脂肪量和肥胖相关基因多态性与非酒精性脂肪性肝病易感性的关系

马磊; 郝岸华; 胡欣欣; 赵真真; 周林; 辛永宁

doi:10.3969/j.issn.1001-5256.2022.12.009

脂肪量和肥胖相关基因多态性与非酒精性脂肪性肝病易感性的关系

DOI: 10.3969/j.issn.1001-5256.2022.12.009

马磊¹,
郝岸华¹,
胡欣欣¹,
赵真真^2a,
周林¹,
辛永宁^2b, , ,

1.
青岛市城阳区人民医院感染科，山东青岛 266109
2a.
青岛大学附属青岛市市立医院临床研究中心，山东青岛 266071
2b.
青岛大学附属青岛市市立医院感染科，山东青岛 266071

基金项目:

国家自然科学基金 (32171277)

伦理学声明：本研究遵守国家所有相关法规、机构政策和赫尔辛基宣言，并于2017年10月11日经由青岛市市立医院伦理委员会审批，批号：2017临审字第20号(快)。所纳入患者均签署知情同意书。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：马磊、辛永宁负责课题设计，资料分析，撰写论文；郝岸华、胡欣欣、赵真真、周林参与收集数据，修改论文；马磊负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
辛永宁，xinyongning@163.com

计量
- 文章访问数: 1442
- HTML全文浏览量: 968
- PDF下载量: 72
- 被引次数: 0
出版历程
- 收稿日期: 2022-05-24
- 录用日期: 2022-06-28
- 出版日期: 2022-12-20

Association of fat mass- and obesity-associated gene (FTO) polymorphisms with susceptibility to nonalcoholic fatty liver disease

1.
Department of Infectious Diseases, Qingdao Chengyang District People's Hospital, Qingdao, Shandong 266109, China
2a.
Clinical Research Center, Qingdao Municipal Hospital affiliated to Qingdao University, Qingdao, Shandong 266071, China
2b.
Department of Infectious Diseases, Qingdao Municipal Hospital affiliated to Qingdao University, Qingdao, Shandong 266071, China

Research funding:

National Natural Science Foundation of China (32171277)

More Information

Corresponding author: XIN Yongning, xinyongning@163.com (ORCID: 0000-0002-3692-7655)

摘要

摘要: 目的探讨我国青岛地区汉族人群脂肪量和肥胖相关基因(FTO) rs1421085、rs9939609、rs8050136多态性与非酒精性脂肪性肝病(NAFLD)易感性的关系。方法纳入自2018年6月—2019年6月就诊于青岛市市立医院及城阳区人民医院的NAFLD患者(119例)及体检人群(187例)。采集参与者基本信息，抽取空腹静脉血并检测生化指标。提取全血DNA并采用聚合酶链式反应结合测序的方法鉴定FTO基因多态性。计量资料两组间比较采用t检验或Mann-Whitney U检验，基因型分布等定性资料两组间比较采用χ²检验，并计算等位基因频率风险系数比值比和95%CI，评估等位基因与NAFLD风险的关系。结果 NAFLD和对照组基本信息进行比较，两组间年龄、BMI、ALT、GGT、TG及胆红素(Bil)差异均具有统计学意义(P值均＜0.05)。基因型鉴定结果显示，rs1421085(TT、CT、CC)，rs8050136(TT、CT、CC)，rs9939609(TT、AT、AA)位点均具有3种基因型。NAFLD和对照组中FTO rs1421085、rs9939609、rs8050136等位基因频率和基因型比较，分布差异均无统计学意义(P值均＞0.05)。对不同基因型携带者进行比较，各临床指标差异亦均无统计学意义(P值均＞0.05)。结论青岛地区汉族人群FTO rs1421085、rs9939609、rs8050136多态性与NAFLD易感性无显著关系。
- 非酒精性脂肪性肝病 /
- 基因组 /
- 多态性, 单核苷酸
Abstract: Objective To investigate the relationship between Fat Mass- and obesity-associated gene (FTO) polymorphisms and the susceptibility of non-alcohol-related fatty liver disease (NAFLD) in a Han population from Qingdao region of China. Methods A total of 119 NAFLD patients were recruited from Qingdao Municipal Hospital and Chengyang District People's Hospital and 187 control individuals who received annual physical examination were also included. Their clinicopathological information and study questionnaire were collected. Their fasting venous blood was extracted for biochemical analyses and FTO polymorphism genotyping using the polymerase chain reaction combined with DNA sequencing. The data were statistically assessed. Results The data showed statistically significant differences in age, BMI, ALT, GGT, TG and Bil between NAFLD patients and normal controls (all P < 0.05). FTO polymorphism genotyping data showed three genotypes of FTO rs1421085 (TT, CT, and CC), rs8050136 (TT, CT, and CC) and rs9939609 (TT, AT, AA). However, there was no statistical difference in both allele frequency and genotype of FTO rs1421085, rs9939609, and rs8050136 between NAFLD and controls (all P > 0.05) and there was also no statistical difference in clinical parameters among these genotype carriers (all P > 0.05). Conclusion NAFLD patients showed significantly statistical differences in age, BMI, ALT, GGT, TG, and BIL vs. those of normal controls. However, this study did not find any association of FTO rs1421085, rs9939609, and rs8050136 polymorphisms with NAFLD susceptibility in this Qingdao region of Han Chinese population.
- Non-alcoholic Fatty Liver Disease /
- Genome /
- Polymorphism, Single Nucleotide

HTML全文

表 1 FTO基因引物序列

Table 1. Primer sequence of FTO gene

位点	引物名称	引物序列5′-3′
rs9939609	primer 1	ACGTTGGATGTTCTAGGTTCCTTGCGACTG
	primer 2	ACGTTGGATGTCCCACTCCATTTCTGACTG
rs1421085	primer 1	ACGTTGGATGGTAGCAGTTCAGGTCCTAAG
	primer 2	ACGTTGGATGGGAGACTACCCTACAAATTC
rs8050136	primer 1	ACGTTGGATGTGACAGTGCCAGCTTCATAG
	primer 2	ACGTTGGATGAAGGCAAAAACCACAGGCTC

下载: 导出CSV

表 2 两组一般临床资料及相关实验室指标比较

Table 2. Comparison of general clinical data and related laboratory indicators between NAFLD and control group

项目	NAFLD(n=119)	对照组(n=187)	统计值	P值
年龄(岁)	43.00(39.00~45.25)	48.00(42.50~59.00)	Z=-5.489	＜0.001
男/女(例)	34/25	78/46	χ²=0.469	0.494
BMI(kg/m²)	26.44±2.57	23.88±3.24	t=5.891	＜0.001
ALT(U/L)	23.71(18.94~44.49)	18.87(13.56~25.71)	Z=-4.977	＜0.001
AST(U/L)	23.65±8.00	22.35±8.46	t=1.111	0.268
GGT(U/L)	30.99(20.92~49.10)	23.45(17.35~31.66)	Z=-4.217	＜0.001
ALP(U/L)	70.31±18.64	75.2±23.23	t=-1.597	0.117
TG(mmol/L)	1.51(1.11~2.24)	1.16(0.90~1.68)	Z=-3.508	＜0.001
TC(mmol/L)	5.43±1.01	5.21±1.71	t=0.985	0.326
HDL(mmol/L)	1.29±0.50	1.33±0.57	t=-0.431	0.667
LDL(mmol/L)	3.23±0.71	3.28±1.57	t=-0.292	0.771
FPG(mmol/L)	5.07±1.27	4.66±0.98	t=2.702	0.007
Bil(μmol/L)	12.98±4.88	14.44±5.39	t=-1.978	0.049

下载: 导出CSV

表 3 FTO基因型及等位基因的频率分布

Table 3. Frequency distribution of FTO genotypes and alleles

基因	NAFLD组(n=119)	对照组(n=187)	χ²值	P值	OR	95%CI
rs1421085
TT	93(78.15)	148(79.57)	0.067	0.795	0.928	0.529~1.628
CT	23(19.33)	33(17.74)
CC	3(2.52)	5(2.69)
T	209(87.82)	329(88.44)	0.055	0.815	0.942	0.570~1.556
C	29(12.18)	43(11.56)
rs8050136
CC	92(77.31)	147(78.61)	0.370	0.831	0.927	0.533~1.612
CA	23(19.33)	32(17.11)
AA	4(3.36)	8(4.28)
C	207(86.97)	326(87.17)	0.005	1.000	0.983	0.606~1.595
A	31(13.03)	48(12.83)
rs9939609
TT	94(79.66)	147(79.46)	1.549	0.213	0.715	0.421~1.214
AT	23(19.49)	33(17.84)
AA	1(0.85)	5(2.70)
T	211(89.41)	327(88.38)	0.153	0.696	1.110	0.658~1.871
A	25(10.59)	43(11.62)
注：rs1421085 CC基因型与rs9939609 AA基因型比例低，不适用于χ²检验，因此将其与杂合子合并后进行χ²检验，三个多态性位点基因型的OR值为合并后数据分别与TT、CC、TT基因型比较所得。

下载: 导出CSV

表 4 rs1421085、rs9939609、rs8050136不同等位基因携带生化指标比较

Table 4. Comparison of biochemical indices of different alleles of rs1421085、rs9939609、rs8050136

指标	rs1421085		rs9939609		rs8050136
指标	非C等位基因携带	C等位基因携带	非A等位基因携带	A等位基因携带	非A等位基因携带	A等位基因携带
BMI(kg/m²)	24.53±3.33	25.03±3.10	24.56±3.33	24.92±3.10	24.54±3.32	25.02±3.13
ALT(U/L)	20.04(14.7~28.95)	19.59(13.95~29.14)	20.01(14.63~28.65)	20.32(14.10~29.67)	20.01(14.67~28.57)	20.32(13.96~29.89)
AST(U/L)	20.91(18.48~24.92)	20.37(18.38~25.42)	20.90(18.50~24.82)	20.58(18.24~25.39)	20.87(18.48~24.71)	21.40(18.38~25.44)
GGT(U/L)	25.52(18.29~35.54)	27.11(18.84~38.38)	25.52(18.22~35.59)	27.11(19.06~36.28)	25.52(18.23~35.63)	27.11(19.01~35.13)
ALP(U/L)	74.01(58.21~86.44)	66.94(57.62~77.79)	73.86(58.13~86.35)	67.89(58.51~79.50)	74.01(58.21~86.76)	66.94(57.62~77.79)
FPG(mmol/L)	4.60(4.22~5.13)	4.70(4.20~5.09)	4.60(4.20~5.14)	4.70(4.21~5.09)	4.60(4.22~5.14)	4.66(4.20~5.08)
TG(mmol/L)	1.26(0.96~1.84)	1.15(0.95~1.67)	1.26(0.97~1.83)	1.15(0.95~1.69)	1.27(0.97~1.84)	1.12(0.94~1.64)
TC(mmol/L)	5.27(4.65~5.95)	5.11(4.56~5.92)	5.27(4.65~5.95)	5.11(4.58~5.89)	5.27(4.66~5.96)	5.11(4.56~5.85)
HDL(mmol/L)	1.24(1.07~1.44)	1.24(1.01~1.42)	1.24(1.07~1.44)	1.26(1.06~1.43)	1.24(1.07~1.44)	1.26(1.04~1.42)
LDL(mmol/L)	3.22(2.72~3.70)	3.13(2.74~3.58)	3.23(2.71~3.71)	3.11(2.75~3.56)	3.23(2.72~3.70)	3.11(2.74~3.55)
Bil(μmol/L)	13.20(10.20~16.90)	14.45(10.53~17.20)	13.20(10.2~16.85)	14.45(10.33~17.30)	13.20(10.20~16.80)	14.45(10.43~17.30)

下载: 导出CSV

参考文献(20)

[1]	BYRNE CD, TARGHER G. NAFLD: a multisystem disease[J]. J Hepatol, 2015, 62(1 Suppl): S47-S64. DOI: 10.1016/j.jhep.2014.12.012.
[2]	LAN N, LU Y, ZHANG Y, et al. FTO - A common genetic basis for obesity and cancer[J]. Front Genet, 2020, 11: 559138. DOI: 10.3389/fgene.2020.559138.
[3]	KOLAČKOV K, ŁACZMAŃSKI Ł, LWOW F, et al. The frequencies of haplotypes of FTO Gene variants and their association with the distribution of body fat in non-obese poles[J]. Adv Clin Exp Med, 2016, 25(1): 33-42. DOI: 10.17219/acem/60645.
[4]	HUANG S, QIN P, CHEN Q, et al. Association of FTO gene methylation with incident type 2 diabetes mellitus: A nested case-control study[J]. Gene, 2021, 786: 145585. DOI: 10.1016/j.gene.2021.145585.
[5]	BOIKO AS, POZHIDAEV Ⅳ, PADERINA DZ, et al. Search for possible associations of FTO gene polymorphic variants with metabolic syndrome, obesity and body mass index in schizophrenia patients[J]. Pharmgenomics Pers Med, 2021, 14: 1123-1131. DOI: 10.2147/PGPM.S327353.
[6]	LI S, WANG X, ZHANG J, et al. Exenatide ameliorates hepatic steatosis and attenuates fat mass and FTO gene expression through PI3K signaling pathway in nonalcoholic fatty liver disease[J]. Braz J Med Biol Res, 2018, 51(8): e7299. DOI: 10.1590/1414-431x20187299.
[7]	CHENG L, YU P, LI F, et al. Human umbilical cord-derived mesenchymal stem cell-exosomal miR-627-5p ameliorates non-alcoholic fatty liver disease by repressing FTO expression[J]. Hum Cell, 2021, 34(6): 1697-1708. DOI: 10.1007/s13577-021-00593-1.
[8]	LIM A, ZHOU J, SINHA RA, et al. Hepatic FTO expression is increased in NASH and its silencing attenuates palmitic acid-induced lipotoxicity[J]. Biochem Biophys Res Commun, 2016, 479(3): 476-481. DOI: 10.1016/j.bbrc.2016.09.086.
[9]	MIZUNO TM. Fat mass and obesity associated (FTO) gene and hepatic glucose and lipid metabolism[J]. Nutrients, 2018, 10(11): 1600. DOI: 10.3390/nu10111600.
[10]	LAU L, WONG SH. Microbiota, obesity and NAFLD[J]. Adv Exp Med Biol, 2018, 1061: 111-125. DOI: 10.1007/978-981-10-8684-7_9.
[11]	STEFAN N, HÄRING HU, CUSI K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies[J]. Lancet Diabetes Endocrinol, 2019, 7(4): 313-324. DOI: 10.1016/S2213-8587(18)30154-2.
[12]	National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical Association, Fatty Liver Expert Committee, Chinese Medical Doctor Association. Guidelines of prevention and treatment for nonalcoholic fatty liver disease: A 2018 update[J]. J Clin Hepatol, 2018, 34(5): 947-957. DOI: 10.3969/j.issn.1001-5256.2018.05.007. 中华医学会肝病学分会脂肪肝和酒精性肝病学组, 中国医师协会脂肪性肝病专家委员会. 非酒精性脂肪性肝病防治指南(2018年更新版)[J]. 临床肝胆病杂志, 2018, 34(5): 947-957. DOI: 10.3969/j.issn.1001-5256.2018.05.007.
[13]	LIU Q, LIU SS, ZHAO ZZ, et al. TRIB1 rs17321515 gene polymorphism increases the risk of coronary heart disease in general population and non-alcoholic fatty liver disease patients in Chinese Han population[J]. Lipids Health Dis, 2019, 18(1): 165. DOI: 10.1186/s12944-019-1108-2.
[14]	TRÉPO E, VALENTI L. Update on NAFLD genetics: From new variants to the clinic[J]. J Hepatol, 2020, 72(6): 1196-1209. DOI: 10.1016/j.jhep.2020.02.020.
[15]	WIJARNPREECHA K, PANJAWATANAN P, LEKUTHAI N, et al. Hyperuricaemia and risk of nonalcoholic fatty liver disease: A meta-analysis[J]. Liver Int, 2017, 37(6): 906-918. DOI: 10.1111/liv.13329.
[16]	ELOUEJ S, NAGARA M, ATTAOUA R, et al. Association of genetic variants in the FTO gene with metabolic syndrome: A case-control study in the Tunisian population[J]. J Diabetes Complications, 2016, 30(2): 206-211. DOI: 10.1016/j.jdiacomp.2015.11.013.
[17]	INANDIKLIOǦLU N, YAŞAR A. Association between rs1421085 and rs9939609 polymorphisms of fat mass and obesity-associated gene with high-density lipoprotein cholesterol and triglyceride in obese Turkish children and adolescents[J]. J Pediatr Genet, 2021, 10(1): 9-15. DOI: 10.1055/s-0040-1713154.
[18]	WANG L, YU Q, XIONG Y, et al. Variant rs1421085 in the FTO gene contribute childhood obesity in Chinese children aged 3-6 years[J]. Obes Res Clin Pract, 2013, 7(1): e14-e22. DOI: 10.1016/j.orcp.2011.12.007.
[19]	GU Z, BI Y, YUAN F, et al. FTO Polymorphisms are associated with metabolic dysfunction-associated fatty liver disease (MAFLD) susceptibility in the older Chinese Han Population[J]. Clin Interv Aging, 2020, 15: 1333-1341. DOI: 10.2147/CIA.S254740.
[20]	HEBBAR P, ABU-FARHA M, MOHAMMAD A, et al. FTO variant rs1421085 associates with increased body weight, soft lean mass, and total body water through interaction with ghrelin and apolipoproteins in Arab population[J]. Front Genet, 2019, 10: 1411. DOI: 10.3389/fgene.2019.01411.