一个家族性高胆固醇血症家系的基因突变筛查与评估

doi:10.3969/j.issn.1004-616x.2020.03.013

Abstract

Abstract: OBJECTIVE: To find pathogenic gene(s) in a clinically diagnosed familial hypercholesterolemia (FH) family using whole exome sequencing. METHODS: Peripheral venous blood of the family members was taken to measure serum TC,TG,LDL cholesterol and HDL cholesterol. DNA of the white blood cell was extracted to perform whole exome sequencing. Four genes (LDLR,APOB,PCSK9,LDLRAP1) associated with FH were chosen to analyze single nucleotide polymorphisms (SNP) and predict the function of protein using Polyphen-2 and SIFT. RESULTS: Four SNPs (rs676210,rs679899,c.10094A > T and c.9937C > G) of APOB might be associated with the elevated lipid levels,but no co-segregating variants were found in this family. No damaging variant was found in LDLR,PCSK9 and LDLRAP1 by Polyphen-2 and SIFT. CONCLUSION: Our study found that some SNPs of APOB may be associated with elevated lipid levels in a clinically diagnosed FH family. The function of these SNPs still needs further experiments to confirm.

Key words: familial hypercholesterolemia, gene mutations, APOB gene, blood lipids

CLC Number:

R124

ZHANG Jiahong, ZHANG Qingying, ZHANG Yanhong, CHEN Jialian, XIE Fang, LIU Ruiguo, WU Rong, WU Longfei. Screening and evaluation of gene mutations in a familial hypercholesterolemia family[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2020, 32(3): 229-232,245.

References

[1] DEFESCHE J C, GIDDING S S, HARADA-SHIBA M, et al. Familial hypercholesterolaemia[J]. Nat Rev Dis Primers, 2017, 3:17093.
[2] NORDESTGAARD B G, CHAPMAN M J, HUMPHRIES S E, et al. 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[J]. Eur Heart J, 2013, 34(45):3478-390a.
[3] SHI Z M, YUAN B J, ZHAO D, et al. Familial hypercholesterolemia in China:prevalence and evidence of underdetection and undertreatment in a community population[J]. Int J Cardiol, 2014, 174(3):834-836.
[4] KHERA A V, WON H H, PELOSO G M, et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia[J]. J Am Coll Cardiol, 2016, 67(22):2578-2589.
[5] DO R, STITZIEL N O, WON H H, et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction[J]. Nature, 2015, 518(7537):102-106.
[6] NORDESTGAARD B G, BENN M. Genetic testing for familial hypercholesterolaemia is essential in individuals with high LDL cholesterol:who does it in the world?[J]. Eur Heart J, 2017, 38(20):1580-1583.
[7] BERBERICH A J, HEGELE R A. The complex molecular genetics of familial hypercholesterolaemia[J]. Nat Rev Cardiol, 2019, 16(1):9-20.
[8] RIOS J, STEIN E, SHENDURE J, et al. Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia[J]. Hum Mol Genet, 2010, 19(22):4313-4318.
[9] 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)[J]. 中华心血管病杂志, 2016, 44(10):833-853.
[10] GOLDBERG A C, HOPKINS P N, TOTH P P, et al. Familial hypercholesterolemia:screening, diagnosis and management of pediatric and adult patients:clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia[J]. J Clin Lipidol, 2011, 5(3 Suppl):S1-S8.
[11] 陈在嘉, 朱清於. 临床冠心病学[M]. 北京:人民军医出版社, 1994.
[12] 谢芳, 刘亚辉, 张庆英, 等. 某乡镇家族性高胆固醇血症患者血脂知信行及其相关因素调查[J]. 汕头大学医学院学报, 2019, 32(1):34-40.
[13] ADZHUBEI I A, SCHMIDT S, PESHKIN L, et al. A method and server for predicting damaging missense mutations[J]. Nat Methods, 2010, 7(4):248-249.
[14] 中华医学会心血管病学分会. 家族性高胆固醇血症筛查与诊治中国专家共识[J]. 中华心血管病杂志, 2018, 46(2):99-103.
[15] PALACIOS L, GRANDOSO L, CUEVAS N, et al. Molecular characterization of familial hypercholesterolemia in Spain[J]. Atherosclerosis, 2012, 221(1):137-142.
[16] CIVEIRA F, ROS E, JARAUTA E, et al. Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia[J]. Am J Cardiol, 2008, 102(9):1187-1193, 1193.e1.
[17] DEVARAJ S, JIALAL I. Biochemistry, apolipoprotein B[M]. Treasure Island:Stat Pearls Publishing LLC, 2019.
[18] GU Q L, HAN Y, LAN Y M, et al. Association between polymorphisms in the APOB gene and hyperlipidemia in the Chinese Yugur population[J]. Braz J Med Biol Res, 2017, 50(11):e6613.
[19] WOJCZYNSKI M K, GAO G M, BORECKI I, et al. Apolipoprotein B genetic variants modify the response to fenofibrate:a GOLDN study[J]. J Lipid Res, 2010, 51(11): 3316-3323.
[20] JUNYENT M, TUCKER K L, SHEN J, et al. A composite scoring of genotypes discriminates coronary heart disease risk beyond conventional risk factors in the Boston Puer to Rican Health Study[J]. Nutr Metab Cardiovasc Dis, 2010, 20(3):157-164.
[21] BENN M, STENE M C, NORDESTGAARD B G, et al. Common and rare alleles in apolipoprotein B contribute to plasma levels of low-density lipoprotein cholesterol in the general population[J]. J Clin Endocrinol Metab, 2008, 93(3):1038-1045.
[22] SEGREST J P, JONES M K, DE LOOF H, et al. Structure of apolipoprotein B-100 in low density lipoproteins[J]. J Lipid Res, 2001, 42(9):1346-1367.
[23] BRADBURY P, MANN C J, KÖCHL S, et al. A common binding site on the microsomal triglyceride transfer protein for apolipoprotein B and protein disulfide isomerase[J]. J Biol Chem, 1999, 274(5):3159-3164.
[24] 陆言巧, 沈兰, 何奔. PCSK9抑制剂的机制及其临床进展[J]. 临床心血管病杂志, 2020, 36(1):14-19.
[25] KHAN S U, TALLURI S, RIAZ H, et al. A Bayesian network meta-analysis of PCSK9 inhibitors, statins and ezetimibe with or without statins for cardiovascular outcomes[J]. Eur J Prev Cardiolog, 2018, 25(8):844-853.
[26] CHORA J R, MEDEIROS A M, ALVES A C, et al. Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia:application of ACMG guidelines and implications for familial hypercholes-terolemia diagnosis[J]. Genet Med, 2018, 20(6):591-598.
[27] ASSELBERGS F W, LOVERING R C, DRENOS F. Progress in genetic association studies of plasma lipids[J]. Curr Opin Lipidol, 2013, 24(2):123-128.

Screening and evaluation of gene mutations in a familial hypercholesterolemia family

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