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1、难治性高血压-基因与遗传背景,惠汝太加拿大临床科学博士北京中国医学科学院阜外医院高血压中心首席专家国家心脏中心国家心血管病重点实验室常务副主任2012-07-07,难治（顽固）性高血压定义,除外近期确诊的高血压、未接受治疗的高血压，3个降压药(包括一个利尿剂)，有效剂量、足时（4-8周）后，血压仍140/90毫米汞柱,或糖尿病、肾病患者仍高于130/80毫米汞柱；为难治性高血压。近来有人认为：4个降压药，血压不达标，可以诊断为难治性高血压。,高血压-复杂原因,在难治性高血压当中，继发性高血压比我们想象的多；单基因高血压是继发性高血压重要病因之一,三级甲等医院4429例难治性高血压中%为继发性高
2、血压，60岁以上的难治性高血压患者中17%为继发性高血压（Anderson GH Jr,etal.J Hypertens 1994;12:609）。一般估计：继发性高血压患病率6%-20%单基因突变导致的高血压：至少19个致病基因 导致嗜铬细胞瘤：9个 导致盐敏感高血压：10个,309 例16-30岁（平均24.05.2岁）青年难治性高血压住院（2002-2008年）患者病因分析,青年顽固性高血压有40%能找到原因，解除病因，免得终生服药。比率 原发性高血压 185例 59.9%继发性高血压占 124例 40.1%肾动脉性高血压 88例 28.5%主动脉缩窄 13例 4.2%原醛 9例 2.9
3、%肾实质高血压 5例 1.6%Liddle 综合征 3例 1.0%其他原因 3例 1.0%未分类 3例 1.0%其他原因：1例白大衣高血压，1例柯兴氏，1例肾素瘤 吴燕，惠汝太等，未发表资料，2010,高血压的遗传度：40%-60%，中国盐敏感高血压58.7%；其中隐藏着导致盐敏感高血压基因变异的贡献？,目前找到的19个高血压致病基因 主要在肾与肾上腺表达,目前多数单基因高血压病因：肾离子通道，肾上腺。,单基因高血压,肾小管：盐皮质类固醇受体（MR）基因变异导致怀孕加重 的高血压，糖皮质素抵抗，ENaC（Liddle氏综合征），WNK4,1（Gordon氏综合征），TheWNK4gene en
4、codes a serine-threonine（丝氨酸-苏氨酸）kinase expressed in distal nephron肾上腺：皮质：GRA，11HSD2（AME）肾上腺增生 髓质：嗜铬细胞瘤20%,盐皮质激素受体活性突变 亦称为妊娠加重的高血压,为常染色体显性遗传疾病，2000年Geller等首次报道盐皮质激素受体（MR）的配体结合域发生突变，第810位丝氨酸被亮氨酸取代(S810L)，使受体的第5螺旋和第3螺旋间发生分子交互作用，构象发生改变，导致该突变受体在无配体结合时也处于半激活状态(活性增加25%左右)。,而生理状态下的MR拮抗剂如螺内酯和孕酮、以及生理状态下不能结合和
5、激活MR的皮质酮，也可结合并激活突变的盐皮质激素受体。怀孕后体内孕酮可升高100倍，因而妊娠后MR突变携带者高血压加重恶化。螺内酯治疗会加重高血压。,Role of the KS-WNK1 isoform in renal physiology,Mutations in the WNK1 and WNK4 genes,encoding members of the WNK(With No lysine(K)family of serine-threonine kinases,are responsible for Familial Hyperkalemic Hypertension(FHHt)
6、,a rare form of human arterial hypertension characterized not only by hyperkalemia and hypertension but also by a hyperchloremic metabolic acidosis.As expected,NCC expression and phosphorylation were increased in KS-WNK1-/-mice.Na+and K+balance was affected as evidenced by increased diastolic blood
7、pressure,decreased urinary aldosterone level and modified K+channels expression.The surprising result was the absence of metabolic disturbance under several regimen despite increased NCC activity,which was explained in part by a counterdownregulation of ENaC expression.(Hadchouel et al.Proc Natl Aca
8、d Sci U S A.2010).,Pseudohypoaldosteronism,PHA-II（Gordon syndrome）is a rare familial renal tubular defect characterized by hypertension and hyperkalemic metabolic acidosis in the presence of low renin and aldosterone levels.机制：renal tubular unresponsiveness or resistance to the action of aldosterone
9、.Volume depletion or hypervolemia;renal salt wasting or retention;hypotension or hypertension,PHA-I itself has been recognized as a heterogeneous syndrome that includes at least 2 clinically distinguishable entities with either renal or multiple target organ defects(MTOD).Early childhood hyperkalemi
10、a,or renal tubular acidosis(RTA)type IV subtype 5,is a variant of the renal form of PHA-I.,microRNAs as new partners for WNK1 expression influenced by Na+,K+regimen,two kidney-specific microRNAS,miR-192 and miR-215,that target sequence in the 3UTR of the gene.In vitro assays showed that miR-192,but
11、not miR-215,is able to regulate WNK1 expression at the post-transcriptional level only.miR-192 expression is strongly inhibited by Na+depletion,K+loading and aldosterone infusion.In addition,L-WNK1 expression,while unaffected by any of the conditions at the RNA level,was increased at the post-transc
12、riptional level by aldosterone and confirmed that KS-WNK1 transcripts level was increased by K+loading and aldosterone.Taken together,these results suggest that down-regulation of miR-192 could be involved in the stimulation of WNK1 expression by aldosterone in the kidney.A new working hypothesis un
13、der which microRNAs could play a role in the regulation of ion transport in the kidney(Elvira-Matelot et al.J Am Soc Nephrol.2010).,拟盐皮质激素增多症（AME）,本病为常染色体隐性遗传疾病。人体内糖皮质激素(皮质醇)和醛固酮对盐皮质激素受体具有同样的亲和性，生理情况下体内循环中皮质醇比醛固酮高1000倍，但由于肾脏内存在11-羟类固醇脱氢酶型(11-HSD)，可将皮质醇转化生成不能激活盐皮质激素受体的皮质酮，因此盐皮质激素受体不会被糖皮质激素激活。HSD11B基因
14、位于16q22，该基因发生突变可导致11-HSD酶无活性或活性降低，大量皮质醇不能被转化成皮质酮，,大量蓄积的皮质醇占据远端肾小管的盐皮质激素受体，激活转录因子及血清糖皮质类固醇激酶，使泛素连酶Nedd4-2磷酸化，磷酸化的Nedd4-2不能与ENaC结合进而灭活ENaC，导致ENaC活性升高，钠重吸收增加，出现类似醛固酮增高的临床表现高血压和低血钾，即称类盐皮质激素增多症(AME)。HSD11B基因突变不仅导致基因表达降低或对底物的亲和力降低，也可导致11-HSD蛋白酶的稳定性降低，半衰期显著缩短。,Recessive and dominantKLHL3mutations in PHAII
15、kindreds,Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalitiesNature482,98102(02 February 2012)doi:10.1038/nature10814,recessive(a)Dominant(b)KLHL3 MutationsAffected,unaffected and phenotype-undetermined subjects are denoted by black,white and grey symbols,respectiv
16、ely.KLHL3alleles are denoted by+(wild type),d(recessive mutation)and D(dominant mutation).Sequence traces show wild-type(WT)and mutant(*)alleles and encoded amino acids.het.,heterozygous;hom.,homozygous,家族性与散发原醛的遗传机制 三种临床类型：FH-1:GRA，嵌合基因突变（CYP11B2/B1)FH-2:最常见的两侧肾上腺增生（BAH，bilateral adrenal hyperplasi
17、a),致病基因突变尚未找到，连锁位点7p22；FH-3:KCNJ5 突变引起产生醛固酮的腺瘤（APAs aldosterone producing adenomas)。其他点突变、遗传重排伴LOH尚待证实。FHx：其他孟德尔型的原醛可能存在。,家族与散发原发性醛固酮增多症遗传机制FH:家族性高醛固酮血症Circ Res 2011;108:1417,FH1：GRA,CYP11B2/B1嵌合基因突变FH3：致病基因：KCNJ5，编码钾通道Kir3.4，FH2:连锁在7p22,家族性,散发性,Liddles 综合征：上皮钠通道激活型突变（epithelial Na channel，ENaC);Gor
18、dons 综合征：两种调节激酶突变 with no lysine(K)serine/threonine protein kinases(WNK)1 or WNK4;and类盐皮质类固醇增多症（AME-apparent mineralocorticoid excess)：调节糖皮质类固醇11HD2 灭活突变（glucocorticoid-metabolizing 11-hydroxysteroid dehydrogenase type 2 enzyme).,Liddle 氏综合征：最常见的单基因高血压,诊断：周围血基因组DNA，治疗：低钠饮食，ENaC抑制剂（阿米洛利或三甲阿番）盐皮质类固醇受体
19、拮抗剂无效,远曲小管（DCT）主要的apical Na 转运体 是噻嗪敏感的Na-Cl交换体(NCC)及集合管主细胞（PC）阿米洛利 敏感的上皮钠通道epithelial sodium channel(ENaC)K 分泌：通过尖膜肾髓外钾通道renal outer medulla K channel(ROMK)分泌钾,WNK4 phosphorylates NCC,which prevents incorporation of the transporter into the apical membrane.WNK4 exerts a tonic baseline suppression on
20、 NCC activity,which explains why interference with WNK4 can lead to augmented Na transport.,Gordons 综合征(家族性高血钾高血压,假性低醛固酮血症II型),Gordons 表型特征：常染色体显性遗传，高血钾,轻度代谢性酸中毒,高血压，对小剂量噻嗪敏感。正常情况下，WNK4抑制远曲小管NCC；WNK4灭活突变，导致NCC释放，肾DCT重吸收Na增加。高血钾：WNK激活突变，增强对ROMK抑制（分泌钾减少）2nd 类型的Gordon：大的内含子突变，增加WNK1 表达。WNK1 间接激活NCC，促进N
21、a转运；WNK1 也可通过SGK1 激活 ENaC；近来证明肾脏有两种WNK1异构体；对ROMK具有相反的作用。另外至少两种单基因型的Gordons 综合征与WNK 激酶无关,致病基因尚未找到。,Gordons 综合征,高血钾、高血Cl代酸发生在高血压之前，直到成年方出现高血压。儿童Spitzer-Weinstein 综合征：高血钾,代酸,生长迟缓，但没有高血压，是Gordons综合征的早期表现；类似IV型肾小管酸中毒。诊断：高血钾，酸中毒，PRA抑制，醛固酮正常或高（尽管高血容量，但是，高血钾刺激醛固酮分泌）。与IV 肾小管酸中毒不同：Gordon肾功多正常；常伴高血钙。高血压、与代谢异常均
22、对小剂量噻嗪利尿剂敏感。,拟盐皮质类固醇增多症,常染色体隐性遗传，11HD2 酶灭活突变，使皮质醇不能转化为皮质酮（皮质酮不能与盐皮质类固醇受体结合），皮质醇占据与激活盐皮质类固醇受体Na重吸收增加,K与H分泌，肾浓缩障碍，高钙，肾结石诊断：低肾素,低醛固酮高血压，盐皮质类固醇增多征象；基因诊断治疗：盐皮质类固醇受体拮抗剂,补K,限制饮食 Na；伊普利酮，阿米洛利（保钾），噻嗪类用于减轻高血钙,拟盐皮质类固醇增多症Apparent mineralocorticoid excess(AME),妊娠加重的高血压,常染色体显性遗传。诊断名称不太合适，此病不限于女性;有报告先症者15-岁男性。盐皮质类
23、固醇受体激活型突变，Na重吸收增加。高血压可见于非怀孕者，但是，怀孕会加重。突变受体对非盐皮质类固醇敏感，如孕酮，螺内酯能激活突变受体。治疗：限制盐摄入，噻嗪利尿剂，ENaC 拮抗剂（阿米洛利，三甲阿番）;禁忌：盐皮质类固醇受体拮抗剂（螺内酯，依普利酮）,Glucocorticoid-remediable aldosteronism(GRA)familial hyperaldosteronism type I,常染色体显性遗传。多数受累者儿时高血压，心血管死亡率高，脑动脉瘤，颅内出血，早作MRA检查。轻度低血钾，轻度代碱，PRA 抑制，血浆醛固酮高，血浆醛固酮(ng/dl)/PRA(ng/ml
24、/h)30(正常20)，高度提示原醛。地塞米松抑制试验,尿类固醇谱(18-oxocortisol升高),肾上腺影像，肾上腺静脉血样被基因诊断取代。治疗：糖皮质激素，螺内酯或伊普利酮，小剂量地塞米松0.1250.24mg qd 或 强的松（prednisolone）2.55mg qd 足够。辅助治疗：ENaC 拮抗剂 阿米洛利 或三甲阿番,Familial hyperaldosteronism type II(FH II),similar to GRA(FH I)in that excess mineralocorticoid production is responsible for the
25、development of hypertension,but the hypertension is not suppressible by dexamethasone.Autosomal dominant inheritance suggests that FH II is due to a single gene mutation and,although the gene has not been identified,the locus has recently been narrowed to a band on chromosome 7 Many patients with FH
26、 II have a family history of adrenal hyperplasia or adenoma,which suggests that a growth factor may be involved.Widened criteria for screening have revealed FH II to be more common than previously believed,and it may be the most common inherited type of hypertension in adults.However,although renin-
27、aldosterone abnormalities have been reported in affected adolescents,hypertension due to FH II typically does not manifest until adulthood.FH II is clinically and biochemically indistinguishable from noninherited primary aldosteronism,and currently,the diagnosis can be only confirmed by positive fam
28、ily history until genetic detection is available.,Congenital adrenal hyperplasia,Defects in 11-hydroxylase and 17-hydroxylase result in overproduction of 21-hydroxylated steroids,which activate MR.伴性征异常。The hypertension responds to treatment with an MR antagonist.Note that the most common type of co
29、ngenital adrenal hyperplasia,21-hydroxylase deficiency,is an Na-losing state and does not cause hypertension.,Familial glucocorticoid resistance,病因：唐皮质类固醇受体突变？Diagnosis of this rare disorder rests of documentation of markedly elevated plasma cortisol levels.The hypertension responds to MR blockade.,基因突变（10个）引起的继发性高血压,第三组：嗜铬细胞瘤（20-30%遗传有关）9个基因突变,谢谢,
