季林丹，钱海霞，徐进2,

1. 宁波大学医学院生物化学系，宁波 315211；

2. 中国科学院昆明动物研究所遗传资源与进化国家重点实验室, 昆明 650223；

3. 宁波大学医学院预防医学系，宁波 315211

高血压易感基因的分子进化

季林丹1,2，钱海霞3，徐进2,3

1. 宁波大学医学院生物化学系，宁波 315211；

2. 中国科学院昆明动物研究所遗传资源与进化国家重点实验室, 昆明 650223；

3. 宁波大学医学院预防医学系，宁波 315211

利用家系连锁分析、候选基因法及全基因组关联研究均未能有效发现普通人群的高血压易感基因或位点。遗传学研究表明，人类许多疾病易感性的形成与走出非洲时的环境适应性进化密切相关，这为高血压遗传学研究提供了新思路。文章系统综述了高血压易感基因分子进化研究的理论基础和最新进展，介绍了本研究小组运用分子进化思路在中国汉族人群高血压遗传学研究中的发现，对未来的研究方向进行了展望，以期为高血压和其他疾病的遗传学研究提供参考。

高血压；遗传易感性；进化；适应

原发性高血压(Essential hypertension, EH)是一种以血压升高为主要临床表现而病因尚未明确的独立疾病，约占所有高血压的90%～95%。在遗传和环境因素的共同影响下，EH已经成为危害人类健康的世界性公共卫生问题[1,2]。在发达国家，超过1/4的成年人患有高血压；据世界卫生组织估计，到2020年全球高血压患者将超过15亿人[3]。我国曾进行了4次大规模高血压流行病学调查，高血压的患病率从50年代的5.11%增加至2002年的18.8%，并且呈现出明显的低龄化趋势。据卫生部估计，我国高血压患病人数已经超过 2亿，每年高血压的直接医疗费用高达 300亿元人民币，与高血压相关的心脑血管疾病耗费更是达到3000亿元人民币[4]。由此可见，高血压已经严重影响了中国及全球诸多国家的经济发展、社会稳定和居民生活质量。

为了更好地开展高血压及相关心血管疾病的防治工作，国内外研究人员对高血压的遗传病因进行了大量研究。家系研究提示收缩压和舒张压具有较高的遗传度(31%～68%)[5]，可是在封闭家系研究中发现的少数“高血压基因”，在普通人群中却很难证实与高血压具有相关性[6]。在家系连锁分析无法取得突破时，研究人员开始采用大样本病例-对照研究对大量的候选基因进行筛选[7]，但不同的研究小组往往得到不同的结果，目前尚无被广泛接受的高血压遗传易感位点[8,9]。随着芯片技术的飞速发展，全基因组关联研究(Genome-wide association study, GWAS)广泛地应用于高血压等复杂疾病的遗传学研究。截至2014年5月，已发表20多项与血压性状或高血压相关的GWAS(http://www.genome.gov/gwastudies/)。对国际上主要的几个高血压 GWAS[10～12]进行 meta分析后，得到数个单核苷酸多态性(Single nucleotide polymorphism, SNP)与血压性状或高血压相关，但这些SNP仅仅贡献了1%～2%的遗传度[12～14]。虽然GWAS通过全基因组SNP系统扫描避免了偏倚并减少了假阳性，但多重统计检验及严格的校正也降低了其检出真实信号的效能[15]。以往连锁分析和候选基因法得到的“高血压易感SNP”极少在这些高血压GWAS中被检出，不同GWAS之间的阳性结果也很少有重叠，大样本人群对GWAS结果的验证大部分以失败而告终[9,16,17]。目前商业化的 SNP芯片主要依据高加索人群的遗传多态性进行设计，考虑到不同人群遗传背景的差异，将其直接应用于非洲或亚洲人群时可能存在较大偏倚[18]。利用家系连锁分析、病例-对照候选基因法及 GWAS，依旧不能有效地发现普通人群的高血压易感基因或位点[19,20]。正是这些困难的存在，需要人们对高血压遗传学的研究策略做出调整，尝试从不同的角度开展研究。

1 人类走出非洲与“节俭基因假说”

根据化石、古人类DNA和现代人DNA等证据，解剖学上的现代人(Anatomically modern human, AMH)，即智人(Homo sapiens)大约于20万年前起源于非洲[21～23]。大约在10万年前，非洲人从东非走出非洲，随后迁徙至世界各地定居生存[24～26]。在历史迁徙过程中，对不同环境选择压力的广泛适应形成了今天人类的遗传多样性，而这些遗传多样性又与不同人群的表型和疾病易感性差异密切相关[27～35]。随着人类学、流行病学、遗传学等研究领域的不断发展，科研人员开始从分子进化角度对人类的疾病易感性展开研究[36～39]。

1962年，美国密歇根大学的人类遗传学家James V. Neel教授从生物进化的角度对人类肥胖和糖尿病等问题进行了分析，首次提出了“节俭基因假说”(The thrifty gene hypothesis)[40,41]。该假说认为：在采集-狩猎型社会和农业社会初期，人们经常受到食物短缺或饥荒的威胁。人类的祖先为了适应当时食物缺乏的环境，逐渐进化出能有效储存能量的能力，以提高自身生存的机会。经过长期的适应过程，那些能够在进食后较多地将食物能量储存起来的个体因为其较易耐受长期饥饿而存活下来，那些能有效控制能量储存的基因就叫做“节俭基因”。因此，节俭基因在食物贫瘠的时代，对人类的生存和种族繁衍具有重要作用。随着社会经济的发展，食物获取不再困难，甚至出现了过剩的现象，这些曾经有利的节俭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”的环境温度适应与高血压易感性

在非洲炎热的环境中，人体主要通过大量出汗来维持体温恒定，当时的非洲人出汗量最高时可达2 L/h[42]。大量出汗导致钠盐流失，而在非洲热带气候中钠盐的供给又非常少。因此，机体需要极力阻止钠盐的流失以维持正常的生理功能。热带环境中生活的人类及其他灵长类动物均有很强的钠盐亲和性，为这个假说提供了很好的证据。大量出汗还会造成夜间血容量不足，从而导致动脉张力和心肌收缩增强以维持正常的血液供应[43]。因此，那些能增强钠盐保留及动脉、心肌收缩性的基因变异能帮助早期非洲人适应当地炎热的气候环境。

大约在10万年前，我们的祖先从东非出发，经过几万年的迁徙，在世界各地繁衍生息。在走出非洲的过程中，气温和环境湿度也发生了巨大的变化，人体的气候环境适应需求也发生改变，如适应寒冷气候人群的需求从散热逐步转变为保暖[44]，不需要过多的钠潴留，血管反应性也开始降低[45]。因此，在走出非洲的过程中，钠盐亲和力及动脉、心肌收缩性的选择压力也发生变化以适应当地的生存气候环境。随着近代工业发展和交通便利，出现了频繁的大规模地域间移民。适应世代居住环境并相对稳定的遗传背景与移民后新的生活环境之间的矛盾将可能导致诸多疾病的产生，而不同的钠盐亲和力与血管反应性也可能造成不同人群在同一生活环境中高血压的易感性差异。如美国第3次全国健康与营养调查发现：在现有美国居民中，与欧洲移民后代相比，非洲移民的后代更容易发生高血压，而且发病趋于低龄化，病情更严重[46,47]。因此，Young等[29]提出人群间不同的高血压易感性可能与人类走出非洲时经历了不同气候进化选择的遗传背景相关。

为了验证这个观点，3个研究小组分别对AGT、CYP3A5和 GNB3等与血压调控密切相关的基因进行了自然选择分析。与高钠盐亲和力密切相关的AGT-6A、CYP3A5*1和GNB3 825T等祖先等位基因频率与纬度均存在显著的负相关性。这些祖先等位基因在赤道附近的非洲人群中具有较高的频率；而走出非洲后，能降低钠盐亲和力的衍生等位基因的频率显著增高[29,48,49]。对AGT-6G和GNB3 825C这两个衍生等位基因的邻近序列分析发现，它们两侧存在广泛的连锁不平衡和较少的单倍型[29,48]。这些证据都证明了这3个多态位点中能降低钠盐亲和性的衍生等位基因频率在环境正选择作用下逐渐升高，以适应走出非洲后相对寒冷的生存环境。适应古老环境并且相对稳定的遗传背景很难在进化尺度上很短的时间内(比如近代的人群迁徙、定居)重新快速适应移民后的新环境，从而使得人群的遗传背景与生活环境产生了偏差。因此，在近代人类移居到寒冷环境时，能降低钠盐亲和性的衍生等位基因受到正选择，而那些适应了炎热气候的祖先等位基因就可能成了“有害”的高血压遗传易感位点[50]。虽然这方面研究目前仅涉及上述 3个基因，但为高血压的遗传学研究提供了新的思路。

3 中国人群环境温度适应与高血压易感性研究

中国科学院昆明动物研究所张亚平院士领导的研究小组和复旦大学金力院士领导的研究小组分别通过线粒体DNA、Y染色体和全基因组遗传多态性研究，发现走出非洲的现代人类祖先约于 1.8～6万年前首先扩散到东南亚大陆，随后向北方扩张和迁移，因此中华民族起源于南方[24,51～54]。我国的高血压流行病学调查显示，北方地区的患病率要高于南方，中部地区居中[4]。上述流行病学调查数据及东亚人群的南方起源和史前北迁历史提示我国不同地区人群高血压的易感性差异也很可能与气候环境密切相关。相较于全球人群，中国人群遗传背景相对均一，但人群居住地域广阔、居住地气候环境复杂多样，因此通过分子进化研究很有可能发现中国人群高血压的真正致病基因及易感位点。

本研究小组从CEPH-HGDP数据库中获取了肾素-血管紧张素-醛固酮系统(Renin-angiotensin-aldosterone system, RAAS)的 AGT、ACE、AGTR1、AGTR2、CYP11B2和REN等6个基因共241个SNP，进行环境因素的Pearson关联分析、多元线性回归分析和进化分析(FST、iHS)，发现有5个SNP在亚洲人群中与环境温度适应相关，且均位于AGTR1基因。通过大样本中国汉族人群的原发性高血压病例-对照研究，发现其中的2个SNP与高血压的易感性密切相关。如图1所示，该项研究中发现的与温度适应相关且增加高血压患病风险的SNP1的C等位基因和SNP2的A等位基因在非洲人群中都是高频等位基因，而在欧洲和亚洲人群中则是低频等位基因，这也说明了在近代人类移居到寒冷环境时，那些适应了炎热气候的祖先等位基因就可能成了“有害”的高血压遗传易感位点。目前本研究小组正从全基因组水平筛选受环境温度选择的 SNP，并明确其与高血压的相关性及作用机理。

图1 环境温度与高血压易感等位基因频率的相关性与高血压易感性密切相关的AGTR1基因SNP1 C和SNP2 A等位基因频率与环境温度存在显著的正相关性。

该项研究中，RAAS基因受环境温度进化选择的所有 SNP均落在编码 1型血管紧张素 II受体的AGTR1基因上，且其中两个SNP与高血压相关并非偶然。血管紧张素受体主要有4种类型，其中在人体中以1型受体(Angiotensin type 1 receptor, AT1)和2型受体(AT2)为主。人体内参与血压调控主要是AT1，它的激活可引起血管收缩、肾小管重吸收钠增加和心脏收缩能力增强[55,56]。正是血管紧张素受体在血压调控中的重要作用，血管紧张素受体拮抗剂已成为血管紧张素转换酶抑制剂后的最新一代的治疗高血压临床用药[57]。血管紧张素受体在高血压病理生理过程中的重要作用与本研究的结果相互印证，既说明AGTR1基因很可能是原发性高血压的易感基因，也说明从分子进化角度来研究高血压的遗传易感性具有重要的意义。

4 展 望

不同的气候环境(温度、湿度、降水等)对居住人群产生了不同选择压力。而近代频繁的国际间移民，使得遗传背景与居住环境之间产生偏差从而导致了疾病的易感性差异。类似的进化研究思路已经在人类体型大小、皮肤色素沉着和代谢疾病的研究中得到了很好的证实和应用[37,58～60]。由此可见，从进化选择角度来探索高血压的遗传易感性可能为高血压遗传学研究提供了新的切入点。

此外，疾病易感等位基因的地理分布或流行性显得尤为重要。通过探索这些疾病易感基因(或位点)的群体遗传学、分子进化史等，如不同地域人群中的等位基因频率、等位基因的亚群体分化、群体历史，和邻近位点的连锁不平衡等信息对于理解这些疾病易感基因的起源和人类进化历史非常重要。因而，从疾病易感基因(或位点)的分子起源角度来研究临床疾病可能为今后的研究提供一种新的、行之有效的思路。

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(责任编委: 赵彦艳)

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

国家自然科学基金项目(编号：81402747)和浙江省自然科学基金项目(编号：LQ13C060001)资助

季林丹，博士后，讲师，研究方向：分子进化与疾病遗传学。E-mail: jilindan@nbu.edu.cn

徐进，副教授，硕士生导师，研究方向：分子进化与疾病遗传学。E-mail: xujin1@nbu.edu.cn

10.3724/SP.J.1005.2014.1195

时间: 2014-9-24 14:08:02

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