hakonarson concluded. "Other asthma-related genes remain to be discovered, but finding a way to target this common gene variant could benefit large numbers of children."
The Children's Hospital of Philadelphia, the state of Pennsylvania, the Cotswold Foundation, the Lundbeck Foundation, and the National Institutes of Health supported this study. The study authors have disclosed no relevant financial relationships.
N Engl J Med. Published online December 23, 2009.
