與缺血性中風有關的基因變化

作者：Jacquelyn K. Beals, PhD  
出處：WebMD醫學新聞

　　April 16, 2009 — 一篇回溯族群基礎研究發現人類第12染色體NINJ2基因附近的變化，與缺血性中風風險有強烈關聯。在大型白人世代發現與缺血性中風有顯著關聯之基因組的兩個單核甘酸多型性(SNPs)中，一個SNP在荷蘭與黑人參與者中獲得再度確認。
　　
　　波士頓大學醫學院神經科副教授Sudha Seshadri醫師以電子郵件向Medscape Neurology & Neurosurgery表示，他們也計畫對包括中國人、台灣人、新加坡人與南亞族群進行研究。
　　
　　在雙胞胎與家族研究中發現與中風有關的基因因素，但在一般族群並未發現與中風有關的基因因素。這篇發表於4月15日新英格蘭醫學期刊的研究，指出以往未曾發現過的特定基因與發生中風的關聯。
　　
　　荷蘭與美國的科學家對已發現的樣本—Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)研究中、4個世代共19,602名自我描述的白人樣本—追蹤平均11年。基因組的顯著閾值為P < 5 × 10-8；分析僅限於這4個世代中，共通的200萬個以上的自體SNPs。
　　
　　中風被分類為缺血性、出血性或自發性。缺血性中風次分類為粥狀動脈栓塞性(因為粥狀動脈硬化導致腦血管血栓)或者心因性(因為心臟方面的血栓或血塊有關的腦血管阻塞)。
　　
　　在這19,602名病患中，1,544人於觀察期間發生中風，其中1,164人確認為缺血性中風。只有在第12染色體的兩個SNP顯示與整體中風(SNP rs11833579: P = 4.8 × 10-9; rs12425791: P = 1.5 × 10-8)和缺血性中風(SNP rs11833579: P = 2.3 × 10-10; rs12425791: P = 2.6 × 10-9)有顯著的基因組關聯；這兩個SNP與非缺血性中風都沒有顯著關聯(兩者之P = .20)。
　　
　　兩個SNP都顯示與粥狀動脈栓塞症中風有比整體缺血性中風有更強烈的關聯。rs12425791的整體中風風險比為1.30 (粥狀動脈栓塞性中風95% 信心區間[CI]為1.19 – 1.42)，至於缺血性中風為1.33 (95% CI, 1.21 – 1.47)、粥狀動脈栓塞性中風為1.37 (95% CI, 1.23 – 1.54)。 而rs11833579也有類似的數據。
　　
　　邁阿密大學Miller醫學院神經科主席Ralph L. Sacco醫師於電子郵件中向Medscape Neurology & Neurosurgery表示，有關此基因變化[rs12425791]如何引起缺血性中風的可能性還未能定論。如作者所指出的，本研究顯示出強烈關聯，他們發現的特定SNP也可能不是原因所在。
　　
　　在三組再現世代中，兩個SNP基因型都與中風風險有關：
　　* 2,430名自我報告無中風風險的黑人參與者中；在15年追蹤期間，這組發生了共215例中風，191例為缺血性；這些缺血性中風之中有153例為粥狀動脈硬化性。
　　* 574名自我報告無中風風險的黑人參與者中；85人在追蹤期間發生中風，68例為缺血性；這些缺血性中風之中有57例為粥狀動脈硬化性。
　　* 652名荷蘭白人中風病患案例控制樣本與3,613名年齡相仿的控制組病患中，案例組其中501人為缺血性；這些缺血性中風之中有400例為粥狀動脈硬化性。
　　
　　在黑人族群中，rs12425791與中風、缺血性中風、粥狀動脈硬化中風有顯著關聯(P值分別為P = .04; P = .02; and P = .04)；而此一族群中，rs11833579與中風風險無關聯。在樣本較少的黑人族群中，兩個SNP都與中風風險無關。在荷蘭族群中，rs12425791與中風、缺血性中風、粥狀動脈硬化中風有關聯(P值分別為P = .03; P = .04; and P = .005)；rs11833579與粥狀動脈硬化中風有顯著關聯(P = .05)。
　　
　　NINJ2是最靠近中風相關SNP的基因。它的基因產物ninjurin 2屬於神經損傷誘導蛋白質，是受到神經損傷所誘導。作者認為ninjurin2 表現程度會影響腦部對缺血現象的耐受度。
　　
　　Seshadri醫師指出，以前研究的基因多數是與血管損傷、加速粥狀硬化、引起高血壓或增加血栓風險等有關的候選基因，也就是，這些基因會引起缺血。雖然NINJ2 的角色依舊是推論，我們認為這個基因和其他已經發現的基因與對缺血和損傷的反應有關。
　　
　　Sacco醫師觀察發現，這類研究點出了以往未曾考慮過的病理路徑。他表示，這不是首次讓我們對疾病分類方法再度思考的基因結果。基因風險評估有助於我們再度釐清風險，可以促成行為改變或者更早的藥物介入。
　　
　　他表示，此類研究大有幫助，不過，我們不能忘記風險因素控制與生活型態調整對大眾在幫助預防心血管疾病和中風方面的好處，這與基因風險無關。
　　
　　Seshadri醫師與 Sacco醫師都宣稱沒有相關財務關係。

Genetic Variant Associated With Ischemic Stroke

By Jacquelyn K. Beals, PhD
Medscape Medical News

April 16, 2009 — A prospective population-based study has found variants near gene NINJ2, on human chromosome 12, to be strongly associated with risk for ischemic stroke. Of the 2 single nucleotide polymorphisms (SNPs) with genomewide significance associated with ischemic stroke in the large white discovery cohort, 1 SNP was further validated in individual replication samples with white Dutch and black participants.

Sudha Seshadri, MD, associate professor, Department of Neurology, Boston University School of Medicine, Massachusetts, told Medscape Neurology and Neurosurgery via email that they also "plan to study Asians and are collaborating with Chinese, Taiwanese, Singapore, [and] South Asian groups."

Genetic factors in stroke incidence are evident in twin and family studies, but no genes for stroke risk had been identified in the general population. The present study, published online April 15 in the New England Journal of Medicine, demonstrates a "previously unsuspected association" between specific loci and incident stroke.

Scientists in the Netherlands and the United States followed discovery sample participants — 19,602 self-described white individuals from 4 cohorts forming the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) — for an average of 11 years. The threshold for genomewide significance was P < 5 × 10?8; analysis was "limited" to more than 2 million autosomal SNPs common to all 4 cohorts.

Strokes were classified as ischemic, hemorrhagic, or idiopathic. Ischemic strokes were subtyped as atherothrombotic (a blood clot in a cerebral vessel already affected by atherosclerosis) or cardioembolic (cerebral vessels blocked with a clot or other debris of cardiac origin).

Of the 19,602 participants, 1544 suffered strokes during the observation period, 1164 of which were defined as ischemic. Only 2 SNPs, both on chromosome 12, demonstrated significant genomewide association with risk for total stroke (SNP rs11833579: P = 4.8 × 10?9; rs12425791: P = 1.5 × 10?8) and ischemic stroke (SNP rs11833579: P = 2.3 × 10?10; rs12425791: P = 2.6 × 10?9). Neither SNP was significantly associated with nonischemic stroke (P = .20 for each).

Both SNPS showed stronger associations with atherothrombotic strokes than with ischemic strokes overall. The rs12425791 hazard ratio for total stroke was 1.30 (95% confidence interval [CI], 1.19 – 1.42), for ischemic stroke it was 1.33 (95% CI, 1.21 – 1.47), and for atherothrombotic stroke it was 1.37 (95% CI, 1.23 – 1.54). Similar values were obtained for rs11833579.

"It is probably still too early to know how and if this genetic variant [rs12425791] may cause ischemic stroke," said Ralph L. Sacco, MD, FAAN, FAHA, chairman, Department of Neurology, Miller School of Medicine, University of Miami, Florida, in email comments to Medscape Neurology and Neurosurgery. "The study shows a strong signal of association and, as the authors point out, the specific SNP they found may not even be the causal variant," he said.

Individuals in 3 replication cohorts were genotyped for both SNPs associated with stroke risk:

A stroke-free group of 2430 self-identified black participants; during a 15-year follow-up, the group experienced 215 total strokes, 191 of which were ischemic; 153 of these ischemic strokes were atherothrombotic.
A stroke-free group of 574 self-identified black participants; 85 experienced stroke during follow-up, 68 of which were ischemic; 57 of these ischemic strokes were atherothrombotic.
A case-control sample of 652 white Dutch participants with stroke (501 of which were ischemic; 400 of these ischemic strokes were atherothrombotic) and 3613 age-matched control participants.
rs12425791 was significantly associated with the risk for stroke, ischemic stroke, and atherothrombotic stroke (P = .04; P = .02; and P = .04, respectively) in the larger black group; no association was demonstrated between rs11833579 and stroke risk in this group. Neither SNP was associated with stroke risk in the smaller black sample. In the Dutch group, rs12425791 was associated with risk for stroke, ischemic stroke, and atherothrombotic stroke (P = .03; P = .04; and P = .005, respectively); rs11833579 was significantly associated with atherothrombotic stroke (P = .05).

NINJ2 is the gene nearest the stroke-associated SNPs. Its gene product, ninjurin 2, belongs to the "nerve-injury-induced protein" family and is inducible by injury to nerves. The authors suggest that ninjurin2 expression levels might affect "how the brain tolerates ischemic insults."

"Most genes previously studied as 'candidate genes' were ones that damaged vessels, accelerated atherosclerosis, caused a high blood pressure or increased risk of clotting," noted Dr. Seshadri. "[T]hat is, they were genes causing ischemia." Although the exact role of NINJ2 is still speculative, "we think this and other yet-to-be-discovered genes may determine response to ischemia and injury," she said.

Dr. Sacco observed that such discovery studies can point to pathogenetic pathways not previously considered. "[I]t would not be the first time that we had genetic results causing us to rethink our classification of disease approaches," he said. "Genetic risk assessment will hopefully refine our estimate of risk, improve earlier detection, and could motivate behavioral change or lead to earlier pharmacological interventions.

"[S]tudies like this are helping greatly," he said. However, "We cannot forget about the benefits of risk factor control and lifestyle modification for wider segments of our population, regardless of genetic risk, to help prevent cardiovascular disease and stroke," Dr. Sacco concluded.

Dr. Seshadri and Dr. Sacco have disclosed no relevant financial relationships.

N Engl J Med. 2009;360:1718–1728.