高血壓易感基因的分子進(jìn)化

季林丹，錢海霞，徐進(jìn)2,

1. 寧波大學(xué)醫(yī)學(xué)院生物化學(xué)系，寧波 315211；

2. 中國(guó)科學(xué)院昆明動(dòng)物研究所遺傳資源與進(jìn)化國(guó)家重點(diǎn)實(shí)驗(yàn)室, 昆明 650223；

3. 寧波大學(xué)醫(yī)學(xué)院預(yù)防醫(yī)學(xué)系，寧波 315211

高血壓易感基因的分子進(jìn)化

季林丹1,2，錢海霞3，徐進(jìn)2,3

1. 寧波大學(xué)醫(yī)學(xué)院生物化學(xué)系，寧波 315211；

2. 中國(guó)科學(xué)院昆明動(dòng)物研究所遺傳資源與進(jìn)化國(guó)家重點(diǎn)實(shí)驗(yàn)室, 昆明 650223；

3. 寧波大學(xué)醫(yī)學(xué)院預(yù)防醫(yī)學(xué)系，寧波 315211

利用家系連鎖分析、候選基因法及全基因組關(guān)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(diǎn)。遺傳學(xué)研究表明，人類許多疾病易感性的形成與走出非洲時(shí)的環(huán)境適應(yīng)性進(jìn)化密切相關(guān)，這為高血壓遺傳學(xué)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(jìn)化研究的理論基礎(chǔ)和最新進(jìn)展，介紹了本研究小組運(yùn)用分子進(jìn)化思路在中國(guó)漢族人群高血壓遺傳學(xué)研究中的發(fā)現(xiàn)，對(duì)未來的研究方向進(jìn)行了展望，以期為高血壓和其他疾病的遺傳學(xué)研究提供參考。

高血壓；遺傳易感性；進(jìn)化；適應(yīng)

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(dú)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(dá)國(guó)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(jì)，到2020年全球高血壓患者將超過15億人[3]。我國(guó)曾進(jìn)行了4次大規(guī)模高血壓流行病學(xué)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(shì)。據(jù)衛(wèi)生部估計(jì)，我國(guó)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(fèi)用高達(dá) 300億元人民幣，與高血壓相關(guān)的心腦血管疾病耗費(fèi)更是達(dá)到3000億元人民幣[4]。由此可見，高血壓已經(jīng)嚴(yán)重影響了中國(guó)及全球諸多國(guó)家的經(jīng)濟(jì)發(fā)展、社會(huì)穩(wěn)定和居民生活質(zhì)量。

為了更好地開展高血壓及相關(guān)心血管疾病的防治工作，國(guó)內(nèi)外研究人員對(duì)高血壓的遺傳病因進(jìn)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(shí)與高血壓具有相關(guān)性[6]。在家系連鎖分析無法取得突破時(shí)，研究人員開始采用大樣本病例-對(duì)照研究對(duì)大量的候選基因進(jìn)行篩選[7]，但不同的研究小組往往得到不同的結(jié)果，目前尚無被廣泛接受的高血壓遺傳易感位點(diǎn)[8,9]。隨著芯片技術(shù)的飛速發(fā)展，全基因組關(guān)聯(lián)研究(Genome-wide association study, GWAS)廣泛地應(yīng)用于高血壓等復(fù)雜疾病的遺傳學(xué)研究。截至2014年5月，已發(fā)表20多項(xiàng)與血壓性狀或高血壓相關(guān)的GWAS(http://www.genome.gov/gwastudies/)。對(duì)國(guó)際上主要的幾個(gè)高血壓 GWAS[10～12]進(jìn)行 meta分析后，得到數(shù)個(gè)單核苷酸多態(tài)性(Single nucleotide polymorphism, SNP)與血壓性狀或高血壓相關(guān)，但這些SNP僅僅貢獻(xiàn)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(jì)檢驗(yàn)及嚴(yán)格的校正也降低了其檢出真實(shí)信號(hào)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(jié)果也很少有重疊，大樣本人群對(duì)GWAS結(jié)果的驗(yàn)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(jìn)行設(shè)計(jì)，考慮到不同人群遺傳背景的差異，將其直接應(yīng)用于非洲或亞洲人群時(shí)可能存在較大偏倚[18]。利用家系連鎖分析、病例-對(duì)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(diǎn)[19,20]。正是這些困難的存在，需要人們對(duì)高血壓遺傳學(xué)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(xué)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(duì)不同環(huán)境選擇壓力的廣泛適應(yīng)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(guān)[27～35]。隨著人類學(xué)、流行病學(xué)、遺傳學(xué)等研究領(lǐng)域的不斷發(fā)展，科研人員開始從分子進(jìn)化角度對(duì)人類的疾病易感性展開研究[36～39]。

1962年，美國(guó)密歇根大學(xué)的人類遺傳學(xué)家James V. Neel教授從生物進(jìn)化的角度對(duì)人類肥胖和糖尿病等問題進(jìn)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(rèn)為：在采集-狩獵型社會(huì)和農(nóng)業(yè)社會(huì)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(yīng)當(dāng)時(shí)食物缺乏的環(huán)境，逐漸進(jìn)化出能有效儲(chǔ)存能量的能力，以提高自身生存的機(jī)會(huì)。經(jīng)過長(zhǎng)期的適應(yīng)過程，那些能夠在進(jìn)食后較多地將食物能量?jī)?chǔ)存起來的個(gè)體因?yàn)槠漭^易耐受長(zhǎng)期饑餓而存活下來，那些能有效控制能量?jī)?chǔ)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(shí)代，對(duì)人類的生存和種族繁衍具有重要作用。隨著社會(huì)經(jīng)濟(jì)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(yīng)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(dāng)時(shí)的非洲人出汗量最高時(shí)可達(dá)2 L/h[42]。大量出汗導(dǎo)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(jī)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(zhǎng)類動(dòng)物均有很強(qiáng)的鈉鹽親和性，為這個(gè)假說提供了很好的證據(jù)。大量出汗還會(huì)造成夜間血容量不足，從而導(dǎo)致動(dòng)脈張力和心肌收縮增強(qiáng)以維持正常的血液供應(yīng)[43]。因此，那些能增強(qiáng)鈉鹽保留及動(dòng)脈、心肌收縮性的基因變異能幫助早期非洲人適應(yīng)當(dāng)?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(yīng)需求也發(fā)生改變，如適應(yīng)寒冷氣候人群的需求從散熱逐步轉(zhuǎn)變?yōu)楸Ｅ痆44]，不需要過多的鈉潴留，血管反應(yīng)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(dòng)脈、心肌收縮性的選擇壓力也發(fā)生變化以適應(yīng)當(dāng)?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(yīng)世代居住環(huán)境并相對(duì)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(dǎo)致諸多疾病的產(chǎn)生，而不同的鈉鹽親和力與血管反應(yīng)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(guó)第3次全國(guó)健康與營(yíng)養(yǎng)調(diào)查發(fā)現(xiàn)：在現(xiàn)有美國(guó)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(yán)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(shí)經(jīng)歷了不同氣候進(jìn)化選擇的遺傳背景相關(guān)。

為了驗(yàn)證這個(gè)觀點(diǎn)，3個(gè)研究小組分別對(duì)AGT、CYP3A5和 GNB3等與血壓調(diào)控密切相關(guān)的基因進(jìn)行了自然選擇分析。與高鈉鹽親和力密切相關(guān)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(fù)相關(guān)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(duì)AGT-6G和GNB3 825C這兩個(gè)衍生等位基因的鄰近序列分析發(fā)現(xiàn)，它們兩側(cè)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(gè)多態(tài)位點(diǎn)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(yīng)走出非洲后相對(duì)寒冷的生存環(huán)境。適應(yīng)古老環(huán)境并且相對(duì)穩(wěn)定的遺傳背景很難在進(jìn)化尺度上很短的時(shí)間內(nèi)(比如近代的人群遷徙、定居)重新快速適應(yīng)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(shí)，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(yīng)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(diǎn)[50]。雖然這方面研究目前僅涉及上述 3個(gè)基因，但為高血壓的遺傳學(xué)研究提供了新的思路。

3 中國(guó)人群環(huán)境溫度適應(yīng)與高血壓易感性研究

中國(guó)科學(xué)院昆明動(dòng)物研究所張亞平院士領(lǐng)導(dǎo)的研究小組和復(fù)旦大學(xué)金力院士領(lǐng)導(dǎo)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(kuò)散到東南亞大陸，隨后向北方擴(kuò)張和遷移，因此中華民族起源于南方[24,51～54]。我國(guó)的高血壓流行病學(xué)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(xué)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(guó)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(guān)。相較于全球人群，中國(guó)人群遺傳背景相對(duì)均一，但人群居住地域廣闊、居住地氣候環(huán)境復(fù)雜多樣，因此通過分子進(jìn)化研究很有可能發(fā)現(xiàn)中國(guó)人群高血壓的真正致病基因及易感位點(diǎn)。

本研究小組從CEPH-HGDP數(shù)據(jù)庫(kù)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(gè)基因共241個(gè)SNP，進(jìn)行環(huán)境因素的Pearson關(guān)聯(lián)分析、多元線性回歸分析和進(jìn)化分析(FST、iHS)，發(fā)現(xiàn)有5個(gè)SNP在亞洲人群中與環(huán)境溫度適應(yīng)相關(guān)，且均位于AGTR1基因。通過大樣本中國(guó)漢族人群的原發(fā)性高血壓病例-對(duì)照研究，發(fā)現(xiàn)其中的2個(gè)SNP與高血壓的易感性密切相關(guān)。如圖1所示，該項(xiàng)研究中發(fā)現(xiàn)的與溫度適應(yīng)相關(guān)且增加高血壓患病風(fēng)險(xiǎn)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(shí)，那些適應(yīng)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(diǎn)。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(guān)性及作用機(jī)理。

圖1 環(huán)境溫度與高血壓易感等位基因頻率的相關(guān)性與高血壓易感性密切相關(guān)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(guān)性。

該項(xiàng)研究中，RAAS基因受環(huán)境溫度進(jìn)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(gè)SNP與高血壓相關(guān)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(qiáng)[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(zhuǎn)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(jié)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(jìn)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(duì)居住人群產(chǎn)生了不同選擇壓力。而近代頻繁的國(guó)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(dǎo)致了疾病的易感性差異。類似的進(jìn)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(shí)和應(yīng)用[37,58～60]。由此可見，從進(jìn)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(xué)研究提供了新的切入點(diǎn)。

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(diǎn))的群體遺傳學(xué)、分子進(jìn)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(diǎn)的連鎖不平衡等信息對(duì)于理解這些疾病易感基因的起源和人類進(jìn)化歷史非常重要。因而，從疾病易感基因(或位點(diǎn))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。

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(責(zé)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(guó)家自然科學(xué)基金項(xiàng)目(編號(hào)：81402747)和浙江省自然科學(xué)基金項(xiàng)目(編號(hào)：LQ13C060001)資助

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

徐進(jìn)，副教授，碩士生導(dǎo)師，研究方向：分子進(jìn)化與疾病遺傳學(xué)。E-mail: xujin1@nbu.edu.cn

10.3724/SP.J.1005.2014.1195

時(shí)間: 2014-9-24 14:08:02

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