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        高血壓易感基因的分子進化

        2014-05-25 00:33:02季林丹錢海霞徐進2
        遺傳 2014年12期
        關鍵詞:易感性等位基因非洲

        季林丹,錢海霞,徐進2,

        1. 寧波大學醫(yī)學院生物化學系,寧波 315211;

        2. 中國科學院昆明動物研究所遺傳資源與進化國家重點實驗室, 昆明 650223;

        3. 寧波大學醫(yī)學院預防醫(yī)學系,寧波 315211

        高血壓易感基因的分子進化

        季林丹1,2,錢海霞3,徐進2,3

        1. 寧波大學醫(yī)學院生物化學系,寧波 315211;

        2. 中國科學院昆明動物研究所遺傳資源與進化國家重點實驗室, 昆明 650223;

        3. 寧波大學醫(yī)學院預防醫(yī)學系,寧波 315211

        利用家系連鎖分析、候選基因法及全基因組關聯(lián)研究均未能有效發(fā)現(xiàn)普通人群的高血壓易感基因或位點。遺傳學研究表明,人類許多疾病易感性的形成與走出非洲時的環(huán)境適應性進化密切相關,這為高血壓遺傳學研究提供了新思路。文章系統(tǒng)綜述了高血壓易感基因分子進化研究的理論基礎和最新進展,介紹了本研究小組運用分子進化思路在中國漢族人群高血壓遺傳學研究中的發(fā)現(xiàn),對未來的研究方向進行了展望,以期為高血壓和其他疾病的遺傳學研究提供參考。

        高血壓;遺傳易感性;進化;適應

        原發(fā)性高血壓(Essential hypertension, EH)是一種以血壓升高為主要臨床表現(xiàn)而病因尚未明確的獨立疾病,約占所有高血壓的90%~95%。在遺傳和環(huán)境因素的共同影響下,EH已經(jīng)成為危害人類健康的世界性公共衛(wèi)生問題[1,2]。在發(fā)達國家,超過1/4的成年人患有高血壓;據(jù)世界衛(wèi)生組織估計,到2020年全球高血壓患者將超過15億人[3]。我國曾進行了4次大規(guī)模高血壓流行病學調(diào)查,高血壓的患病率從50年代的5.11%增加至2002年的18.8%,并且呈現(xiàn)出明顯的低齡化趨勢。據(jù)衛(wèi)生部估計,我國高血壓患病人數(shù)已經(jīng)超過 2億,每年高血壓的直接醫(yī)療費用高達 300億元人民幣,與高血壓相關的心腦血管疾病耗費更是達到3000億元人民幣[4]。由此可見,高血壓已經(jīng)嚴重影響了中國及全球諸多國家的經(jīng)濟發(fā)展、社會穩(wěn)定和居民生活質(zhì)量。

        為了更好地開展高血壓及相關心血管疾病的防治工作,國內(nèi)外研究人員對高血壓的遺傳病因進行了大量研究。家系研究提示收縮壓和舒張壓具有較高的遺傳度(31%~68%)[5],可是在封閉家系研究中發(fā)現(xiàn)的少數(shù)“高血壓基因”,在普通人群中卻很難證實與高血壓具有相關性[6]。在家系連鎖分析無法取得突破時,研究人員開始采用大樣本病例-對照研究對大量的候選基因進行篩選[7],但不同的研究小組往往得到不同的結果,目前尚無被廣泛接受的高血壓遺傳易感位點[8,9]。隨著芯片技術的飛速發(fā)展,全基因組關聯(lián)研究(Genome-wide association study, GWAS)廣泛地應用于高血壓等復雜疾病的遺傳學研究。截至2014年5月,已發(fā)表20多項與血壓性狀或高血壓相關的GWAS(http://www.genome.gov/gwastudies/)。對國際上主要的幾個高血壓 GWAS[10~12]進行 meta分析后,得到數(shù)個單核苷酸多態(tài)性(Single nucleotide polymorphism, SNP)與血壓性狀或高血壓相關,但這些SNP僅僅貢獻了1%~2%的遺傳度[12~14]。雖然GWAS通過全基因組SNP系統(tǒng)掃描避免了偏倚并減少了假陽性,但多重統(tǒng)計檢驗及嚴格的校正也降低了其檢出真實信號的效能[15]。以往連鎖分析和候選基因法得到的“高血壓易感SNP”極少在這些高血壓GWAS中被檢出,不同GWAS之間的陽性結果也很少有重疊,大樣本人群對GWAS結果的驗證大部分以失敗而告終[9,16,17]。目前商業(yè)化的 SNP芯片主要依據(jù)高加索人群的遺傳多態(tài)性進行設計,考慮到不同人群遺傳背景的差異,將其直接應用于非洲或亞洲人群時可能存在較大偏倚[18]。利用家系連鎖分析、病例-對照候選基因法及 GWAS,依舊不能有效地發(fā)現(xiàn)普通人群的高血壓易感基因或位點[19,20]。正是這些困難的存在,需要人們對高血壓遺傳學的研究策略做出調(diào)整,嘗試從不同的角度開展研究。

        1 人類走出非洲與“節(jié)儉基因假說”

        根據(jù)化石、古人類DNA和現(xiàn)代人DNA等證據(jù),解剖學上的現(xiàn)代人(Anatomically modern human, AMH),即智人(Homo sapiens)大約于20萬年前起源于非洲[21~23]。大約在10萬年前,非洲人從東非走出非洲,隨后遷徙至世界各地定居生存[24~26]。在歷史遷徙過程中,對不同環(huán)境選擇壓力的廣泛適應形成了今天人類的遺傳多樣性,而這些遺傳多樣性又與不同人群的表型和疾病易感性差異密切相關[27~35]。隨著人類學、流行病學、遺傳學等研究領域的不斷發(fā)展,科研人員開始從分子進化角度對人類的疾病易感性展開研究[36~39]。

        1962年,美國密歇根大學的人類遺傳學家James V. Neel教授從生物進化的角度對人類肥胖和糖尿病等問題進行了分析,首次提出了“節(jié)儉基因假說”(The thrifty gene hypothesis)[40,41]。該假說認為:在采集-狩獵型社會和農(nóng)業(yè)社會初期,人們經(jīng)常受到食物短缺或饑荒的威脅。人類的祖先為了適應當時食物缺乏的環(huán)境,逐漸進化出能有效儲存能量的能力,以提高自身生存的機會。經(jīng)過長期的適應過程,那些能夠在進食后較多地將食物能量儲存起來的個體因為其較易耐受長期饑餓而存活下來,那些能有效控制能量儲存的基因就叫做“節(jié)儉基因”。因此,節(jié)儉基因在食物貧瘠的時代,對人類的生存和種族繁衍具有重要作用。隨著社會經(jīng)濟的發(fā)展,食物獲取不再困難,甚至出現(xiàn)了過剩的現(xiàn)象,這些曾經(jīng)有利的節(jié)儉基因反而成了肥胖和糖尿病等疾病的易感基因。

        2 “走出非洲”的環(huán)境溫度適應與高血壓易感性

        在非洲炎熱的環(huán)境中,人體主要通過大量出汗來維持體溫恒定,當時的非洲人出汗量最高時可達2 L/h[42]。大量出汗導致鈉鹽流失,而在非洲熱帶氣候中鈉鹽的供給又非常少。因此,機體需要極力阻止鈉鹽的流失以維持正常的生理功能。熱帶環(huán)境中生活的人類及其他靈長類動物均有很強的鈉鹽親和性,為這個假說提供了很好的證據(jù)。大量出汗還會造成夜間血容量不足,從而導致動脈張力和心肌收縮增強以維持正常的血液供應[43]。因此,那些能增強鈉鹽保留及動脈、心肌收縮性的基因變異能幫助早期非洲人適應當?shù)匮谉岬臍夂颦h(huán)境。

        大約在10萬年前,我們的祖先從東非出發(fā),經(jīng)過幾萬年的遷徙,在世界各地繁衍生息。在走出非洲的過程中,氣溫和環(huán)境濕度也發(fā)生了巨大的變化,人體的氣候環(huán)境適應需求也發(fā)生改變,如適應寒冷氣候人群的需求從散熱逐步轉變?yōu)楸E痆44],不需要過多的鈉潴留,血管反應性也開始降低[45]。因此,在走出非洲的過程中,鈉鹽親和力及動脈、心肌收縮性的選擇壓力也發(fā)生變化以適應當?shù)氐纳鏆夂颦h(huán)境。隨著近代工業(yè)發(fā)展和交通便利,出現(xiàn)了頻繁的大規(guī)模地域間移民。適應世代居住環(huán)境并相對穩(wěn)定的遺傳背景與移民后新的生活環(huán)境之間的矛盾將可能導致諸多疾病的產(chǎn)生,而不同的鈉鹽親和力與血管反應性也可能造成不同人群在同一生活環(huán)境中高血壓的易感性差異。如美國第3次全國健康與營養(yǎng)調(diào)查發(fā)現(xiàn):在現(xiàn)有美國居民中,與歐洲移民后代相比,非洲移民的后代更容易發(fā)生高血壓,而且發(fā)病趨于低齡化,病情更嚴重[46,47]。因此,Young等[29]提出人群間不同的高血壓易感性可能與人類走出非洲時經(jīng)歷了不同氣候進化選擇的遺傳背景相關。

        為了驗證這個觀點,3個研究小組分別對AGT、CYP3A5和 GNB3等與血壓調(diào)控密切相關的基因進行了自然選擇分析。與高鈉鹽親和力密切相關的AGT-6A、CYP3A5*1和GNB3 825T等祖先等位基因頻率與緯度均存在顯著的負相關性。這些祖先等位基因在赤道附近的非洲人群中具有較高的頻率;而走出非洲后,能降低鈉鹽親和力的衍生等位基因的頻率顯著增高[29,48,49]。對AGT-6G和GNB3 825C這兩個衍生等位基因的鄰近序列分析發(fā)現(xiàn),它們兩側存在廣泛的連鎖不平衡和較少的單倍型[29,48]。這些證據(jù)都證明了這3個多態(tài)位點中能降低鈉鹽親和性的衍生等位基因頻率在環(huán)境正選擇作用下逐漸升高,以適應走出非洲后相對寒冷的生存環(huán)境。適應古老環(huán)境并且相對穩(wěn)定的遺傳背景很難在進化尺度上很短的時間內(nèi)(比如近代的人群遷徙、定居)重新快速適應移民后的新環(huán)境,從而使得人群的遺傳背景與生活環(huán)境產(chǎn)生了偏差。因此,在近代人類移居到寒冷環(huán)境時,能降低鈉鹽親和性的衍生等位基因受到正選擇,而那些適應了炎熱氣候的祖先等位基因就可能成了“有害”的高血壓遺傳易感位點[50]。雖然這方面研究目前僅涉及上述 3個基因,但為高血壓的遺傳學研究提供了新的思路。

        3 中國人群環(huán)境溫度適應與高血壓易感性研究

        中國科學院昆明動物研究所張亞平院士領導的研究小組和復旦大學金力院士領導的研究小組分別通過線粒體DNA、Y染色體和全基因組遺傳多態(tài)性研究,發(fā)現(xiàn)走出非洲的現(xiàn)代人類祖先約于 1.8~6萬年前首先擴散到東南亞大陸,隨后向北方擴張和遷移,因此中華民族起源于南方[24,51~54]。我國的高血壓流行病學調(diào)查顯示,北方地區(qū)的患病率要高于南方,中部地區(qū)居中[4]。上述流行病學調(diào)查數(shù)據(jù)及東亞人群的南方起源和史前北遷歷史提示我國不同地區(qū)人群高血壓的易感性差異也很可能與氣候環(huán)境密切相關。相較于全球人群,中國人群遺傳背景相對均一,但人群居住地域廣闊、居住地氣候環(huán)境復雜多樣,因此通過分子進化研究很有可能發(fā)現(xiàn)中國人群高血壓的真正致病基因及易感位點。

        本研究小組從CEPH-HGDP數(shù)據(jù)庫中獲取了腎素-血管緊張素-醛固酮系統(tǒng)(Renin-angiotensin-aldosterone system, RAAS)的 AGT、ACE、AGTR1、AGTR2、CYP11B2和REN等6個基因共241個SNP,進行環(huán)境因素的Pearson關聯(lián)分析、多元線性回歸分析和進化分析(FST、iHS),發(fā)現(xiàn)有5個SNP在亞洲人群中與環(huán)境溫度適應相關,且均位于AGTR1基因。通過大樣本中國漢族人群的原發(fā)性高血壓病例-對照研究,發(fā)現(xiàn)其中的2個SNP與高血壓的易感性密切相關。如圖1所示,該項研究中發(fā)現(xiàn)的與溫度適應相關且增加高血壓患病風險的SNP1的C等位基因和SNP2的A等位基因在非洲人群中都是高頻等位基因,而在歐洲和亞洲人群中則是低頻等位基因,這也說明了在近代人類移居到寒冷環(huán)境時,那些適應了炎熱氣候的祖先等位基因就可能成了“有害”的高血壓遺傳易感位點。目前本研究小組正從全基因組水平篩選受環(huán)境溫度選擇的 SNP,并明確其與高血壓的相關性及作用機理。

        圖1 環(huán)境溫度與高血壓易感等位基因頻率的相關性與高血壓易感性密切相關的AGTR1基因SNP1 C和SNP2 A等位基因頻率與環(huán)境溫度存在顯著的正相關性。

        該項研究中,RAAS基因受環(huán)境溫度進化選擇的所有 SNP均落在編碼 1型血管緊張素 II受體的AGTR1基因上,且其中兩個SNP與高血壓相關并非偶然。血管緊張素受體主要有4種類型,其中在人體中以1型受體(Angiotensin type 1 receptor, AT1)和2型受體(AT2)為主。人體內(nèi)參與血壓調(diào)控主要是AT1,它的激活可引起血管收縮、腎小管重吸收鈉增加和心臟收縮能力增強[55,56]。正是血管緊張素受體在血壓調(diào)控中的重要作用,血管緊張素受體拮抗劑已成為血管緊張素轉換酶抑制劑后的最新一代的治療高血壓臨床用藥[57]。血管緊張素受體在高血壓病理生理過程中的重要作用與本研究的結果相互印證,既說明AGTR1基因很可能是原發(fā)性高血壓的易感基因,也說明從分子進化角度來研究高血壓的遺傳易感性具有重要的意義。

        4 展 望

        不同的氣候環(huán)境(溫度、濕度、降水等)對居住人群產(chǎn)生了不同選擇壓力。而近代頻繁的國際間移民,使得遺傳背景與居住環(huán)境之間產(chǎn)生偏差從而導致了疾病的易感性差異。類似的進化研究思路已經(jīng)在人類體型大小、皮膚色素沉著和代謝疾病的研究中得到了很好的證實和應用[37,58~60]。由此可見,從進化選擇角度來探索高血壓的遺傳易感性可能為高血壓遺傳學研究提供了新的切入點。

        此外,疾病易感等位基因的地理分布或流行性顯得尤為重要。通過探索這些疾病易感基因(或位點)的群體遺傳學、分子進化史等,如不同地域人群中的等位基因頻率、等位基因的亞群體分化、群體歷史,和鄰近位點的連鎖不平衡等信息對于理解這些疾病易感基因的起源和人類進化歷史非常重要。因而,從疾病易感基因(或位點)的分子起源角度來研究臨床疾病可能為今后的研究提供一種新的、行之有效的思路。

        [1] The Lancet. Hypertension: an urgent need for global control and prevention. Lancet, 2014, 383(9932): 1861.

        [2] James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC Jr, Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr, Narva AS, Ortiz E. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA, 2014, 311(5): 507-520.

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        (責任編委: 趙彥艷)

        The evolutionary study of susceptibility genes for essential hypertension

        Lindan Ji1,2, Haixia Qian3, Jin Xu2,3

        1. Department of Biochemistry, School of Medicine, Ningbo University, Ningbo 315211, China;
        2. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China;
        3. Department of Preventive Medicine, School of Medicine, Ningbo University, Ningbo 315211, China

        Genetic studies, including familial linkage analysis, candidate gene approach and genome-wide association study, to some extent, have failed in detecting confirmative susceptibility genes/loci for essential hypertension (EH) in the general population. Previous genetic studies have suggested that differential susceptibility to many metabolic diseases is due to different environmental adaptation patterns during the out-of-Africa expansion, which provides a new strategy for the genetic study of EH. In this review, we introduce the principle and the latest progress of evolutionary study of susceptibility genes for EH. Furthermore, our recent evolutionary screening for EH susceptible genes/loci in Chinese Han population is also summarized. This review is expected to provide useful information for future genetic studies of EH and many other diseases.

        essential hypertension; genetic susceptibility; evolution; adaptation

        2014-08-20;

        2014-09-15

        國家自然科學基金項目(編號:81402747)和浙江省自然科學基金項目(編號:LQ13C060001)資助

        季林丹,博士后,講師,研究方向:分子進化與疾病遺傳學。E-mail: jilindan@nbu.edu.cn

        徐進,副教授,碩士生導師,研究方向:分子進化與疾病遺傳學。E-mail: xujin1@nbu.edu.cn

        10.3724/SP.J.1005.2014.1195

        時間: 2014-9-24 14:08:02

        URL: http://www.cnki.net/kcms/detail/11.1913.R.20140926.1342.003.html

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