2型糖尿病患者血清SUMO1水平与高甘油三酯血症相关性研究

doi:10.3969/j.issn.1674-8115.2024.10.008

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (10): 1266-1272.doi: 10.3969/j.issn.1674-8115.2024.10.008

• 论著 · 临床研究 • 上一篇

2型糖尿病患者血清SUMO1水平与高甘油三酯血症相关性研究

张新燕(), 李涵, 冉慧, 苏青, 张洪梅()

上海交通大学医学院附属新华医院内分泌科，上海 200092

收稿日期:2024-04-28 接受日期:2024-05-21 出版日期:2024-10-28 发布日期:2024-10-28
通讯作者: 张洪梅 E-mail:zhangxinyanmm@163.com;zhanghongmei02@xinhuanmed.com.cn;zhanghongmei02@xinhuamed.com.cn
作者简介:张新燕（1998—），女，硕士生；电子信箱：zhangxinyanmm@163.com。
基金资助:
上海市浦江人才计划(2019PJD033);国家自然科学基金(82100848)

Correlation between serum SUMO1 level and hypertriglyceridemia in type 2 diabetes mellitus patients

ZHANG Xinyan(), LI Han, RAN Hui, SU Qing, ZHANG Hongmei()

Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China

Received:2024-04-28 Accepted:2024-05-21 Online:2024-10-28 Published:2024-10-28
Contact: ZHANG Hongmei E-mail:zhangxinyanmm@163.com;zhanghongmei02@xinhuanmed.com.cn;zhanghongmei02@xinhuamed.com.cn
Supported by:
Shanghai Pujiang Program(2019PJD033);National Natural Science Foundation of China(82100848)

摘要/Abstract

摘要：

目的·探究2型糖尿病（type 2 diabetes mellitus，T2DM）患者血清小泛素样修饰分子1（small ubiquitin-like modifier-1，SUMO1）水平与高甘油三酯血症（hypertriglyceridemia，HTG）之间的相关性。方法·选取2020年9月至2021年3月在上海交通大学医学院附属新华医院内分泌科门诊就诊的新诊断为2型糖尿病的患者共239例，其中T2DM合并HTG组患者92例，T2DM不合并HTG组患者147例。收集患者基本信息和实验室指标，分析2组患者血清SUMO1水平的差异。采用二元Logistic回归分析T2DM合并HTG的影响因素，采用多元线性逐步回归分析血清SUMO1水平对T2DM合并HTG风险的影响。结果·与T2DM不合并HTG的患者相比，T2DM合并HTG患者的血清SUMO1水平明显升高（1 114.99 pg/mL vs 902.43 pg/mL，P<0.001）。二元Logistic回归分析提示血清SUMO1水平（OR=1.527，95%CI 1.200~1.943）、糖化血红蛋白（OR=1.202，95%CI 1.038~1.391）、血尿酸（OR=1.006，95%CI 1.003~1.010）是T2DM合并HTG的独立危险因素。将血清SUMO1水平按照四分位分层，校正各种混杂因素后，以Q1层作为对照，Q4层T2DM合并HTG的风险是Q1层的2.707倍（95%CI 1.231~5.951）。多元线性逐步回归分析发现女性、腰臀比、甘油三酯、血肌酐是血清SUMO1水平升高的独立危险因素。结论·T2DM合并HTG患者血清SUMO1水平显著高于不合并HTG患者，血清SUMO1水平是T2DM合并HTG的独立危险因素。

关键词: 小泛素样修饰分子1, SUMO化修饰, 高甘油三酯血症, 2型糖尿病

Abstract:

Objective ·To explore the correlation between serum small ubiquitin-like modifier 1 (SUMO1) levels and hypertriglyceridemia in patients with type 2 diabetes mellitus (T2DM). Methods ·A total of 239 newly diagnosed T2DM patients were recruited from the endocrinology clinic of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, between September 2020 and March 2021. Among them, 92 patients had hypertriglyceridemia, and 147 patients did not. Basic information and laboratory parameters were collected. The differences in serum SUMO1 levels between the two groups were analyzed. Factors influencing hypertriglyceridemia in patients with T2DM were analyzed, and the impact of serum SUMO1 levels on the risk of hypertriglyceridemia in T2DM patients was investigated. Results ·Patients with T2DM and hypertriglyceridemia had significantly higher serum SUMO1 levels compared to those without hypertriglyceridemia (1 114.99 pg/mL vs 902.43 pg/mL, P<0.001). Binary Logistic regression analysis suggested that serum SUMO1 levels (OR=1.527, 95%CI 1.200?1.943), glycated hemoglobin (OR=1.202, 95%CI 1.038?1.391), and blood uric acid (OR=1.006, 95%CI 1.003?1.010) were independent risk factors for hypertriglyceridemia in patients with T2DM. After adjusting for various confounding factors and stratifying serum SUMO1 levels into quartiles, the risk of hypertriglyceridemia in T2DM patients with the highest quartile (Q4) of serum SUMO1 levels was 2.707 times higher compared to those in the lowest quartile (Q1) (95%CI 1.231?5.951). Multiple linear stepwise regression analysis revealed that female gender, waist-to-hip ratio, triglycerides and serum creatinine were independent risk factors for elevated serum SUMO1 levels. Conclusion ·Serum SUMO1 level in patients with T2DM complicated with HTG is significantly higher than that in patients without HTG, and the serum SUMO1 level is an independent risk factor for T2DM complicated with HTG.

Key words: small ubiquitin-like modifier (SUMO1), SUMOylation, hypertriglyceridemia, type 2 diabetes mellitus (T2DM)

中图分类号:

R587.1

张新燕, 李涵, 冉慧, 苏青, 张洪梅. 2型糖尿病患者血清SUMO1水平与高甘油三酯血症相关性研究[J]. 上海交通大学学报（医学版）, 2024, 44(10): 1266-1272.

ZHANG Xinyan, LI Han, RAN Hui, SU Qing, ZHANG Hongmei. Correlation between serum SUMO1 level and hypertriglyceridemia in type 2 diabetes mellitus patients[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(10): 1266-1272.

图/表 4

参考文献 44

1	LI Y, TENG D, SHI X, et al. Prevalence of diabetes recorded in mainland China using 2018 diagnostic criteria from the American Diabetes Association: national cross sectional study[J]. BMJ, 2020, 369: m997.
2	ZHENG Y, LEY S H, HU F B. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications[J]. Nat Rev Endocrinol, 2018, 14: 88-98.
3	AL-SULAITI H, DIBOUN I, AGHA M V, et al. Metabolic signature of obesity-associated insulin resistance and type 2 diabetes[J]. J Transl Med, 2019, 17(1): 348.
4	POPKIN B M. Synthesis and implications: China's nutrition transition in the context of changes across other low- and middle-income countries[J]. Obes Rev, 2014, 15(Suppl 1): 60-67.
5	GORDON-LARSEN P, WANG H, POPKIN B M. Overweight dynamics in Chinese children and adults[J]. Obes Rev, 2014, 15(Suppl 1): 37-48.
6	SUBRAMANIAN S, CHAIT A. Hypertriglyceridemia secondary to obesity and diabetes[J]. Biochim Biophys Acta, 2012, 1821(5): 819-825.
7	REINER Ž. Hypertriglyceridaemia and risk of coronary artery disease[J]. Nat Rev Cardiol, 2017, 14: 401-411.
8	YANG A L, MCNABB-BALTAR J. Hypertriglyceridemia and acute pancreatitis[J]. Pancreatology, 2020, 20(5): 795-800.
9	ALEXOPOULOS A S, QAMAR A, HUTCHINS K, et al. Triglycerides: emerging targets in diabetes care? review of moderate hypertriglyceridemia in diabetes[J]. Curr Diabetes Rep, 2019, 19(4): 13.
10	GEISS-FRIEDLANDER R, MELCHIOR F. Concepts in sumoylation: a decade on[J]. Nat Rev Mol Cell Biol, 2007, 8: 947-956.
11	FLOTHO A, MELCHIOR F. Sumoylation: a regulatory protein modification in health and disease[J]. Annu Rev Biochem, 2013, 82: 357-385.
12	GAREAU J R, LIMA C D. The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition[J]. Nat Rev Mol Cell Biol, 2010, 11: 861-871.
13	LIANG Y C, LEE C C, YAO Y L, et al. SUMO5, a novel poly-SUMO isoform, regulates PML nuclear bodies[J]. Sci Rep, 2016, 6: 26509.
14	FAGERBERG L, HALLSTRÖM B M, OKSVOLD P, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics[J]. Mol Cell Proteom, 2014, 13(2): 397-406.
15	CHANG H M, YEH E T H. SUMO: from bench to bedside[J]. Physiol Rev, 2020, 100(4): 1599-1619.
16	BARRY J, LOCK R B. Small ubiquitin-related modifier-1: wrestling with protein regulation[J]. Int J Biochem Cell Biol, 2011, 43(1): 37-40.
17	ZHENG Q, CAO Y, CHEN Y L, et al. Senp2 regulates adipose lipid storage by de-SUMOylation of Setdb1[J]. J Mol Cell Biol, 2018, 10(3): 258-266.
18	MOORADIAN A D. Dyslipidemia in type 2 diabetes mellitus[J]. Nat Rev Endocrinol, 2009, 5: 150-159.
19	COCATE P G, NATALI A J, DE OLIVEIRA A, et al. Red but not white meat consumption is associated with metabolic syndrome, insulin resistance and lipid peroxidation in Brazilian middle-aged men[J]. Eur J Prev Cardiol, 2015, 22(2): 223-230.
20	KELLEY D E, GOODPASTER B H. Skeletal muscle triglyceride. An aspect of regional adiposity and insulin resistance[J]. Diabetes Care, 2001, 24(5): 933-941.
21	YANG Y, HE Y, WANG X, et al. Protein SUMOylation modification and its associations with disease[J]. Open Biol, 2017, 7(10): 170167.
22	BOHREN K M, NADKARNI V, SONG J H, et al. A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus[J]. J Biol Chem, 2004, 279(26): 27233-27238.
23	WOO C H, ABE J. SUMO: a post-translational modification with therapeutic potential?[J]. Curr Opin Pharmacol, 2010, 10(2): 146-155.
24	YEH E T. SUMOylation and De-SUMOylation: wrestling with life's processes[J]. J Biol Chem, 2009, 284(13): 8223-8227.
25	SEGERSTOLPE Å, PALASANTZA A, ELIASSON P, et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes[J]. Cell Metab, 2016, 24(4): 593-607.
26	DAI X Q, PLUMMER G, CASIMIR M, et al. SUMOylation regulates insulin exocytosis downstream of secretory granule docking in rodents and humans[J]. Diabetes, 2011, 60(3): 838-847.
27	HE X Y, LAI Q H, CHEN C, et al. Both conditional ablation and overexpression of E2 SUMO-conjugating enzyme (UBC9) in mouse pancreatic beta cells result in impaired beta cell function[J]. Diabetologia, 2018, 61(4): 881-895.
28	SAPIR A. Not so slim anymore-evidence for the role of SUMO in the regulation of lipid metabolism[J]. Biomolecules, 2020, 10(8): E1154.
29	CARIOU B, CHARBONNEL B, STAELS B. Thiazolidinediones and PPARγ agonists: time for a reassessment[J]. Trends Endocrinol Metab, 2012, 23(5): 205-215.
30	TONTONOZ P, SPIEGELMAN B M. Fat and beyond: the diverse biology of PPARgamma[J]. Annu Rev Biochem, 2008, 77: 289-312.
31	MIKKONEN L, HIRVONEN J, JÄNNE O A. SUMO-1 regulates body weight and adipogenesis via PPARγ in male and female mice[J]. Endocrinology, 2013, 154(2): 698-708.
32	AHMADIAN M, SUH J M, HAH N, et al. PPARγ signaling and metabolism: the good, the bad and the future[J]. Nat Med, 2013, 19: 557-566.
33	WADOSKY K M, WILLIS M S. The story so far: post-translational regulation of peroxisome proliferator-activated receptors by ubiquitination and SUMOylation[J]. Am J Physiol Heart Circ Physiol, 2012, 302(3): H515-H526.
34	KERSHAW E E, SCHUPP M, GUAN H P, et al. PPARgamma regulates adipose triglyceride lipase in adipocytes in vitro and in vivo[J]. Am J Physiol Endocrinol Metab, 2007, 293(6): E1736-E1745.
35	WOLFRUM C, STOFFEL M. Coactivation of Foxa2 through Pgc-1beta promotes liver fatty acid oxidation and triglyceride/VLDL secretion[J]. Cell Metab, 2006, 3(2): 99-110.
36	BELAGULI N S, ZHANG M, BRUNICARDI F C, et al. Forkhead box protein A2 (FOXA2) protein stability and activity are regulated by sumoylation[J]. PLoS One, 2012, 7(10): e48019.
37	LIU Y, DOU X, ZHOU W Y, et al. Hepatic small ubiquitin-related modifier (SUMO)-specific protease 2 controls systemic metabolism through SUMOylation-dependent regulation of liver-adipose tissue crosstalk [J]. Hepatology, 2021, 74(4): 1864-1883.
38	HIRANO Y, MURATA S, TANAKA K, et al. Sterol regulatory element-binding proteins are negatively regulated through SUMO-1 modification independent of the ubiquitin/26 S proteasome pathway[J]. J Biol Chem, 2003, 278(19): 16809-16819.
39	ARITO M, HORIBA T, HACHIMURA S, et al. Growth factor-induced phosphorylation of sterol regulatory element-binding proteins inhibits sumoylation, thereby stimulating the expression of their target genes, low density lipoprotein uptake, and lipid synthesis[J]. J Biol Chem, 2008, 283(22): 15224-15231.
40	LIU B, WANG T, MEI W, et al. Small ubiquitin-like modifier (SUMO) protein-specific protease 1 de-SUMOylates Sharp-1 protein and controls adipocyte differentiation[J]. J Biol Chem, 2014, 289(32): 22358-22364.
41	SHIMANO H, SATO R. SREBP-regulated lipid metabolism: convergent physiology—divergent pathophysiology[J]. Nat Rev Endocrinol, 2017, 13: 710-730.
42	SOYAL S M, NOFZIGER C, DOSSENA S, et al. Targeting SREBPs for treatment of the metabolic syndrome[J]. Trends Pharmacol Sci, 2015, 36(6): 406-416.
43	WANG Q, ZHANG N, YANG X, et al. ERα promotes SUMO1 transcription by binding with the ERE and enhances SUMO1-mediated protein SUMOylation in breast cancer[J]. Gland Surg, 2023, 12(7): 963-973.
44	CHO S J, YUN S M, LEE D H, et al. Plasma SUMO1 protein is elevated in Alzheimer's disease[J]. J Alzheimers Dis, 2015, 47(3): 639-643.

编辑推荐 0

Metrics

阅读次数

全文

447

HTML			PDF

最新录用	在线预览	正式出版	最新录用	在线预览	正式出版
0	0	9	0	0	438

来源	本网站	其他网站

次数	117	330
比例	26%	74%

摘要

209

最新录用	在线预览	正式出版

0	0	209

来源	本网站	其他网站

次数	143	66
比例	68%	32%

Index	T2DM with HTG (n=92)	T2DM without HTG (n=147)	P value
Age/year	52.43±11.84	58.29±12.66	<0.001
Male/n (%)	64 (69.56)	84 (57.14)	0.054
BMI/(kg·m^-2)	26.34±4.00	25.04±3.20	0.006
WHR	0.94±0.06	0.92±0.05	0.024
SBP/mmHg	139.42±17.71	137.32±16.18	0.349
DBP/mmHg	87.83±11.89	83.53±11.48	0.006
HbA1c/n(%)	8.74±2.13	8.11±2.14	0.029
FBG/(mmol·L^-1)	9.36±3.07	8.33±2.61	0.006
HDL/(mmol·L^-1)	1.11±0.21	1.31±0.34	<0.001
LDL/(mmol·L^-1)	3.43±1.02	3.17±0.99	0.055
TC/(mmol·L^-1)	5.62±1.13	5.05±1.17	<0.001
TAG/(mmol·L^-1)	2.37 (2.00, 3.48)	1.25 (0.88, 1.48)	<0.001
Insulin/(pmol·L^-1)	57.00 (42.45, 94.45)	50.88 (34.52, 78.73)	0.028
Scr/(μmol·L^-1)	64.09±15.16	61.63±16.03	0.243
ALT/(U·L^-1)	32.00 (20.00, 50.25)	24.00 (17.00, 34.25)	0.100
AST/(U·L^-1)	24.50 (20.00, 33.00)	21.50 (17.75, 26.00)	0.327
UA/(μmol·L^-1)	375.76±94.36	325.33±87.76	<0.001
Smoking/n(%)	31 (33.69)	33 (22.45)	0.060
Drinking/n(%)	26 (28.26)	33 (22.45)	0.325

Index	T2DM with HTG (n=92)	T2DM without HTG (n=147)	P value
Age/year	52.43±11.84	58.29±12.66	<0.001
Male/n (%)	64 (69.56)	84 (57.14)	0.054
BMI/(kg·m^-2)	26.34±4.00	25.04±3.20	0.006
WHR	0.94±0.06	0.92±0.05	0.024
SBP/mmHg	139.42±17.71	137.32±16.18	0.349
DBP/mmHg	87.83±11.89	83.53±11.48	0.006
HbA1c/n(%)	8.74±2.13	8.11±2.14	0.029
FBG/(mmol·L^-1)	9.36±3.07	8.33±2.61	0.006
HDL/(mmol·L^-1)	1.11±0.21	1.31±0.34	<0.001
LDL/(mmol·L^-1)	3.43±1.02	3.17±0.99	0.055
TC/(mmol·L^-1)	5.62±1.13	5.05±1.17	<0.001
TAG/(mmol·L^-1)	2.37 (2.00, 3.48)	1.25 (0.88, 1.48)	<0.001
Insulin/(pmol·L^-1)	57.00 (42.45, 94.45)	50.88 (34.52, 78.73)	0.028
Scr/(μmol·L^-1)	64.09±15.16	61.63±16.03	0.243
ALT/(U·L^-1)	32.00 (20.00, 50.25)	24.00 (17.00, 34.25)	0.100
AST/(U·L^-1)	24.50 (20.00, 33.00)	21.50 (17.75, 26.00)	0.327
UA/(μmol·L^-1)	375.76±94.36	325.33±87.76	<0.001
Smoking/n(%)	31 (33.69)	33 (22.45)	0.060
Drinking/n(%)	26 (28.26)	33 (22.45)	0.325

Independent variable	β	Exp (β)	95%CI	P value
SUMO1	0.423	1.527	1.200-1.943	<0.001
HbA1c	0.184	1.202	1.038-1.391	0.010
UA	0.006	1.006	1.003-1.010	<0.001

Independent variable	β	Exp (β)	95%CI	P value
SUMO1	0.423	1.527	1.200-1.943	<0.001
HbA1c	0.184	1.202	1.038-1.391	0.010
UA	0.006	1.006	1.003-1.010	<0.001

SUMO1 quartile	n/total	Crude OR OR (95%CI)	Model 1 OR (95%CI)	Model 2 OR (95%CI)
Q1 (<691 pg·mL^-1)	15/59	1.000	1.000	1.000
Q2 (692-887 pg·mL^-1)	18/60	1.257 (0.562~2.812)	1.270 (0.566~2.850)	1.319 (0.584~2.976)
Q3 (888-1 187 pg·mL^-1)	27/58	2.550^① (1.170~5.578)	2.440^① (1.112~5.355)	2.419^① (1.097~5.332)
Q4 (≥1 188 pg·mL^-1)	32/62	3.129^① (1.450~6.752)	2.886^① (1.322~6.298)	2.707^① (1.231~5.951)
P value for trend		0.008	0.010	0.010

2型糖尿病患者血清SUMO1水平与高甘油三酯血症相关性研究

Correlation between serum SUMO1 level and hypertriglyceridemia in type 2 diabetes mellitus patients

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 4

参考文献 44

相关文章 15

编辑推荐 0

Metrics

Independent variable	Standardized β	t	P value
Male	-0.218	-3.438	0.001
WHR	0.165	2.538	0.012
TAG	0.151	2.324	0.021
Scr	0.205	3.186	0.002

[1]	刘美志, 王子杨, 姜雅宁, 弥萌, 孙永宁. 番泻苷A对2型糖尿病小鼠动脉粥样硬化斑块形成及5-羟色胺信号分子表达的影响[J]. 上海交通大学学报（医学版）, 2024, 44(8): 991-998.
[2]	杜亚格, 卢言慧, 安宇, 宋颖, 郑婕. 肠道菌群在糖尿病认知功能障碍中的作用机制及靶向干预的研究进展[J]. 上海交通大学学报（医学版）, 2024, 44(4): 494-500.
[3]	吴凌恒, 陈建雄, 张梦娇, 沙蕾, 曹萌萌, 沈崔琴, 杜联芳, 李朝军. 血糖控制不理想对2型糖尿病患者亚临床心肌收缩功能的影响研究[J]. 上海交通大学学报（医学版）, 2023, 43(8): 1024-1031.
[4]	栾家妍, 李朋, 韩邦旻. SUMO化修饰在精子发生过程中的作用[J]. 上海交通大学学报（医学版）, 2022, 42(7): 925-930.
[5]	张静静, 祝超瑜, 肖元元, 蒋伏松, 高清歌, 方云云, 魏丽. 胰高血糖素样肽1受体基因rs3765467变异与2型糖尿病的关联研究[J]. 上海交通大学学报(医学版), 2021, 41(9): 1215-1221.
[6]	张佳思, 邹春波, 卢宇, 陈茜, 张伟亚, 何姣姣. 血脂蛋白磷脂酶A2和中性粒细胞明胶酶相关脂质运载蛋白在诊断早期糖尿病肾病中的价值[J]. 上海交通大学学报(医学版), 2021, 41(6): 770-775.
[7]	孙敏, 张冬颖. 钠-葡萄糖共转运蛋白2抑制剂对2型糖尿病患者心血管保护作用的研究进展[J]. 上海交通大学学报(医学版), 2021, 41(3): 391-395.
[8]	丁远森, 王枫, 孙家悦, 邵正威, 邹德荣, 陆家瑜. 不同年龄2型糖尿病患者牙周健康流行病学调查[J]. 上海交通大学学报(医学版), 2021, 41(2): 217-222.
[9]	郝艳云, 俞思慧, 陆静, 顾湘, 张帆, 程金科, 王田实. SIRT3去SUMO化修饰调节乳腺癌细胞MCF7增殖及化疗药物敏感性的研究[J]. 上海交通大学学报(医学版), 2021, 41(12): 1557-1563.
[10]	王婷婷 1, 2，李明杰 1，林宁 1，钮忆欣 1，简蔚霞 1，苏青 1. 血清高尿酸水平与住院糖尿病患者白蛋白尿短期进展的关系研究[J]. 上海交通大学学报（医学版）, 2019, 39(7): 754-.
[11]	高玮 1，王雪姣 2，甄琴 2，丁晓颖 2，徐浣白 2，王育璠 2，彭永德 2. 2型糖尿病患者心率变异性降低的危险因素分析[J]. 上海交通大学学报（医学版）, 2019, 39(6): 629-.
[12]	王凌霄，刘婷婷，杨晓辉，姚智卿，蔡慧珍. 枸杞多糖对髓样分化因子 88基因敲除小鼠 2型糖尿病模型炎症因子的影响[J]. 上海交通大学学报（医学版）, 2019, 39(2): 136-.
[13]	王秀芝，左勇. PPARγ1的SUMO化修饰对巨噬细胞M2极化的抑制作用[J]. 上海交通大学学报（医学版）, 2019, 39(12): 1402-.
[14]	陈丽，陈颖超，仰礼真. 2型糖尿病患者糖化血红蛋白与血黏度及外周动脉血流的相关性研究[J]. 上海交通大学学报（医学版）, 2019, 39(12): 1442-.
[15]	金志萍 1，张珊 2，于雪梅 2，陈海冰 3，胡承 3. 社区 2型糖尿病患者甲状腺结节危险因素研究分析[J]. 上海交通大学学报（医学版）, 2018, 38(9): 1066-.