家族性高胆固醇血症研究进展

doi:10.16288/j.yczz.21-218

遗传 ›› 2021, Vol. 43 ›› Issue (11): 1011-1022.doi: 10.16288/j.yczz.21-218

家族性高胆固醇血症研究进展

蒋琬姿¹(), 张丽雯²(), 贺彩红^2,³, 阮梅花², 季勇⁴(), 于建荣^2,³(), 周红文¹()

1. 南京医科大学第一附属医院内分泌科,南京 210029
2. 中国科学院上海生命科学信息中心,中国科学院上海营养与健康研究所,上海 200031
3. 中国科学院大学,北京 100049
4. 南京医科大学,南京 210029

收稿日期:2021-06-22 修回日期:2021-08-12 出版日期:2021-11-20 发布日期:2021-09-06
通讯作者: 季勇,于建荣,周红文 E-mail:1995jwz@sina.com;zhangliwen@sibs.ac.cn;yongji@njmu.edu.cn;yujianrong@sibs.ac.cn;drhongwenzhou@njmu.edu.cn
作者简介:蒋琬姿,在读博士研究生,专业方向：肥胖、脂代谢和罕见代谢病。E-mail: 1995jwz@sina.com|张丽雯,硕士,馆员,研究方向：生物情报学。E-mail: zhangliwen@sibs.ac.cn; 蒋琬姿和张丽雯并列第一作者。
基金资助:
国家重点研发计划项目编号(2019YFA0802701);国家重点研发计划项目编号(2018YFA0506904);国家自然科学基金重大研究计划项目编号(91854122);国家自然科学基金专项项目编号资助(L1924031)

Progress on familial hypercholesterolemia

Wanzi Jiang¹(), Liwen Zhang²(), Caihong He^2,³, Meihua Ruan², Yong Ji⁴(), Jianrong Yu^2,³(), Hongwen Zhou¹()

1. Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
2. Shanghai Information Center for Life Sciences, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China
3. University of Chinese Academy of Sciences, Beijing 100049, China
4. Nanjing Medical University, Nanjing 210029, China

Received:2021-06-22 Revised:2021-08-12 Online:2021-11-20 Published:2021-09-06
Contact: Ji Yong,Yu Jianrong,Zhou Hongwen E-mail:1995jwz@sina.com;zhangliwen@sibs.ac.cn;yongji@njmu.edu.cn;yujianrong@sibs.ac.cn;drhongwenzhou@njmu.edu.cn
Supported by:
Supported by the National Key Research and Development Program of China Nos(2019YFA0802701);Supported by the National Key Research and Development Program of China Nos(2018YFA0506904);the Major Research Plan of the National Natural Science Foundation of China No(91854122);the National Natural Science Foundation of China No(L1924031)

摘要/Abstract

摘要：

家族性高胆固醇血症(familial hypercholesterolemia, FH)是以肌腱黄瘤、低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)显著升高和早发冠心病(premature coronary artery disease, PCAD)为特征的一种常染色体显性或隐性遗传病。本文分析了FH的国内外研究现状,总结了目前中国已报道的FH人群相关的基因突变位点及治疗现状,同时统计了FH相关专利及药物研发情况。在论文发表方面,FH致病机制与治疗、未成年FH患者研究等成为研究热点;在专利方面,再生元制药、阿斯利康、默克等大型药企在FH检测、诊断、治疗等方面积极探索;在药物研发方面,已有12种药物在美国、日本、欧洲等国家/地区上市,为FH患者带来希望。

关键词: 家族性高胆固醇血症, 罕见病, FH基因突变位点, 研究现状

Abstract:

Familial hypercholesterolemia (FH) is an autosomal inherited disease characterized by a significant increase in low density lipoprotein cholesterol (LDL-C), tendon xanthoma and premature coronary artery disease (PCAD). In this paper, we analyze the current research status of FH, summarize the reported mutation gene loci in Chinese FH patients and treatment for them, and elaborate the current status of patents and drug researches. The results show that scientific outcomes of FH are increasing with a good developmental trend and the most popular topics of FH study are pathogenesis, treatment of FH, and research on juvenile FH patients. In terms of patents, large pharmaceutical companies, such as Regeneron Pharmaceuticals Inc, AstraZeneca Plc, Merck & Co Inc, are actively engaged in FH detection, diagnosis and treatment. In addition, 12 drugs have been launched in the United States, Japan, Europe and other countries or regions, bringing hope to FH patients.

Key words: familial hypercholesterolemia, rare disease, gene loci, research status

蒋琬姿, 张丽雯, 贺彩红, 阮梅花, 季勇, 于建荣, 周红文. 家族性高胆固醇血症研究进展[J]. 遗传, 2021, 43(11): 1011-1022.

Wanzi Jiang, Liwen Zhang, Caihong He, Meihua Ruan, Yong Ji, Jianrong Yu, Hongwen Zhou. Progress on familial hypercholesterolemia[J]. Hereditas(Beijing), 2021, 43(11): 1011-1022.

图/表 11

图1

图2

图3

表1

附表1

中国FH患者LDLR基因突变的致病位点总结"

一般情况				治疗前血脂		临床表现			基因诊断			发表时间
序号	性别 (女/男)	年龄 (岁)	省/市	TC (mmol/L)	LDL-C (mmol/L)	冠心病	黄色瘤	角膜弓	纯合子/ 复合杂合	cDNA 突变	氨基酸突变	发表时间
1	男	6	天津	6.88	5.25				纯合子	c. 611G>A	p.Cys204Tyr	2020^[1]
2	男	7	陕西	21.24	15.51		+		纯合子	c.418G>A	p.Glu140Lys	2020^[2]
3	198/ 110	48.3±11.2		11.06?±?1.58	8.41?±?1.39					c.12G>A	p.Trp4*	2020^[3]
										c.17G>A	p.Trp6*
										c.81C>A	p.Cys27*
										c.97C>T	p.Gln33*
										c.138C>A	p.Cys46*
										c.224G>A	p.Cys75Tyr
										c.268G>A	p.Asp90Asn
										c.285C>A	p.Cys95*
										c.301G>A	p.Glu101Lys
										c.327C>A	p.Cys109*
										c.400T>C	p.Cys134Arg
										c.418G>T	p.Glu140*
										c.510delC	p.Asp170fs
										c.622G>A	p.Glu208Lys
										c.682G>T	p.Glu228*
										c.718G>A	p.Glu240Lys
										c.769C>T	p.Arg257Trp
										c.974G>A	p.Cys325Tyr
										c.1135T>C	p.Cys379Arg
										c.1206delC	p.Phe402fs
										c.1222G>A	p.Glu408Lys
										c.1285G>A	p.Val429Met
										c.1448G>A	p.Trp483*
										c.1474G>A	p.Asp492Asn
										c.1538delG	p.Arg513fs
										c.1567G>A	p.Val523Met
										c.1599G>A	p.Trp533*
										c.1618G>A	p.Ala540Thr
										c.1633G>C	p.Gly545Arg
										c.1747C>T	p.His583Tyr
一般情况				治疗前血脂		临床表现			基因诊断			发表时间
序号	性别 (女/男)	年龄 (岁)	省/市	TC (mmol/L)	LDL-C (mmol/L)	冠心病	黄色瘤	角膜弓	纯合子/ 复合杂合	cDNA 突变	氨基酸突变	发表时间
										c.1765G>A	p.Asp589Asn
										c.1864G>T	p.Asp622Tyr
										c.1879G>A	p.Ala627Thr
										c.1948delG	p.Glu650fs
										c.2054C>T	p.Pro685Leu
										c.2389G>A	p.Val797Met
										c.2439G>A	p.Trp813*
										c.10579C>T	p.Arg3527Trp
										c.1336C>T	p.Arg446*
										c.461G>A	p.Arg154His
4	男	30		22.31	12.25	+			纯合子	c.1470G>A	p.Trp469*	2019^[4]
5	男	35	海南	9.96	7.44					c.986G>A	p.Cys329Tyr	2019^[5]
6	37/188	46.64±7.21			4.86	225				c.241C?>?T	p.Arg81Cys	2019^[6]
					3.89					c.292G?>?A	p.Gly98Ser
					8.00					c.1525A?>?G	p.Lys509Glu
					7.25					c.1691A?>?G	p.Asn564Ser
					5.72					c.1867A?>?T	p.Ile623Phe
					7.74					c.2054C?>?T	p.Pro685Leu
7	1/9	44.80± 6.36		5.04 (4.03-5.91)	3.39 (2.58-4.08)	+			杂合子	c.129G>C	p.Lys43Asn	2019^[7]
						+			杂合子	c.241C>T	p.Arg81Cys
						+			杂合子	c.292G>A	p.Gly98Ser
						+			杂合子	c.1525A>G	p.Ile509Glu
						+			杂合子	c.1691A>G (2人)	p.Ala564Ser
						+			杂合子	c.1867A>T	p.Ile623Phe
						+			杂合子	c.2054C>T (2人)	p.Pro685Leu
8	女	4	河北	16.4	15.06		+	+	复合杂合	c.727T>A, c.1003G>T	p.Cys243Ser, p.Gly335Cys	2019^[8]
9	女	52		8.10	5.02				杂合	c.1731G>A	p.Trp577*	2018^[9]
	男	22		8.20	4.86		+		杂合	c.1731G>A	p.Trp577*
	女	45		9.40	4.93				杂合	c.2054C>T	p.Pro685Leu
	男	27		18.30	11.60		+	+	杂合	c.1731G>A,c.2054C>T	p.Trp577*,p.Pro685Leu
10	男	10		20.31	14.87		+		杂合子	c.724C>T,c.1747C>T	p.Gln242*,p.His583Tyr	2018^[10]
11	52/41	M: 50.2±11.9 F: 53.2±10.3	中国香港	M: 9.3±1.9 F: 9.7±2.3	M: 7.6±1.9 F: 7.8±2.2	M: 18 F: 20	M: 9 F: 8		纯合子	c.1474G>A	p.Asp492Asn	2018^[11]
一般情况				治疗前血脂		临床表现			基因诊断			发表时间
序号	性别 (女/男)	年龄 (岁)	省/市	TC (mmol/L)	LDL-C (mmol/L)	冠心病	黄色瘤	角膜弓	纯合子/ 复合杂合	cDNA 突变	氨基酸突变	发表时间
12	女	16		20.15	13.16		+		复合杂合	c.28893T>G, deletions in exon 18	p.Cys377Gly,NA	2018^[12]
13	女	13		14.73	13.44		+		纯合子	c.655_c.660 delGGCCCC	p.219Ala_220Prodel	2018^[13]
14	男	12	北京	23.51	14.17		+	+	复合杂合	c.1129G>T, c.1268T>C	p.Cys365Gly, p.Ile402Thr	2018^[14]
15	女	8		7.6	5.37		+		杂合子	c.357delG	p.Gly119fs*86	2018^[15]
16	112/173	?49 ± 12		7.03±2.53	5.22±2.12	233	28			c.285C > G	p.Cys95Trp	2018^[16]
										c.302A > T	p.Glu101Val
										c.393delC	p.Asp131fs
										c.524A > G	p.Asp175Gly
										c.728G > A	p.Cys243Tyr
										c.1206delC	p.Phe402fs
										c.1934A > T	p.Asn645Ile
										c.1448G > A	p.Trp483*
										c.1879G > A	p.Ala627Thr
										c.769C > T	p.Arg257Trp
										c.1765G > A	p.Asp589Asn
										c.1187-10G > A	NA
										c.1747C > T	p.His583Tyr
										c.1864G > T	p.Asp622Tyr
17	28		中国台湾	9.03-12.05	6.47-9.67				杂合子	c.1186+2T>G(6人)	NA	2018^[17]
			中国台湾	15.00	13.78				复合杂合	c.986G>A, c.1291G>A	p.Cys329Tyr p.Ala431Thr
			中国台湾	8.30	6.05				杂合子	c.12G>A	p.Trp4*
			中国台湾	9.03	7.08				杂合子	c.298G>A	p.Asp100Asn
			中国台湾	12.77	9.44				杂合子	c.809G>A	p.Cys270Tyr
			中国台湾	8.69-11.45	5.95-8.10				杂合子	c.986G>A(2人)	p.Cys329Tyr
			中国台湾	9.72	7.50				杂合子	c.1176C>A	p.Cys392*
			中国台湾	11.43	9.31				杂合子	c.1216C>A	p.Arg406=
			中国台湾	15.36	8.69				杂合子	c.1246C>T	p.Arg416Trp
			中国台湾	11.53	9.30				杂合子	c.1322 T>C	p.Ile441Thr
			中国台湾	9.67	6.75				杂合子	c.1432G>A	p.Gly478Arg
			中国台湾	10.34	8.40				杂合子	c.1592 T>A	p.Met531Lys
			中国台湾	8.87	6.80				杂合子	c.1952_1953del	p.Asp651fs
			中国台湾	9.28	5.97				杂合子	c.2054C>T	p.Pro685Leu
			中国台湾	9.18	5.95				杂合子	c.2205_2206insTT	p.Ala735fs
			中国台湾	20.43	9.96				杂合子	c.2237delT	p.Val746fs

附表1

附表1

续"

一般情况				治疗前血脂		临床表现			基因诊断			发表时间
序号	性别 (女/男)	年龄 (岁)	省/市	TC (mmol/L)	LDL-C (mmol/L)	冠心病	黄色瘤	角膜弓	纯合子/ 复合杂合	cDNA 突变	氨基酸突变	发表时间
18	女	23	北京	17.66	15.78		+		复合杂合	c.2390-2AbG, c.1687C>T	p.Pro563Ser	2017^[18]
18	女	29	北京	13.38	11.16	+	+		复合杂合	c.292G>A, c.1864G>A	p.Gly98Ser, p.Asp622Asn	2017^[18]
19	男	52	山东	9.34	7.88		+	+		c.1885_1889delinsGATCATCAACC	p.Phe629_ser630delinsAspHisGlnPro	2017^[19]
	女	68	山东	9.79	7.59		+
	女	48	山东	9.52	6.88		+
	男	13	山东	10.45	8.46		+
20	男	7	河南	19.79	13.93				复合杂合	c. 97 C > T, c. 890 A > C, c. 892delA	p. Gln12, p. Asn276Thr, p. Met277Trpfs72	2017^[20]
20	男	1	河南	24.83	17.80		+		复合杂合	c. 292 G > A, c. 971delG, c. 1864 G > A	p. Gly77Ser, p. Gly303Alafs*46, p. Asp601Asn	2017^[20]
21	女	23	河南	19.0	16.7		+		纯合子	c.97C>T	p.Gln33*	2017^[21]
22	119/162	50.3±15.6		9.12±3.35	6.5±2.46	178	15			c.280G>A	p.Asp94Asn	2017^[22]
										c.327C>A	p.Cys109*
										c.470G>A	p.Cys157Tyr
										c.724G>A	p.Val242Met
										c.1066T>G	p.Trp356Gly
										c.1343T>C	p.Leu448Pro
										c.1393G>A	p.Gly465Arg
										c.1562C>A	p.Ser521Tyr
										c.1522G>C	p.Gly508Arg
										c.1810A>T	p.Lys604*
23	115/104	?31.15 ± 15.21		?11.15 ± 3.96	?8.32 ± 3.83	?46	?25			?c.97C > T	?p.Gln33*	2017^[23]
										?c.268G > A	?p.Asp90Asn
										?c.284G > C	?p.Cys95Ser
										?c.485C > T	?p.Pro162Leu
										?c.494G > A	?p.Trp165*
										?c.530C > T	?p.Ser177Leu
										?c.605T > C	?p.Phe202Ser
										?c.682G > T	?p.Glu228*
										?c.718G > A	?p.Glu240Lys
										?c.760C > T	?p.Gln254*
										?c.763T > C	?p.Cys255Arg
										?c.796G > C	?p.Asp266His
										?c.986G > A	?p.Cys329Tyr
										?c.1048C > T	?p.Arg350*
										?c.1132C > T	?p.Gln378*
一般情况				治疗前血脂		临床表现			基因诊断			发表时间
序号	性别 (女/男)	年龄 (岁)	省/市	TC (mmol/L)	LDL-C (mmol/L)	冠心病	黄色瘤	角膜弓	纯合子/ 复合杂合	cDNA 突变	氨基酸突变	发表时间
										?c.1253A > G	?p.Glu418Gly
										?c.1258C > A	?p.Trp419*
										?c.1448G > A	?p.Trp483*
										?c.1747C > T	?p.His583Tyr
										?c.1860G > A	?p.Trp620*
										?c.1879G > A	?p.Ala627Thr
										?c.1897C > T	?p.Arg633Cys
										?c.1954delAT	?p.Met652Glyfs*16
										?c.2030G > A	?p.Cys677Tyr
										?c.2000delG	?p.Cys667Leufs*6
										?c.2416insG	?p.Val806Glyfs*11
										?c.1984dupA	?p.Arg662Lysfs*7
										?c.2381_2382delTC	?p.Leu794Profs*22
										?c.218T > G	?p.Phe73Cys
										?c.516C > A	?p.Asp172Glu
										?c.1279C > T	?p.Arg427Trp
										?c.1601C > T	?p.Thr534Ile
										?c.1720C > A	?p.Arg574Ser
24	10/10	14.8±8.8		16.1±2.9	13.2±2.4	3	20	17	复合杂合	c.1439C>T,c.1729T>G	p.Ala480Val,p.Trp577Gly	2016^[24]
										c.1864G>T	p.Asp622Tyr
										c.1879G>A	p.Ala627Thr
									复合杂合	c.611G>A,c.673delA	p.Cys204Tyr,p.Lys225Asnfs*40
										c.691T>C	p.Cys231Arg
										c.2054C>T	p.Pro685Leu
									复合杂合	c.1448G>A,c.1363delC	p.Trp483,p.Gln455Serfs52
									复合杂合	c.517T>C,c.1757C>A	p.Cys173Arg,p.Ser586*
									复合杂合	c.428G>A,c.1744C>T	p.Cys143Tyr,p.Leu582Phe
									复合杂合	c.1448G>A,c.1879G>A	p.Trp483*,p.Ala627Thr
									复合杂合	c.1129T>G,c.1268T>C	p.Cys377Gly,p.Ile423Thr
									复合杂合	c.818-2A>G,c.1448G>A	NA,p.Trp483*
									复合杂合	c.1448G>A,c.2475C>G	p.Trp483*,p.Asn825Lys
									复合杂合	c.1448G>A,c.1216C>A	p.Trp483*,p.Arg406Arg
									复合杂合	c.514G>C,c.1723C>T	p.Asp172His,p.Leu575Phe
									复合杂合	c.1246C>T,c.1747C>T	p.Arg416Trp,p.His583Tyr
一般情况				治疗前血脂		临床表现			基因诊断			发表时间
序号	性别 (女/男)	年龄 (岁)	省/市	TC (mmol/L)	LDL-C (mmol/L)	冠心病	黄色瘤	角膜弓	纯合子/ 复合杂合	cDNA 突变	氨基酸突变	发表时间
									复合杂合	c.1448G>A,c.2132G>A	p.Trp483*,p.Cys711Tyr
									复合杂合	c.665G>T,c.2054C>T	p.Cys222Phe,p.Pro685Leu
25	女	26	天津	12	9.8				纯合子	c.1864G>T	p.Asp601Tyr	2016^[25]
26	女	14	湖南	17.1	16.6				纯合子	c.516C>A	p.Asp172Glu	2016^[26]
	女	25	湖南	20.2	18.2		+		复合杂合	c.760C>T, c.1216C>A	p.Gln254*, p.Arg406=
	女	31	湖南	18.5	16.5	+			复合杂合	c.1132C>T, c.1448G>A	p.Gln378, p.Trp483
	女	16	安徽	20.3	18.4		+	+	纯合子	c.1448G>A	p.Trp483*
27	男	8	安徽	15.9	13.9	+	+	+	复合杂合	c.1448G>A, c.1879G>A	p.Trp483*, p.Ala627Thr	2016^[27]
	男	26	安徽	14.8	11.3	+	+	+	复合杂合	c.1448G>A, c.1363delC	p.Trp483*,p.Gln455Serfs
	女	6	辽宁	17.3	12.8	+	+	+	复合杂合	c.1448G>A, c.2132G>T	p.Trp483*, p.Cys711Tyr
	女	21	湖南	15.7	14.7		+	+	复合杂合	c.1448G>A, c.2475C>G	p.Trp483*, p.Asn825Lys
	男	12	安徽	17.0	11.6	+	+	+	纯合子	c.1448G>A	p.Trp483*
	女	13	江苏	16.3	12.8	+	+	+	复合杂合	c.1448G>A, c.818-2A>G	p.Trp483*, NA
	女	22	四川	15.7	14.4		+	+	复合杂合	c.1448G>A, c.418G.A	p.Trp483*, p.Glu140Lys
	男	9	广西	16.1	12.6	+	+		复合杂合	c.1448G>A, c.1729T>G	p.Trp483*, p.Trp577Gly
	男	2.5	安徽	20.0	18.4		+		复合杂合	c.1448G>A, c.760C>T	p.Trp483, p.Gln254
	男	20	河北	16.0	15.4	+	+	+	复合杂合	c.1448G>A, c.1216C>A	p.Trp483*, p.Arg406=
28	女	22	江苏	22.6	18.9	+			纯合子	c.632_634delACT	p.His211_Ser212delinsPro	2016^[28]
29	女	3	湖南		16.2		+		复合杂合	c.796G>C, c.1048C>T	p.Asp266His, p.Arg350*	2016^[29]
	男	8	湖南		15.0		+		复合杂合	c.1448G>A, c.1720C>A	p.Trp483*, p.Arg574Ser
	男	3	湖南		19.2		+		纯合子	c.605T>C	p.Phe202Ser
	女	3	湖南		19.8		+		复合杂合	c.2030G>A, c.1257C>A	p.Cys677Tyr, p.Tyr419*
30	男	25	湖北	10.7#	8.7#	+	+		复合杂合	c.1879G>A, c.482T> C	p.Ala627Thr, p.Ile161Thr	2015^[30]
31	男	5	河南	21.2	19.8		+	+	纯合子	c.1187-10G> A	NA	2015^[31]
32	男	15	湖南	11.6#	10.3#	+	+		纯合子	c.298G>A	p.Asp100Asn	2015^[32]
33	女	22	陕西	11#	9.2#		+		复合杂合	c.400T>C, c.1246C> T	p.Cys134Arg, p.Arg416Trp	2015^[33]
34	男	32	湖南	9.9	9.0		+		纯合子	c.605T>C	p.Phe202Ser	2015^[34]
	男	12	湖南	19.0	16.4		+		纯合子	c.2030G>A	p.Cys677Tyr
	男	14	湖南	21.5	18.6				纯合子	c.605T>C	p.Phe202Ser
35	男	7	河南	19.8	13.9	+	+		复合杂合	c.97C>T, c.892delA, c.890A>C	p.Gln33*, p.Met298Cysfs, p.Asn297Thr	2015^[35]
36	男	23	中国台湾	14.95 mg/dl	12.69 mg/dl		+		复合杂合	c.1449G>A, c1879G>A	p.Trp483*, p.Ala627Thr	2015^[36]
37		6	中国台湾	595 mg/dl	438 mg/dl				复合杂合		p.Cys308Tyr, p.Ala410Thr	2015^[37]
		21	中国台湾	517 mg/dl	404 mg/dl				复合杂合		p.Cys308Tyr, p.His562Tyr
		18	中国台湾	460 mg/dl	NA mg/dl				复合杂合		p.Cys308Tyr, p.Asp69Asn
一般情况				治疗前血脂		临床表现			基因诊断			发表时间
序号	性别 (女/男)	年龄 (岁)	省/市	TC (mmol/L)	LDL-C (mmol/L)	冠心病	黄色瘤	角膜弓	纯合子/ 复合杂合	cDNA 突变	氨基酸突变	发表时间
		17	中国台湾	576 mg/dl	474 mg/dl				复合杂合		p.Cys308Tyr, p.Gly457Arg
		4	中国台湾	384 mg/dl	334 mg/dl				复合杂合		p.His562Tyr, p.Ala410Thr
		11	中国台湾	598 mg/dl	415 mg/dl				复合杂合		p.Trp462*, p.Asp679Gly
		8	中国台湾	672 mg/dl	528 mg/dl				复合杂合		p.Cys308Tyr, p.Ala410Thr
		11	中国台湾	848 mg/dl	NA mg/dl				复合杂合		p.Arg395Trp, exon 3-5 duplication
		4	中国台湾	1200 mg/dl	1125 mg/dl				复合杂合	c.64del G, c.1953-1954 delTA
		21	中国台湾	>800 mg/dl	NA mg/dl				复合杂合		p.Asp47Asn, NA
38	男	12	上海	18.7	18.3	+	+	+	纯合子	c.2389G>A	p.Val797Met	2014^[38]
38	男	3	上海	27.6	22.9	+	+		杂合子	c.513delC, c.1959T>C	p.Pro171fs, p.Val653=	2014^[38]
39	女	5	北京	11.98	9.22		+	+	杂合子	c.1257C>A	p.Tyr398*	2014^[39]
40	女	17	上海	21.5	19.4	+	+		纯合子	c.541C>T	p.Pro181Ser	2014^[40]
41	男	2	北京	24.7	14.8		+	+	复合杂合	c.1268T>C, c.1129T>G	p.Ile425Thr, p.Cys377Gly	2014^[41]
42	女	40	北京	16.9#	13.9#	+	+		杂合子	c.1907G>T	p.Gly615Val	2014^[42]
43	男	12	北京	19.5	17.1	+	+	+	杂合子	c.97C>T	p.Gln33*	2013^[43]
44	女	17	安徽	18.9	10.9	+	+		杂合子	c.1448G>A	p.Trp462*	2012^[44]
45	男	9	上海	14.0	11.3		+		复合杂合	c.1747C>T, c.2054C>T	p.His583Tyr, p.Pro685Leu	2012^[45]
46	3/1	20(12-45)	中国台湾	477(410-694) mg/dl	411(321-570) mg/dl	2	3		复合杂合	c.986G>A, c.268G>A, c.1291G>A, 1432G>A, c.769C>T/1765G>A	p.Cys329Tyr, p.Asp90Asn, p.Ala431Thr, p.Gly478Arg, p.Arg257Trp, p.Asp589Asn	2012^[46]
	7/6	50(11-69)	中国台湾	343(314-445) mg/dl	263(204-370) mg/dl	5	4		杂合子	c.986G>A	p.Cys329Tyr
	8/6	45(6-69)	中国台湾	332(282-453) mg/dl	233(204-354) mg/dl	4	3		杂合子	c.1747C>T	p.His583Tyr
47	男	19	山东	12.6#	11.1	+	+	+	纯合子	c. 1581G>A	NA	2011^[47]
	男	17	山东	15.5	13.0	+	+	+	纯合子	c. 1581G>A	NA
	女	16	山东	14.5	12.0	+	+		纯合子	c. 1581G>A	NA
48	组1：26/15 组2：54/31	40±20 43±16	中国台湾	408±83 mg/dl 338±49 mg/dl	311±78 mg/dl 250±45 mg/dl					c.268G>A	p.Asp90Asn	2011^[48]
										c.310T>C	p.Cys104Arg
										c.344G>A	p.Arg115His
										c.516C>G	p.Asp172Glu
										c.590G>A	p.Cys197Tyr
										c.599T>G	p.Phe200Cys
										c.682G>T	p.Glu228*
										c.769C>T	p.Arg257Trp
										c.828C>A	p.Cys276*

附表1

附表1

续"

一般情况				治疗前血脂		临床表现			基因诊断			发表时间
序号	性别 (女/男)	年龄 (岁)	省/市	TC (mmol/L)	LDL-C (mmol/L)	冠心病	黄色瘤	角膜弓	纯合子/ 复合杂合	cDNA 突变	氨基酸突变	发表时间
53	男	16	北京	15.5	13.8	+	+	+	纯合子	c.1448G>A	p.Trp462*	2009^[53]
	男	13	北京	28.8	27.7	+	+	+	纯合子	c.313+1G>A	p.Leu64_Pro105delinsSer
	女	13	北京	14.7	13.3		+	+	复合杂合	c.428G>A, c.1211T>C	p.Cys122Tyr, p.Thr383Ile
	男	34	北京	17.1	14.5	+			纯合子	c.691T>C	p.Cys231Arg
54	女	34	湖北	16.2	13.8		+		纯合子	c.1879G>A	p.Ala627Thr	2009^[54]
54	男	23		8.36	6.47				杂合子	c. 1511G>A	p.Trp483*	2009^[54]
55	男	6	安徽	16.4	14.7	+	+		复合杂合	c.1448G>A, c.1879G>A	p.Trp462*, p.Ala606Thr	2009^[55]
56	女	4	河南	23.3	19.9	+	+	+	复合杂合	c.1879A>G, c.1864G>T	p.Ala606Thr, p. Asp601Tyr	2009^[56]
57	男	6	安徽	19.5	18.0		+		纯合子	c.1075C>T	p.Gln359*	2009^[57]
58	男	8		14.91	12.85				纯合子	c.1439C>T	p.Ala459Val	2008^[58]
59	男	23	北京	11.81	8.33		+		杂合子	c.358G>T	p.Asp108Tyr	2008^[59]
60	男	9	北京	19.5	15.3				复合杂合	c.685del A, c.386A>G	NA, p.Asp129Gly	2007^[60]
61	男	12		20.34	16.78				杂合子	c.558G>A	p.Trp165*	2007^[61]
61	男	9	北京	20.3	16.8	+	+		杂合子/ 纯合子	c.495G>A/IVS5-1G>A	p.Trp165*/NA	2007^[61]
62	男	9		19.49	15.25		+		复合杂合	c.80T>C,c.1413G> A,c.685delA,c.386A>G	p.Trp6=,p.Gly450=, p.685del 1,p.Asp129Gly	2007^[60]
	男	41		10.64	8.75				复合杂合	c.80T>C,c.1413G> A,c.685delA	p.Trp6=,p.Gly450=, p.685del 1
	女	40		8.11	6.33				杂合子	c.80T>C,c.386A>G	p.Trp6=,p.Asp129Gly
63	29/22	55 (48-64)	中国台湾	311 (281-343) mg/L	208 (189-245) mg/L		+	+		c.1747C>T	p.His562Tyr	2006^[62]
						+	+	+		c.1953delTA	NA
										c.1592T>A	p.Met510Lys
						+				c.1597T>C	P.Trp512Arg
										c.1816G>A	p.Ala606Thr
										c.986G>A	p.Cys329Tyr
									复合杂合	c.769C>T,c.1765G>A	p.Arg236Trp,p.Asp568Asn
										c.1246C>T	p.Arg395Trp
										c.1322T>C	p.Ile420Thr
										c.268G>A	p.Asp90Asn
										c.681C>A	p.D206E
										c.682G>T	p.E207X
64	女	29		13.38	11.16		+		复合杂合	?c.292G>A, ?c.1864G>A	?p.Gly98Ser, ?p.Asp622Asn	2005^[63]
65	男	36	中国台湾	8.33	6.67				杂合子	c.2043C>G	p.Cys660Trp	2005^[64]
66	男	26	浙江	19.1	17.1	+	+		纯合子	c.2048A>C	p.Glu683Ala	2004^[65]
67	女	4		17.81	15.22		+		纯合子	c.1304A>G	p.Glu414Gly	2004^[66]
一般情况				治疗前血脂		临床表现			基因诊断			发表时间
序号	性别 (女/男)	年龄 (岁)	省/市	TC (mmol/L)	LDL-C (mmol/L)	冠心病	黄色瘤	角膜弓	纯合子/ 复合杂合	cDNA 突变	氨基酸突变	发表时间
	女	33		14.93	10.44	+	+		纯合子	c.1329delG	p.422fs
	男	12		12.09	10.44		+		纯合子	c.1544A>G	p.Asn494Ser
	男	7		21.3	19.2	+	+		纯合子	c.2400insC	p.779fs
	女	19		15.66	14.68		+		复合杂合	c.1849 A>G, c.1877C>T	p.Lys596Glu, p.Glu605Val
	女	6		22.3	18.29		+		纯合子	c. 2021A>G	p.Asn653Ser
	男	15		15.48			+		纯合子	c. 1100T>A	p.Leu346His
	女	19		15.66	14.68		+		纯合子	c. 826T>G	p.Cys255Arg
68	男	10	北京	14.7	12.5		+		杂合子	c. 444T>A	p.Cys127Trp	2004^[67]
69	女	10	北京	14.7	13.4	+	+		复合杂合	c. 428G>A, c.1211C>T	p.Cys122Tyr, p.Thr383Ile	2003^[68]
70	男	11	江苏	15.7	15.1	+			纯合子	c.890delA	p.Asn297Thrfs	2003^[69]
70	男	2	江苏	17.4	16.4	+			纯合子	c.890delA	p.Asn297Thrfs	2003^[69]
71	男		浙江						纯合子	c.683A>C	p.Gln207Ala	2002^[70]
72	女	14	北京	15.4	11	+	+		纯合子	c.1816G>A	p.Ala606Thr	2001^[71]
	女	12	北京	18.6	13.4	+	+		纯合子	c.1816G>A	p.Ala606Thr
	男	10	北京	23.9	19.8	+	+		纯合子	c.850T>C	p.Cys263Arg
73	男	3	北京	23.9	16.2		+		纯合子	c.850T>C	p.Cys263Arg	2001^[72]
74	男	11	山东	21.3	19.6	+	+		复合杂合	c.811G>A, c.814C>T, c.830G>A	p.Val271Ile, NA	2001^[73]
75	男	62		8.3	6.7		+		纯合子	c. ?-152 G>T	NA	2000^[74]
	女	53		9.9	8.1				纯合子	c. ?2108insTGCTGGC	p.682fs
	女	71		7.1	5	+			纯合子	c.2048G>A	p.Ala663Thr
	男	44		9.6	6.7	+			纯合子	c.2087G>A	p.Cys675Tyr
	男	44	-	11	9.3		+		纯合子	c.757C>T	p.Arg232Trp
	女	59		10		+	+	+	纯合子	c.986G>A	p.Cys329Tyr
	男	44	-	11	9.3	+	+		纯合子	c.344G>A	p.Arg94His
	男	31	-	9.2	7.1		+		纯合子	?c.77del GA	p.Cys5Thrfs
76	男	43	中国香港	16.0	14.3	+	+		复合杂合	c.-44C>T, c.2054C>T	NA, p.Pro664Leu	1998^[75]
	女	54		8.8	5.9			+	杂合子	c.1432G>A	p.Gly478Arg
	女	55		12	10.2		+		杂合子	c.1285G>A	p.Val408Met
	女	19		10.9	9.6		+		杂合子	c.1880C>T	p.Ala606Val
	男	42		9.5	7.6			+	杂合子	c.1474G>A	p.Asp471Asn
	男	47		10.3	8.7		+		杂合子	c.1779delC	p.572fs
	女	80		11.3	9.8		+		纯合子	?c.1706-1G3T	NA
	男	44		9.5	7.9			+	杂合子	c.1241T>G	p.Leu393Arg
	女	39		8.8	6.8		+		纯合子	c.364A>T	?p.Ile101Phe
	女	46		10.1	8.3				纯合子	c.571C>T	?p.Gly170*
一般情况				治疗前血脂		临床表现			基因诊断			发表时间
序号	性别 (女/男)	年龄 (岁)	省/市	TC (mmol/L)	LDL-C (mmol/L)	冠心病	黄色瘤	角膜弓	纯合子/ 复合杂合	cDNA 突变	氨基酸突变	发表时间
77				9.33	7.63	+			杂合子	c.550C>T	p.Cys163Arg	1998^[76]
78	7			9.3-12.0	6.3-10.2					c.986G>A	p.Cys329Tyr	1998^[77]
										c.1241T>G	p.Leu393Arg
										c.1285G>A	p.Val408Met
79	男	11	江苏	15.8	14.1		+		复合杂合	Described as Exons 11-14 deleted, c.1747C > T	NA, p.His583Tyr	1994^[78]
	男	9	江苏	19.0	17.3		+		纯合子	c.1448G>A	p.Trp483*
	女	22	江苏	14.0	12.8	+	+		纯合子	c.682G>T	p.Glu228*
	男	37	江苏	15.5	14.62		+	+	杂合子	c.2015delT	p.615fs
	女	12	江苏	11.2	9.8		+		复合杂合	c.2415delC, c.1664T>C	p.Gly805Glyfs, p.Leu555Pro
	女	9	江苏	8.2#	6.8#		+		复合杂合	c.1816G>A, c.809G>A	p.Ala606Thr, p.Cys270Tyr
	男	37	江苏	15.5	14.6	+	+		复合杂合	c.12G>A, c.1952delA	p.Trp4*, p.Asp651Aspfs
	女	34	江苏	20.1	18.7	+	+		复合杂合	c.12G>A, c.1952delA	p.Trp4*, p.Asp651Aspfs
	女	13	江苏	15.4	13.8		+		杂合子	NA	NA
	女	34	江苏	20.08	18.72	+	+	+	复合杂合	c.13G>A, c.1952delA	p.Trp18*, p.Asp651Aspfs

附表1

附表2

中国FH患者Apo B基因突变致病位点总结"

一般情况				治疗前血脂		临床表现			基因诊断			发表时间
序号	性别 (女/男)	年龄 (岁)	省/市	TC (mmol/L)	LDL-C (mmol/L)	冠心病	黄色瘤	角膜弓	纯合子/ 复合杂合	cDNA突变	氨基酸突变	发表时间
1	198/110	48.3?±?11.2		11.06?±?1.58	8.41?±?1.39	127	9			c.10579C>T	p.Arg3527Trp	2020^[3]
2	40/40	54.21±13.38		8.85 (7.95-10.00)	5.52 (4.96-6.28)	48			复合杂合	c.C8216T,c.C1853T	p.Pro2739Leu,p.Ala618Val	2019^[79]
2	40/40	54.21±13.38		8.85 (7.95-10.00)	5.52 (4.96-6.28)				复合杂合	c.C10579T,c.C8216T, c.C1853T	p.Arg3527rp,p.Pro2739Leu,p.Ala618Val	2019^[79]
3	1/9	44.80 ± 6.36		5.04 (4.03-5.91)	3.39 (2.58-4.08)	+			杂合子	c.10579C>T	p.Arg3527Trp	2019^[7]
4	37/188	46.64?±?7.21			3.63 (2.97- 4.35)				杂合子	c.10579C>T	p.Arg3527Trp	2019^[6]
5	6/99	31.69±5.65		6.62±7.49	5.77±3.38	20	12			c.1594C>T	p.Arg532Trp	2018^[80]
										c.6110T>C	p.Ile2037Thr
										c.7223C>T	p.Ser2408Phe
										c.8267G>T	p.Gly2756Val
										c.8462C>T	p.Pro2821Leu
										c.889C>T	p.Arg297Cys
										c.9164A>G	p.Asn3055Ser
6	112/173	?49 ± 12		?7.03 ± 2.53	?5.22 ± 2.12	233	28			c.10093C > G	p.His3365Asp	2018^[16]
一般情况				治疗前血脂		临床表现			基因诊断			发表时间
序号	性别 (女/男)	年龄 (岁)	省/市	TC (mmol/L)	LDL-C (mmol/L)	冠心病	黄色瘤	角膜弓	纯合子/ 复合杂合	cDNA突变	氨基酸突变	发表时间
7	115/104	31.15 ± 15.21		11.15 ± 3.96	8.32 ± 3.83	46	25			c.11052A>T	p.Leu3684Phe	2017^[23]
										c.11585T>C	p.Ile3862Thr
										c.10579C>T	p.Arg3527Trp
										c.10580G>A	p.Arg3527Gln
8	女	31	北京	13.13	11.32	+	+		复合杂合	c.1594C>T	p.Arg532Trp	2017^[18]
	男	12	北京	10.92	9.26	+	+		复合杂合	c.1594C>T	P.Arg532Trp
	男	21	北京	19.12	14.09	+	+		复合杂合	c.581C>T	p.Thr194Met
9	男	20		7.8	5.47				杂合子	c.10579C>T	p.Arg3500Trp	2016^[26]
10	10/2	57(23-69)	中国台湾	327(300-394) mg/dl	235(200-318) mg/dl	5	5		杂合子	c.10579C>T	p.Arg3500Trp	2012^[46]
11	组1：26/15 组2：54/31	40±20 43±16	中国台湾	408±83mg/dl 338±49mg/dl	311±78 mg/dl 250±45 mg/dl					c.10579C > T	p.Arg3500Trp	2011^[48]
12	女	5		16.8	13.1		+	+		c.10707C>T	p.Arg3500Trp	2010^[52]

附表2

附表3

附表4

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药物类别	名称	作用机制	参考文献
HMG-CoA 还原酶抑制剂	瑞舒伐他汀、匹伐他汀、氟伐他汀等	通过增强胆固醇调节元件结合蛋白2激活,上调 LDLR表达,促进对血液中胆固醇的吸收,降低血液中的LDL-C 水平	[35]
尼曼-匹克C1型类似蛋白1抑制剂	依折麦布	作用于小肠绒毛刷状缘,通过抑制胆固醇转运蛋白尼曼-匹克C1型类似蛋白1,选择性地抑制肠道对胆固醇的吸收,减少肝胆固醇储备,?上调肝细胞表面LDLR,从而增加对血LDL-C的清除,且不影响肠道对其他脂质的吸收	[36]
胆汁酸螯合剂	考来烯胺、考来替泊	胆酸螯合剂为碱性阴离子交换树脂,可阻断肠道内胆汁酸中胆固醇的重吸收,促进肝细胞内胆固醇向胆汁酸转化并上调LDLR的表达,从而降低血LDL-C水平	[16]
PCSK9抑制剂	依洛尤单抗	直接阻止循环中PCSK9与LDLR相结合,减少PCSK9 介导的LDLR的分解,加强其对LDL-C的清除能力	[37]
MTTP抑制剂	洛美他派	直接抑制MTTP活性,抑制甘油三酯向Apo B的转运,减少极低密度脂蛋白的合成,从而降低血LDL-C的水平	[38]
Apo B合成抑制剂	米泊美生	可与Apo B mRNA结合并抑制其翻译从而减少载脂蛋白Apo B合成的反义寡核苷酸,降低血LDL-C的水平	[38]
ANGPTL3抑制剂	依维苏单抗	可独立于LDLR降低LDL-C水平,并可降低发生心血管事件的风险	[39]
白细胞介素-1β 配体抑制剂	卡那津单抗	抗炎作用,抑制白细胞介素6信号通路,可降低发生心血管事件的风险	[40]

家族性高胆固醇血症研究进展

Progress on familial hypercholesterolemia

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