家族性高胆固醇血症研究进展

doi:10.16288/j.yczz.21-218

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

• Research Trends • Previous Articles Next Articles

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)

Abstract

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

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.

Figures/Tables 11

Fig. 1

Fig. 2

Fig. 3

Table 1

Supplementary Table 1

Summary of the mutation gene loci of previously reported Chinese patients with LDLR mutations"

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

Supplementary Table 1

Supplementary Table 1

Continued"

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*

Supplementary Table 1

Supplementary Table 1

Continued"

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

Supplementary Table 1

Supplementary Table 2

Summary of the mutation gene loci of previously reported Chinese patients with Apo B mutations"

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]

Supplementary Table 2

Supplementary Table 3

Supplementary Table 4

References 82

[1]	Krogh HW, Mundal L, Holven KB, Retterstol K. Patients with familial hypercholesterolaemia are characterized by presence of cardiovascular disease at the time of death. Eur Heart J, 2016, 37(17):1398-1405.
[2]	Li S, Zhang Y, Zhu CG, Guo YL, Wu NQ, Gao Y, Qing P, Li XL, Sun J, Liu G, Dong Q, Xu RX, Cui CJ, Li JJ. Identification of familial hypercholesterolemia in patients with myocardial infarction: A Chinese cohort study. J Clin Lipidol, 2016, 10(6):1344-1352. doi: 10.1016/j.jacl.2016.08.013
[3]	Defesche JC, Gidding SS, Harada-Shiba M, Hegele RA, Santos RD, Wierzbicki AS. Familial hypercholesterolaemia. Nat Rev Dis Primers, 2017, 3:17093. doi: 10.1038/nrdp.2017.93 pmid: 29219151
[4]	Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Borén J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AFH, Stroes E, Taskinen MR, Tybjaerg-Hansen A, European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J, 2013, 34(45):3478-3490a. doi: 10.1093/eurheartj/eht273
[5]	Gidding SS, Champagne MA, de Ferranti SD, Defesche J, Ito MK, Knowles JW, McCrindle B, Raal F, Rader D, Santos RD, Lopes-Virella M, Watts GF, Wierzbicki AS, American Heart Association Atherosclerosis, Hypertension, and Obesity in Young Committee of Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and Council on Lifestyle and Cardiometabolic Health. The agenda for familial hypercholesterolemia: a scientific statement from the American heart Association. Circulation, 2015, 132(22):2167-2192. doi: 10.1186/s12881-019-0901-0
[6]	Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, Kuivenhoven JA, Nordestgaard BG, Descamps OS, Steinhagen-Thiessen E, Tybjaerg-Hansen A, Watts GF, Averna M, Boileau C, Borén J, Catapano AL, Defesche JC, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Ray KK, Stalenhoef AFH, Stroes E, Taskinen MR, Wiegman A, Wiklund O, Chapman MJ, European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J, 2014, 35(32):2146-2157. doi: 10.1093/eurheartj/ehu274
[7]	Ding YM, Ding YN, Sun WQ, Liu JG. Talking about chronic disease management from the diagnosis and treatment status of patients with familial hypercholesterolemia in China. Chin J Gerontol, 2020, 40(17):3803-3807.
	丁雅明, 丁亚娜, 孙婉琴, 刘建根. 从中国家族性高胆固醇血症患者的诊断及治疗现状谈慢病管理. 中国老年学杂志, 2020, 40(17):3803-3807.
[8]	Teng HB, Gao Y, Guo YL, Wu CQ, Zhang HB, Zheng X, Lu JP, Li Y, Qiao SB, Liu JM. Detection rate and clinical characteristics of familial hypercholesterolemia among Chinese patients with coronary artery disease. Chin Circul J, 2021, 36(5):444-450.
	滕浩波, 高岩, 郭远林, 吴超群, 张海波, 郑昕, 路甲鹏, 李艳, 乔树宾, 刘佳敏. 我国成人冠心病患者中家族性高胆固醇血症检出率及治疗现状. 中国循环杂志, 2021, 36(5):444-450.
[9]	Chen PP, Chen X, Zhang SY. Current Status of Familial Hypercholesterolemia in China: A Need for Patient FH Registry Systems. Front Physiol, 2019, 10:280.
[10]	Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet, 2003, 34(2):154-156. doi: 10.1038/ng1161
[11]	Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, Calandra S, Bertolini S, Cossu F, Grishin N, Barnes R, Cohen JC, Hobbs HH. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science, 2001, 292(5520):1394-1398.
[12]	Zhu CG, Li S, Wang ZF, Yin KL, Wu NQ, Guo YL, Gao Y, Li XL, Qing P, Liu G, Dong Q, Zhou Z, Li JJ. Homozygous familiar hypercholesterolemia in China: Case series from the national lipid clinics and literature review. IJC Met & Endocr, 2017, 14:75-80.
[13]	Atherosclerosis and Coronary Heart Disease Working Group of Chinese Society of Cardiology, Editorial Board of Chinese Journal of Cardiology. Chinese expert consensus on screening, diagnosis and treatment of familial hypercholesterolemia. Chin J Cardiol, 2018, 46(2):99-103.
	中华医学会心血管病学分会动脉粥样硬化及冠心病学组, 中华心血管病杂志编辑委员会. 家族性高胆固醇血症筛查与诊治中国专家共识. 中华心血管病杂志, 2018, 46(2):99-103.
[14]	Peng J, Wu X, Wang SL, Zhang S, Wang XM, Liu ZS, Hong J, Ye PC, Lin J. Familial hypercholesterolemia in China half a century: a review of published literature. Atheroscler Suppl, 2019, 36:12-18. doi: 10.1016/j.atherosclerosissup.2019.01.003
[15]	Mahdieh N, Heshmatzad K, Rabbani B. A systematic review of LDLR, PCSK9, and APOB variants in Asia. Atherosclerosis, 2020, 305:50-57. doi: 10.11909/j.issn.1671-5411.2018.06.006 pmid: 30108616
[16]	van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC, Huijgen R, Fouchier SW, Wijburg FA, Kastelein JJP, Wiegman A. Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. Circulation, 2011, 123(11):1167-1173. doi: 10.1161/CIRCULATIONAHA.110.979450
[17]	Cao YX, Wu NQ, Sun D, Liu HH, Jin JL, Li S, Guo YL, Zhu CG, Gao Y, Dong QT, Liu G, Dong Q, Li JJ. Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease. J Transl Med, 2018, 16(1):345. doi: 10.1016/j.atherosclerosis.2018.08.022
[18]	Du R, Fan LL, Lin MJ, He ZJ, Huang H, Chen YQ, Li JJ, Xia K, Zhao SP, Xiang R. Mutation detection in Chinese patients with familial hypercholesterolemia. Springerplus, 2016, 5(1):2095. doi: 10.1186/s40064-016-3763-3
[19]	Xiang R, Fan LL, Lin MJ, Li JJ, Shi XY, Jin JY, Liu YX, Chen YQ, Xia K, Zhao SP. The genetic spectrum of familial hypercholesterolemia in the central south region of China. Atherosclerosis, 2017, 258, 84-88. doi: 10.1371/journal.pone.0189316
[20]	Teng YN, Pan JP, Chou SC, Tai DY, Lee-Chen GJ. Familial defective apolipoprotein B-100: detection and haplotype analysis of the Arg(3500)→Gln mutation in hyperlipidemic Chinese. Atherosclerosis, 2000, 152(2):385-390. doi: S0021-9150(17)30263-0 pmid: 28645073
[21]	Lee C, Cui YX, Song JX, Li SF, Zhang F, Wu MY, Li L, Hu D, Chen H. Effects of familial hypercholesterolemia- associated genes on the phenotype of premature myocardial infarction. Lipids Health Dis, 2019, 18(1):95.
[22]	Chiou KR, Charng MJ, Chang HM. Array-based resequencing for mutations causing familial hypercholesterolemia. Atherosclerosis, 2011, 216(2):383-389. doi: 10.1161/ATVBAHA.116.308456 pmid: 27932355
[23]	Yang KC, Su YN, Shew JY, Yang KY, Tseng WK, Wu CC, Lee YT. LDLR and ApoB are major genetic causes of autosomal dominant hypercholesterolemia in a Taiwanese population. J Formos Med Assoc, 2007, 106(10):799-807. doi: S0021-9150(17)30059-X pmid: 28235710
[24]	Chiou KR, Charng MJ. Common mutations of familial hypercholesterolemia patients in Taiwan: characteristics and implications of migrations from southeast China. Gene, 2012, 498(1):100-106. doi: 10.1016/j.gene.2012.01.092
[25]	Stoekenbroek RM, Kastelein JJP. Proprotein convertase subtilisin/kexin type 9: from genetics to clinical trials. Curr Opin Cardiol, 2018, 33(3):269-275. doi: 10.1097/HCO.0000000000000517 pmid: 29561319
[26]	Guo QY, Feng XX, Zhou YJ. PCSK9 variants in familial hypercholesterolemia: a comprehensive synopsis. Front Genet, 2020, 11:1020. doi: 10.1186/s40064-016-3763-3
[27]	Shaik NA, Al-Qahtani F, Nasser K, Jamil K, Alrayes NM, Elango R, Awan ZA, Banaganapalli B. Molecular insights into the coding region mutations of low-density lipoprotein receptor adaptor protein 1 (LDLRAP1) linked to familial hypercholesterolemia. J Gene Med, 2020, 22(6):e3176. doi: 10.1016/j.jacl.2015.12.016 pmid: 27206941
[28]	Tang L. Screening of novel pathogenic genes of familial hypercholesterolemia and effect of soluble epoxide hydrolase gene mutant on the function of LDLR [Dissertation]. Huazhong University of Science and Technology, 2016. doi: 10.1016/j.ijcard.2016.01.087
	唐玲. 家族性高胆固醇血症患者新致病基因筛查及可溶性环氧化物水解酶基因突变体对细胞LDLR功能的影响[学位论文]. 华中科技大学, 2016. doi: 10.1016/j.ijcard.2016.01.087
[29]	Harris TR, Hammock BD. Soluble epoxide hydrolase: gene structure, expression and deletion. Gene, 2013, 526(2):61-74. doi: 10.1017/S1047951115000591
[30]	El-Sherbeni AA, El-Kadi AOS. The role of epoxide hydrolases in health and disease. Arch Toxicol, 2014, 88(11):2013-2032. doi: 10.1016/j.ijcard.2015.07.092 pmid: 26298359
[31]	Yang SM, Ke XA, Liang HT, Li R, Zhu HJ. Case report: a clinical and genetic analysis of childhood growth hormone deficiency with familial hypercholesterolemia. Front Endocrinol (Lausanne), 2021, 12:691490. doi: 10.1038/srep11380
[32]	Parini P, Angelin B, Lobie PE, Norstedt G, Rudling M. Growth hormone specifically stimulates the expression of low density lipoprotein receptors in human hepatoma cells. Endocrinology, 1995, 136(9):3767-3773. pmid: 7649083
[33]	Khalil YA, Rabès JP, Boileau C, Varret M. APOE gene variants in primary dyslipidemia. Atherosclerosis, 2021, 328:11-22. doi: 10.1016/j.ijporl.2015.04.020
[34]	Brown MS, Goldstein JL. Expression of the familial hypercholesterolemia gene in heterozygotes: mechanism for a dominant disorder in man. Science, 1974, 185(4145):61-63. doi: 10.1007/s12010-015-1554-x
[35]	Besseling J, Hovingh GK, Huijgen R, Kastelein JJP, Hutten BA. Statins in familial hypercholesterolemia: consequences for coronary artery disease and all-cause mortality. J Am Coll Cardiol, 2016, 68(3):252-260. doi: S0735-1097(16)33132-1 pmid: 27417002
[36]	Hamilton-Craig I, Kostner K, Colquhoun D, Woodhouse S. Combination therapy of statin and ezetimibe for the treatment of familial hypercholesterolemia. Vasc Health Risk Manag, 2010, 6:1023-1037. doi: 10.1111/ced.12644 pmid: 25807990
[37]	Qian LJ, Gao Y, Zhang YM, Chu M, Yao J, Xu D. Therapeutic efficacy and safety of PCSK9-monoclonal antibodies on familial hypercholesterolemia and statin- intolerant patients: A meta-analysis of 15 randomized controlled trials. Sci Rep, 2017, 7(1):238. doi: 10.1016/j.jacl.2014.11.011
[38]	Santos RD, Gidding SS, Hegele RA, Cuchel MA, Barter PJ, Watts GF, Baum SJ, Catapano AL, Chapman MJ, Defesche JC, Folco E, Freiberger T, Genest J, Hovingh GK, Harada-Shiba M, Humphries SE, Jackson AS, Mata P, Moriarty PM, Raal FJ, Al-Rasadi K, Ray KK, Reiner Z, Sijbrands EJG, Yamashita S, International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Lancet Diabetes Endocrinol, 2016, 4(10):850-861. doi: 10.1016/S2213-8587(16)30041-9
[39]	Gaudet D, Gipe DA, Pordy R, Ahmad Z, Cuchel M, Shah PK, Chyu KY, Sasiela WJ, Chan KC, Brisson D, Khoury E, Banerjee P, Gusarova V, Gromada J, Stahl N, Yancopoulos GD, Hovingh GK. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N Engl J Med, 2017, 377(3):296-297.
[40]	Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ, CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med, 2017, 377(12):1119-1131. doi: 10.1016/j.ijcard.2014.06.083
[41]	Joint committee issued Chinese guideline for the management of dyslipidemia. 2016 Chinese guideline for the management of dyslipidemia in adults. Chin Circul J, 2016, 31(10):937-950.
	中国成人血脂异常防治指南修订联合委员会. 中国成人血脂异常防治指南(2016年修订版). 中国循环杂志, 2016, 31(10):937-950.
[42]	Thompson GR. Managing homozygous familial hypercholesterolaemia from cradle to grave. Atheroscler Suppl, 2015, 18:16-20. doi: 10.1371/journal.pone.0092703
[43]	Writing Committee, Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD, DePalma SM, Minissian MB, Orringer CE, Smith SC. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American college of cardiology task force on clinical expert consensus documents. J Am Coll Cardiol, 2016, 68(1):92-125. doi: 10.4103/0301-4738.118456 pmid: 24088637
[44]	Zhao L, Wen J, Guo YL. Research progress of liver transplantation for patients with homozygous familial hypercholesterolemia. Chin J Arteriosclerosis, 2021, 29(4):353-358.
	赵量, 温军, 郭远林. 肝脏移植治疗纯合型家族性高胆固醇血症的研究进展. 中国动脉硬化杂志, 2021, 29(4):353-358.
[45]	Stefanutti C, Julius U, Watts GF, Harada-Shiba M, Cossu M, Schettler VJ, De Silvestro G, Soran H, Van Lennep JR, Pisciotta L, Klör HU, Widhalm K, Moriarty PM, MIGHTY MEDIC Multinational Society. Toward an international consensus-integrating lipoprotein apheresis and new lipid-lowering drugs. J Clin Lipidol, 2017, 11(4): 858-871.e3.
[46]	Alim A, Tokat Y, Erdogan Y, Gokkaya Z, Dayangac M, Yuzer Y, Oezcelik A. Liver transplantation for homozygote familial hypercholesterolemia: the only curative treatment. Pediatr Transplant, 2016, 20(8):1060-1064. doi: 10.1016/j.gene.2012.01.092
[47]	Li JJ, Li S, Zhu CG, Wu NQ, Zhang Y, Guo YL, Gao Y, Li XL, Qing P, Cui CJ, Xu RX, Jiang ZW, Sun J, Liu G, Dong Q. Familial hypercholesterolemia phenotype in Chinese patients undergoing coronary angiography. Arterioscler Thromb Vasc Biol, 2017, 37(3):570-579. doi: 10.1161/ATVBAHA.116.308456 pmid: 27932355
[0]	附加材料的参考文献(References):
[1]	Xu G, Zhao P, Cai CQ. Late-onset glutaric aciduria type Ⅱ combined with spinal cord injury with familial hypercholesterolemia: a case report. Tianjin Medical Journal, 2020, 48(9):891-3.
	徐刚, 赵澎, 蔡春泉. 伴脊髓损伤的晚发型戊二酸尿症Ⅱ型合并家族性高胆固醇血症一例报告. 天津医药, 2020, 48(9):891-3.
[2]	Wang DY, Zhang YM, Che FY, Chu JP, Zhang LY, Li H, Liu BL, Yao ZY, Zhao YW. Genotype‑phenotype analysis of a homozygous familial hypercholesterolemia pedigree. Chinese Journal of Pediatrics, 2020, 58(2):101-6.
	王丹颖, 张艳敏, 车凤玉, 楚建平, 张李钰, 李环, 刘百灵, 姚振宇, 赵煜雯. 纯合型家族性高胆固醇血症家系基因型与表型分析. 中华儿科杂志, 2020, 58(2):101-6.
[3]	Wang H, Yang H, Liu Z, Cui K, Zhang Y, Zhang Y, Zhao K, Yin K, Li W, Zhou Z. Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia. J Atheroscler Thromb. 2020, 27(12):1288-98.
[4]	Liu Z, Peng J, Wang S, Jiang T, Zhang W, Zhang C, Chen Y, Meng K, Lin J. Percutaneous coronary intervention for a Chinese familial hypercholesterolemia homozygous under the guidance of optical coherence tomography. Atheroscler Suppl. 2019, 36:19-23.
[5]	Jin W, Zhang Q, Wang B, Pan L, Qin H, Yang D, Zhou X, Du Y, Lin L, Kutryk MJ. Cascade screening for familial hypercholesterolemia-identification of the C308Y mutation in multiple family members and relatives for the first time in mainland China. BMC Med Genet. 2019, 20(1):173.
[6]	Lee C, Cui Y, Song J, Li S, Zhang F, Wu M, Li L, Hu D, Chen H. Effects of familial hypercholesterolemia-associated genes on the phenotype of premature myocardial infarction. Lipids Health Dis. 2019, 18(1):95.
[7]	Cui Y, Li S, Zhang F, Song J, Lee C, Wu M, Chen H. Prevalence of familial hypercholesterolemia in patients with premature myocardial infarction. Clin Cardiol. 2019, 42(3):385-90.
[8]	Liu J, Liu F. Analysis of Pathogenic Gene Mutation in Patients with Familial Hypercholesterolemia. Journal of Medical Research, 2019; 48(12):133-7.
	刘军, 刘芳. LDLR基因突变致家族性高胆固醇血症家系分析. 医学研究杂志, 2019, 48(12):133-7.
[9]	Cheng X, Huang Y, Qiu X, Cheng X, Jin Y, Hu Y, Yang B, Zhao J, Lei Y, Zheng F. Novel compound heterozygous mutations in low density lipoprotein receptor gene causes a severe phenotype in a Chinese hypercholesterolemia family. Exp Ther Med. 2018, 16(2):901-7.
[10]	Ma Y, Gong Y, Garg A, Zhou H. Compound heterozygous familial hypercholesterolemia in a Chinese boy with a de novo and transmitted low-density lipoprotein receptor mutation. J Clin Lipidol. 2018, 12(1):230-5 e6.
[11]	Tan K, Cheung CL, Yeung CY, Siu D, Leung J, Pang HK. Genetic screening for familial hypercholesterolaemia in Hong Kong. Hong Kong Med J. 2018, 24 Suppl 3(3): 7-10.
[12]	Wang F, Fan Q, Tao R, Gu G, Zhang R, Xi R. Genetic analysis in a compound heterozygote family with familial hypercholesterolemia. Mol Med Rep. 2018, 17(6):8439-49.
[13]	Kuang H, Zhou X, Li L, Yi Q, Shou W, Lu T. Early severe coronary heart disease and ischemic heart failure in homozygous familial hypercholesterolemia: A case report. Medicine (Baltimore). 2018, 97(42):e12869.
[14]	Wu WF, Sun LY, Wen WH, Wu Y, Wang LY. Low-density lipoprotein receptor function and gene mutation in familial hypercholesterolemia. China Medicine, 2018, 13(7):965-8.
	武文峰, 孙立元, 温文慧, 吴月, 王绿娅. 家族性高胆固醇血症患者突变基因及低密度脂蛋白受体活性分析. 中国医药, 2018, 13(7):965-8.
[15]	Wang X, Jiang L, Sun LY, Wu Y, Wen WH, Wang XF, Liu W, Zhou YJ, Wang LY. Genetically confirmed familial hypercholesterolemia in outpatients with hypercholesterolemia. J Geriatr Cardiol. 2018, 15(6):434-40.
[16]	Sun D, Zhou BY, Li S, Sun NL, Hua Q, Wu SL, Cao YS, Guo YL, Wu NQ, Zhu CG, Gao Y, Cui CJ, Liu G, Li JJ. Genetic basis of index patients with familial hypercholesterolemia in Chinese population: mutation spectrum and genotype- phenotype correlation. Lipids Health Dis. 2018, 17(1):252.
[17]	Hsiung YC, Lin PC, Chen CS, Tung YC, Yang WS, Chen PL, Su TC. Identification of a novel LDLR disease-causing variant using capture-based next-generation sequencing screening of familial hypercholesterolemia patients in Taiwan. Atherosclerosis. 2018, 277:440-7.
[18]	Zhu C-G, Li S, Wang Z-F, Yin K-L, Wu N-Q, Guo Y-L, Gao Y, Li X-L, Qing P, Liu G, Dong Q, Zhou Z, Li J-J. Homozygous familiar hypercholesterolemia in China: Case series from the national lipid clinics and literature review. IJC Metabolic & Endocrine. 2017, 14:75-80.
[19]	Shu H, Chi J, Li J, Zhang W, Lv W, Wang J, Deng Y, Hou X, Wang Y. A novel indel variant in LDLR responsible for familial hypercholesterolemia in a Chinese family. PLoS One. 2017, 12(12):e0189316.
[20]	Jiang L, Benito-Vicente A, Tang L, Etxebarria A, Cui W, Uribe KB, Pan XD, Ostolaza H, Yang SW, Zhou YJ, Martin C, Wang LY. Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. Atherosclerosis. 2017, 263:163-70.
[21]	Wang W, Xu P, Li L, Yu DH, He Q. The Analysis of Clinical Manifestation and LDL-R Gene Mutation in a Familial Hypercholesterolemia Family. The Chinese Journal of Dermatovenereology, 2017, 31(06): 591-4+8.
	王威, 徐平, 李露, 余德厚, 何勤. 家族性高胆固醇血症一家系临床表现及其低密度脂蛋白受体基因突变分析. 中国皮肤性病学杂志. 2017, 31(06): 591-4+8.
[22]	Li JJ, Li S, Zhu CG, Wu NQ, Zhang Y, Guo YL, Gao Y, Li XL, Qing P, Cui CJ, Xu RX, Jiang ZW, Sun J, Liu G, Dong Q. Familial Hypercholesterolemia Phenotype in Chinese Patients Undergoing Coronary Angiography. Arterioscler Thromb Vasc Biol. 2017, 37(3):570-9.
[23]	Xiang R, Fan LL, Lin MJ, Li JJ, Shi XY, Jin JY, Liu YX, Chen YQ, Xia K, Zhao SP. The genetic spectrum of familial hypercholesterolemia in the central south region of China. Atherosclerosis. 2017, 258:84-8.
[24]	Jiang L, Wu WF, Sun LY, Chen PP, Wang W, Benito-Vicente A, Zhang F, Pan XD, Cui W, Yang SW, Zhou YJ, Martin C, Wang LY. The use of targeted exome sequencing in genetic diagnosis of young patients with severe hypercholesterolemia. Sci Rep. 2016, 6:36823.
[25]	Chai XW, Liu XF. Screening analysis of LDLR gene mutations in familial hyperthyroidism compicated with hyperlipidemia. International Journal of Laboratory Medicine, 2016, 37(10):1344-5.
	柴晓文, 刘旭峰. 家族性甲状腺功能亢进症合并高胆固醇血症家系LDLR基因突变筛查探析. 国际检验医学杂志, 2016, 37(10):1344-5.
[26]	Du R, Fan LL, Lin MJ, He ZJ, Huang H, Chen YQ, Li JJ, Xia K, Zhao SP, Xiang R. Mutation detection in Chinese patients with familial hypercholesterolemia. Springerplus. 2016, 5(1):2095.
[27]	Jiang L, Sun LY, Pan XD, Chen PP, Tang L, Wang W, Zhao LM, Yang SW, Wang LY. Characterization of the unique Chinese W483X mutation in the low-density lipoprotein-receptor gene in young patients with homozygous familial hypercholesterolemia. J Clin Lipidol. 2016, 10(3):538-46 e5.
[28]	Tang L, Jiang L, Pan XD, Chen PP, Wang W, Jiao J, Yang Y, Chen J, Wang LY. Extremely severe aortic stenosis developed in a young female patient with underdiagnosis of homozygous familial hypercholesterolemia: An 8-year follow-up. Int J Cardiol. 2016, 207:372-4.
[29]	Lin M, Dai H, Zhao S. Long-term atorvastatin-ezetimibe-probucol triple therapy for homozygous familial hypercholesterolaemia from early childhood. Cardiol Young. 2016, 26(1):197-201.
[30]	Jiao J, Jiang L, Yang SW, Mi HZ, Wang LY, Wang Q. Use of (18)F-FDG PET and MPI with (99m)Tc-MIBI in a patient with delayed diagnosis of homozygous familial hypercholesterolemia. Int J Cardiol. 2015, 201:145-7.
[31]	Sun LY, Zhang YB, Jiang L, Wan N, Wu WF, Pan XD, Yu J, Zhang F, Wang LY. Identification of the gene defect responsible for severe hypercholesterolaemia using whole-exome sequencing. Sci Rep. 2015, 5:11380.
[32]	Li H, Zhang Y, Wei X, Peng Y, Yang P, Tan H, Chen C, Pan Q, Liang D, Wu L. Rare intracranial cholesterol deposition and a homozygous mutation of LDLR in a familial hypercholesterolemia patient. Gene. 2015, 569(2):313-7.
[33]	Han Y, Gao W, Liang P, Wang S, Chen Y, Qiu J. Clinical features of bilateral temporal bone xanthoma with LDLR gene mutation. Int J Pediatr Otorhinolaryngol. 2015, 79(7):1148-51.
[34]	Fan LL, Lin MJ, Chen YQ, Huang H, Peng DQ, Xia K, Zhao SP, Xiang R. Novel mutations of low-density lipoprotein receptor gene in China patients with familial hypercholesterolemia. Appl Biochem Biotechnol. 2015, 176(1):101-9.
[35]	Jiang L, Gao F, Hu LB, Sun LY, Pan XD, Lin J, Zhang HB, Yong Q, Wang Q, Yang Y, Wang CM, Yang SW, Zhang F, Wang LY. Seven-year clinical follow-up of a Chinese homozygous familial hypercholesterolemia child with premature xanthomas and coronary artery disease--a need for early diagnosis and aggressive treatment. Int J Cardiol. 2014, 177(1):188-91.
[36]	Kong MX, Zhang Q, Cao L, Zhao C, Ru GQ, Bi Q. Familial hypercholesterolaemia with tuberous and tendinous xanthomas: case report and mutation analysis. Clin Exp Dermatol. 2015, 40(7):765-9.
[37]	Huang CH, Chiu PC, Liu HC, Lu YH, Huang JK, Charng MJ, Niu DM. Clinical observations and treatment of pediatric homozygous familial hypercholesterolemia due to a low-density lipoprotein receptor defect. J Clin Lipidol. 2015, 9(2):234-40.
[38]	Xiao YM, Tang YC, Zhang H, Zhang T. Report of 2 cases of familial hypercholesterolemia. Chinese Journal of Evidence Based Pediatrics, 2014; 9(05):398-400.
	肖咏梅, 杨永臣, 张泓, 张婷. 家族性高胆固醇血症2例病例报告. 中国循证儿科杂志. 2014, 9(05):398-400.
[39]	Wang HH, Wang CM, Xu SY, Sun LY, Guan X, Lu K, Pan XD, Liu S, Yang SW. Functional analysis on novel mutants of low density lipoprotein receptor gene in a familial hypercholesterolemia patient. Chinese Journal of Clinical Laboratory Science, 2014, 32(5):324-8.
	王海红, 王春梅, 徐胜媛, 孙立元, 关啸, 鲁昆, 潘晓冬, 刘飒, 杨士伟. 1例家族性高胆固醇血症患者低密度脂蛋白受体基因新突变体功能研究. 临床检验杂志, 2014, 32(5):324-8.
[40]	Zhao X, Bu L, Qin S, Kong D, Fan B, Ge J. Early development of xanthoma and coronary disease in a young female with homozygous familial hypercholesterolemia. Int J Cardiol. 2014, 176(1):e15-9.
[41]	Wu WF, Sun LY, Pan XD, Yang SW, Wang LY. Use of targeted exome sequencing in genetic diagnosis of Chinese familial hypercholesterolemia. PLoS One. 2014, 9(4):e94697.
[42]	Wang H, Xu S, Sun L, Pan X, Yang S, Wang L. Functional characterization of two low-density lipoprotein receptor gene mutations in two Chinese patients with familial hypercholesterolemia. PLoS One. 2014, 9(3):e92703.
[43]	Meng X, Lin J, Gao X, Guo J, Xin C, Wang J. Corneal arcus and xanthomas in homozygous familial hypercholesterolemia: first report from China. Indian J Ophthalmol. 2013, 61(12):770-1.
[44]	Wu H, Xie F, Lang XL, Guo ZF, Zhu N, Bai Y, Chen F, Pan JW, Zheng X, Zhao XX, Qin YW, Huang W. Mutation analysis of low-density lipoprotein receptor gene in 3 patients with familial hypercholesterolemia in two generations. Academic Journal of Second Military Medical University, 2012, 33(04):445-8.
	吴弘, 谢芳, 郎希龙, 郭志福, 朱霓, 白元, 陈峰, 潘静薇, 郑兴, 赵仙先, 秦永文, 黄薇. 2代3人同患家族性高胆固醇血症及其低密度脂蛋白受体基因突变分析. 第二军医大学学报. 2012, 33(04):445-8.
[45]	Yao RE, Wang J, Geng J, Zheng Z, Yu T, Yu Y, Fu Q. Identification of LDLR mutations in two Chinese pedigrees with familial hypercholesterolemia. J Pediatr Endocrinol Metab. 2012, 25(7-8):769-73.
[46]	Chiou KR, Charng MJ. Common mutations of familial hypercholesterolemia patients in Taiwan: characteristics and implications of migrations from southeast China. Gene. 2012, 498(1):100-6.
[47]	Lai H, Feng JB, Wang T, Zhou KH, Hou WK, Chen L.[A genetic and clinical study in a family with familial hypercholesterolemia]. Zhonghua Nei Ke Za Zhi. 2011, 50(2):120-3.
[48]	Chiou KR, Charng MJ, Chang HM. Array-based resequencing for mutations causing familial hypercholesterolemia. Atherosclerosis. 2011, 216(2):383-9. doi: 10.1016/j.atherosclerosis.2011.02.006
[49]	Wang X, Lin J, Pan XD, Xu YJ, Yang Y, Zhang XS, Du LP, Wang LY. Analysis of Low Density Lipoprotein Receptor Gene Mutation in A Child and His Family with Familial Hyper-cholesterolemia. JOURNAL OF APPLIED CLINICAL PEDIATRICS, 2010, 25(2):125-8.
	王旭, 蔺洁, 潘晓冬, 许瑛杰, 杨娅, 张小山, 杜兰平, 王绿娅. 家族性高胆固醇血症患者及其家系成员候选基因突变分析. 实用儿科临床杂志, 2010, 25(2):125-8.
[50]	Marduel M, Carrie A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C, French ADHRN, Boileau C, Varret M, Rabes JP. Molecular spectrum of autosomal dominant hypercholesterolemia in France. Hum Mutat. 2010, 31(11):E1811-24. doi: 10.1002/humu.v31:11
[51]	Sun LY, Pan XD, Su PY, Wang X, Dai YF, Yang Y, Zhang XS, Yong Q, Du LP, Lin J, Zhao JX, Wang LY. Gene Mutation Analysis of A Child with Familial Hypercholesterolemia and His Family. JOURNAL OF APPLIED CLINICAL PEDIATRICS, 2010, 25(13):968-70, 73.
	孙立元, 潘晓冬, 苏鹏宇, 王旭, 代艳芳, 杨娅, 张小山, 勇强, 杜兰平, 蔺洁, 赵景新, 王绿娅. 家族性高胆固醇血症患儿及其家系基因分析. 实用儿科临床杂志, 2010, 25(13):968-70, 73.
[52]	Pan XD, Su PY, Wang LY, Lin J, Liu S, Du LP. Analysis of apolipoprotein B gene in a proband with familial hypercholesterolemia. CHINESE JOURNAL OF CLINICAL LABORATORY SCIENCE, 2010, 28(03):179-81.
	潘晓冬, 苏鹏宇, 王绿娅, 蔺洁, 刘舒, 杜兰平. 1例家族性高胆固醇血症患者的apoB_(100)基因型分析. 临床检验杂志. 2010, 28(03):179-81.
[53]	Wang L, Lin J, Liu S, Cao S, Liu J, Yong Q, Yang Y, Wu B, Pan X, Du L, Wu C, Qin Y, Chen B. Mutations in the LDL receptor gene in four Chinese homozygous familial hypercholesterolemia phenotype patients. Nutr Metab Cardiovasc Dis. 2009, 19(6):391-400. doi: 10.1016/j.numecd.2008.07.011 pmid: 19073363
[54]	Cheng X, Ding J, Zheng F, Zhou X, Xiong C. Two mutations in LDLR gene were found in two Chinese families with familial hypercholesterolemia. Mol Biol Rep. 2009, 36(8):2053-7. doi: 10.1007/s11033-008-9416-z
[55]	Pan XD. Compound Heterozygosis Mutation of Low Density Lipoprotein Receptor Gene in Familial Hypercholestero-lemia Family. JOURNAL OF APPLIED CLINICAL PEDIATRICS, 2009, 24(13).
	潘晓冬. 家族性高胆固醇血症一家系成员低密度脂蛋白受体基因复合杂合突变分析, 实用儿科临床杂志. 2009, 24(13).
[56]	Lin J, Wang LY, Pan XD, Xiao WH, Wang X, Du LP, Jiang ZS. Familial Hypercholesterolemia due to Mutation of Low Density Liporotein Receptor Gene. PROGRESS IN MODERN BIOMEDICINE, 2009, 9(19):3605-8.
	蔺洁, 王绿娅, 潘晓冬, 肖文虎, 王旭, 杜兰平, 姜志胜. 家族性高胆固醇血症患者低密度脂蛋白受体基因复合杂合突变分析. 现代生物医学进展. 2009, 9(19):3605-8.
[57]	Jia F, Wu CF, Lu GP. Pathogenic Gene Mutation Analysis of A Homozygous Phenotype patient with Familial Hypercholesterolemia. JOURNAL OF APPLIED CLINICAL PEDIATRICS. 2009, 36(06):397-8.
	贾方, 吴春芳, 陆国平. 家族性高胆固醇血症纯合表型致病基因突变分析1例. 国际心血管病杂志. 2009, 36(06):397-8.
[58]	Lin J, Wang LY, Liu S, Xia JH, Yong Q, Du LP, Pan XD, Xue H, Chen BS, Jiang ZS. Functional analysis of low-density lipoprotein receptor in homozygous familial hypercholesterolemia patients with novel 1439 C-->T mutation of low-density lipoprotein receptor gene. Chin Med J (Engl). 2008, 121(9):776-81.
[59]	Wang YF, Jin HF, Bu DF, Yang YL, Du JB. Characterization of one novel mutation of the low density lipoprotein receptor gene in patients with familial hypercholesterolemia- one case report. CHINESE JOURNAL OF PRACTICAL INTERNAL MEDICINE, 2008(06):450-2.
	王燕飞, 金红芳, 卜定方, 杨艳玲, 杜军保. 家族性高胆固醇血症低密度脂蛋白受体基因新突变位点的鉴定——附1例报告. 中国实用内科杂志. 2008(06):450-2.
[60]	Chen K, Mu YM, Wang BA, Guo QH, Lu ZH, Dou JT, Lu JM. Two novel mutations 685del 1 and D129G in the low-density lipoprotein receptor gene in a compound heterozygote Chinese family with familial hypercholesterolemia. Metabolism. 2007, 56(5):636-40. doi: 10.1016/j.metabol.2006.12.011
[61]	Xie L, Gong QH, Xie ZG, Liang ZM, Hu ZM, Xia K, Xia JH, Yang YF. Two novel mutations of the LDL receptor gene associated with familial hypercholesterolemia in a Chinese family. Chin Med J (Engl). 2007, 120(19):1694-9.
[62]	Charng MJ, Chiou KR, Chang HM, Cheng HM, Ye ZX, Lin SJ. Identification and characterization of novel low-density lipoprotein receptor mutations of familial hypercholesterolaemia patients in Taiwan. Eur J Clin Invest. 2006, 36(12):866-74. pmid: 17087781
[63]	Zakharova FM, Damgaard D, Mandelshtam MY, Golubkov VI, Nissen PH, Nilsen GG, Stenderup A, Lipovetsky BM, Konstantinov VO, Denisenko AD, Vasilyev VB, Faergeman O. Familial hypercholesterolemia in St-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia. BMC Med Genet. 2005, 6:6. pmid: 15701167
[64]	Chiu CY, Wu YC, Jenq SF, Jap TS. Mutations in low-density lipoprotein receptor gene as a cause of hypercholesterolemia in Taiwan. Metabolism. 2005, 54(8):1082-6. doi: 10.1016/j.metabol.2005.03.012
[65]	Liu YR, Tao QM, Chen JZ, Tao M, Guo XG, Shang YP, Zhu JH, Zhang FR, Zheng LR, Wang XX.[Identification of a novel mutation at the point of low density lipoprotein receptor gene from a subject with familial hypercholesterolemia]. Sheng Li Xue Bao. 2004, 56(5):566-72.
[66]	Pang QF, Wang Y, Xu M, Ding L, Dong W, Mao PJ. Screening for low-density lipoprotein receptor gene mutations in familial hypercholesterolemia Chinese. CHINESE JOURNAL OF INTERNAL MEDICINE. 2004(09):29-32.
	庞庆丰, 王影, 徐明, 丁雷, 董薇, 茅佩鹃. 低密度脂蛋白受体基因突变类型的筛查. 中华内科杂志. 2004(09):29-32.
[67]	Yang YL, Zhao WH, Qian N, Song JQ, Qi Y, Qin J, Li WZ, Wu XR. The clinical and biochemical survey of six patients with familial hypercholesterolemia. THE JOURNAL OF CLINICAL PEDIATRICS, 2004(05):298-301.
	杨艳玲, 赵卫红, 钱宁, 宋金青, 戚豫, 秦炯, 李万镇, 吴希如. 家族性高胆固醇血症6例临床与生化分析. 临床儿科杂志. 2004(05):298-301.
[68]	Wang LY, Cao SC, Lin J, Wu BJ, Liu S, Pan XD, Du LP, Qin YW, Chen BS. Explortion of low density lipoprotein receptor gene mutations in a Chinese patient with familial compound homozygous hypercholesterolemia. CHINESE JOURNAL OF CARDIOLOGY, 2003(09):15-8.
	王绿娅, 曹守春, 蔺洁, 吴邦俊, 刘舒, 潘晓冬, 杜兰平, 秦彦文, 陈保生. 家族性高胆固醇血症患者低密度脂蛋白受体基因复合纯合突变一例. 中华心血管病杂志. 2003(09):15-8.
[69]	Guan XX, Li MF, Fan LQ, Chen Q. Analysis of low density lipoprotein receptor function and gene mutation in familial hypercholesterolemic patients. CHINESE JOURNAL OF MEDICAL GENETICS, 2003(02):54-8.
	管晓翔, 郦明芳, 范乐明, 陈琪. 家族性高胆固醇血症纯合子家系低密度脂蛋白受体功能检测及基因突变分析. 中华医学遗传学杂志. 2003(02):54-8.
[70]	Chen JZ, Shang YP, Li JX, Liu B, Tao QM, Zhu JH, Han H. Gene sequencing research of three familial hypercholesterolemia families. CHINESE JOURNAL OF CARDIOLOGY, 2002(06):30-3.
	陈君柱, 尚云鹏, 李京湘, 刘斌, 陶谦民, 朱建华, 韩华. 家族性高胆固醇血症三个家系的基因测序研究. 中华心血管病杂志. 2002(06):30-3.
[71]	Wang D, Li Y, Mu Y, Gao Q, Heng W, Zhong H, Wang J.[A gene analysis of the low density lipoprotein receptor in Chinese with homozygous familial hyperchol-esterolemia]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2001, 18(4):279-82.
[72]	Wang D, Wu B, Li Y, Heng W, Zhong H, Mu Y, Wang J. A Chinese homozygote of familial hypercholesterolemia: identification of a novel C263R mutation in the LDL receptor gene. J Hum Genet. 2001, 46(3):152-4. pmid: 11310584
[73]	Li XD, Wang JY, Hu WC. New mutations in low-density lipoprotein receptor gene in patients with familial hypercholesterolemia. CHINESE JOURNAL OF MEDICAL GENETICS, 2001, 18(6):491-2.
	李向东, 王瑾瑜, 胡维诚. 家族性高胆固醇血症患者低密度脂蛋白受体基因的新变异. 中华医学遗传学杂志. 2001, 18(6):491-2.
[74]	Khoo KL, van Acker P, Defesche JC, Tan H, van de Kerkhof L, Heijnen-van Eijk SJ, Kastelein JJ, Deslypere JP. Low-density lipoprotein receptor gene mutations in a Southeast Asian population with familial hypercholesterolemia. Clin Genet. 2000, 58(2):98-105. pmid: 11005141
[75]	Mak YT, Pang CP, Tomlinson B, Zhang J, Chan YS, Mak TW, Masarei JR. Mutations in the low-density lipoprotein receptor gene in Chinese familial hypercholesterolemia patients. Arterioscler Thromb Vasc Biol. 1998, 18(10):1600-5. doi: 10.1161/01.ATV.18.10.1600
[76]	Pimstone SN, Sun XM, du Souich C, Frohlich JJ, Hayden MR, Soutar AK. Phenotypic variation in heterozygous familial hypercholesterolemia: a comparison of Chinese patients with the same or similar mutations in the LDL receptor gene in China or Canada. Arterioscler Thromb Vasc Biol. 1998, 18(2):309-15. doi: 10.1161/01.ATV.18.2.309
[77]	Mak YT, Zhang J, Chan YS, Mak TW, Tomlinson B, Masarei JR, Pang CP. Possible common mutations in the low density lipoprotein receptor gene in Chinese. Hum Mutat. 1998, Suppl 1: S310-3.
[78]	Sun XM, Patel DD, Webb JC, Knight BL, Fan LM, Cai HJ, Soutar AK. Familial hypercholesterolemia in China. Identification of mutations in the LDL-receptor gene that result in a receptor-negative phenotype. Arterioscler Thromb. 1994, 14(1):85-94. doi: 10.1161/01.ATV.14.1.85
[79]	Yang Y, Yang S, Jiao X, Li J, Zhu M, Wang L, Qin Y. ANGPTL3 Mutations in Unrelated Chinese Han Patients with Familial Hypercholesterolemia. Curr Pharm Des. 2019, 25(2):190-200. doi: 10.2174/1381612825666190228000932
[80]	Cao YX, Wu NQ, Sun D, Liu HH, Jin JL, Li S, Guo YL, Zhu CG, Gao Y, Dong QT, Liu G, Dong Q, Li JJ. Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease. J Transl Med. 2018, 16(1):345. doi: 10.1186/s12967-018-1737-7
[81]	Lin J, Wang LY, Liu S, Wang XM, Yong Q, Yang Y, Du LP, Pan XD, Wang X, Jiang ZS. A novel mutation in proprotein convertase subtilisin/kexin type 9 gene leads to familial hypercholesterolemia in a Chinese family. Chin Med J (Engl). 2010, 123(9):1133-8.
[82]	Tang L. Screening of novel pathogenic genes of Familial Hypercholesterolemia and Effect of Soluble Epoxide Hydrolase gene mutant on the function of LDLR. Huazhong University of Science and Technology; 2016.
	唐玲. 家族性高胆固醇血症患者新致病基因筛查及可溶性环氧化物水解酶基因突变体对细胞LDLR功能的影响[硕士]: 华中科技大学; 2016.

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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]

Progress on familial hypercholesterolemia

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