KCNJ11 rs5210位点多态性与非酒精性脂肪性肝病及冠心病的遗传易感性分析

徐艳艳; 赵真真; 刘守胜; 宋欢; 辛永宁

doi:10.3969/j.issn.1001-5256.2021.06.027

KCNJ11 rs5210位点多态性与非酒精性脂肪性肝病及冠心病的遗传易感性分析

DOI: 10.3969/j.issn.1001-5256.2021.06.027

徐艳艳^1a,
赵真真^1b,
刘守胜^1b,
宋欢²,
辛永宁^1a, ,

1a.
青岛大学附属青岛市市立医院感染性疾病科，山东青岛 266011
1b.
青岛大学附属青岛市市立医院临床研究中心，山东青岛 266011
2.
大连医科大学临床医学系，辽宁大连 116000

基金项目:

国家自然科学基金面上项目 (31770837)

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：徐艳艳负责课题设计，资料分析，撰写论文；赵真真、刘守胜、宋欢参与收集数据，修改论文；辛永宁负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

作者简介:
徐艳艳(1994—)，女，主要从事非酒精性脂肪性肝病研究

通信作者:
辛永宁，xinyongning@163.com

中图分类号: R575.5
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- 被引次数: 0
出版历程
- 收稿日期: 2020-11-06
- 录用日期: 2020-12-17
- 出版日期: 2021-06-20

KCNJ11 rs5210 polymorphism and genetic susceptibility to nonalcoholic fatty liver disease and coronary artery disease

1a.
Department of Infectious Diseases, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong 266011, China
1b.
Clinical Research Center, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong 266011, China
2.
School of Clinical Medicine, Dalian Medical University, Dalian, Liaoning 116000, China

摘要

摘要: 目的在青岛地区汉族人群中，研究内向整流钾通道蛋白J亚单位11号成员(KCNJ11)基因rs5210位点多态性与非酒精性脂肪性肝病(NAFLD)及冠心病(CAD)的相关性。方法随机纳入2018年12月—2019年9月就诊于青岛市市立医院的246例NAFLD患者为NAFLD组，201例CAD患者为CAD组，116例NAFLD合并CAD患者为合并组，342例健康对照人群为对照组。采集空腹静脉血进行生化检测。提取全血基因组DNA，采用PCR的方法进行KCNJ11 rs5210基因型测定。应用χ²检验分析KCNJ11 rs5210基因频率分布是否符合Hardy-Weinberg平衡法则，以确定检验样本是否具有群体代表性。应用χ²检验分析各组之间性别、基因型及等位基因频率的差异性。符合正态分布的计量资料多组间比较采用单因素方差分析，进一步两两比较采用LSD-t检验；不符合正态分布计量资料多组间比较采用Kruskal-Wallis H检验，两两比较采用Bonferroni法。应用非条件logistic回归模型计算比值比(OR)及95%可信区间。结果经测序发现KCNJ11 rs5210具有AA、GA、GG 3种基因型。对照组、NAFLD组、CAD组及合并组之间进行比较rs5210位点等位基因频率和基因型分布均无统计学差异(P值均＞0.05)。经校正年龄、性别、BMI，差异亦无统计学意义(P值均＞0.05)。全部受试人群中，携带AA基因型受试者ALP水平高于GA基因型(P=0.048)；在NAFLD组中，与携带AA基因型受试者相比，GA基因型携带者具有更高的BMI、TBil水平(P值分别为0.042、0.002)。非条件logistic回归分析表明，BMI升高与NAFLD患病风险相关(OR=1.35，P＜0.01)，HDL降低可提示NAFLD患病风险增加(OR=0.33，P＜0.01)；FPG升高、HDL降低可提示CAD(OR=1.51，P＜0.01;OR=0.11，P＜0.01)、NAFLD+CAD(OR=1.46，P＜0.01;OR=0.06，P＜0.01)患病风险增加。结论青岛地区汉族人群中KCNJ11 rs5210多态性与NAFLD及CAD的发病风险无明显相关性。
- 非酒精性脂肪性肝病 /
- 冠心病 /
- 基因型
Abstract: Objective To investigate the association of KCNJ11 rs5210 single nucleotide polymorphism with nonalcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD) in the Chinese Han population in Qingdao, China. Methods A total of 246 patients with NAFLD who attended Qingdao Municipal Hospital from December 2018 to September 2019 were enrolled as NAFLD group, 201 patients with CAD were enrolled as CAD group, and 116 patients with NAFLD and CAD were enrolled as NAFLD+CAD group; 342 healthy individuals were enrolled as control group. Fasting venous blood samples were collected for biochemical analysis. Whole blood genomic DNA was extracted, and PCR was used to determine KCNJ11 rs5210 genotype. The chi-square test was used to analyze whether the distribution of KCNJ11 rs5210 gene frequencies met the Hardy-Weinberg equilibrium, in order to determine whether the tested samples could represent the population. The chi-square test was used to analyze the differences in sex and genotype/allele frequency between groups. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups; the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups, and the Bonferroni method was used for further comparison between two groups. The unconditional logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval. Results Three genotypes (AA, GA, and GG) of KCNJ11 rs5210 were found by gene sequencing. There were no significant differences in rs5210 allele frequency and genotype distribution between the control group, the NAFLD group, the CAD group, and the NAFLD+CAD group (all P > 0.05), and there were still no significant differences after adjustment for sex, age, and body mass index (BMI) (all P > 0.05). For all subjects, the subjects with AA genotype had a higher level of alkaline phosphatase than those with GA genotype (P=0.048); in the NAFLD group, the patients with GA genotype had significantly higher BMI and total bilirubin than those with AA genotype (P=0.042 and 0.002). The unconditional logistic regression analysis showed that elevated BMI was associated with the risk of NAFLD (OR=1.35, P < 0.01), while decreased high-density lipoprotein (HDL) might indicate an increase in the risk of NAFLD (OR=0.33, P < 0.01); elevated fasting plasma glucose and decreased HDL might indicate an increase in the risk of CAD (OR=1.51 and 0.11, both P < 0.01) and NAFLD with CAD (OR=1.46 and 0.06, both P < 0.01). Conclusion There is no significant association between KCNJ11 rs5210 polymorphism and the risk of NAFLD and CAD in the Chinese Han population in Qingdao.
- Non-Alcoholic Fatty Liver Disease /
- Coronary Disease /
- Genotype

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表 1 4组之间一般临床资料及相关实验室指标比较

指标	对照组(n=342)	NAFLD组(n=246)	合并组(n=116)	CAD组(n=201)	统计值	P值
年龄(岁)	45.00(20.00~75.00)	45.00(24.00~73.00)	62.00(32.00~74.00)¹⁾²⁾	67.00(30.00~75.00)¹⁾²⁾	H=325.83	＜0.01
女/男(例)	150/192	109/137	36/80¹⁾²⁾	74/127	χ²=8.48	0.04
BMI(kg/m²)	23.49±3.08	26.51±2.90¹⁾	25.19±2.58¹⁾²⁾	24.60±3.27¹⁾²⁾	F=130.17	＜0.01
FPG(mmol/L)	4.59(2.92~16.72)	4.77(2.90~16.10)¹⁾	5.42(3.04~16.21)¹⁾²⁾	5.22(1.81~18.33)¹⁾²⁾	H=100.76	＜0.01
TC(mmol/L)	5.20(0.84~18.50)	5.27(2.60~13.90)	4.31(1.64~8.49)¹⁾²⁾	4.48(2.06~12.80)¹⁾²⁾	H=63.95	＜0.01
TG(mmol/L)	1.10(0.33~8.33)	1.51(0.53~32.34)¹⁾	1.46(0.50~40.38)¹⁾	1.38(0.05~6.09)¹⁾	H=61.48	＜0.01
HDL(mmol/L)	1.34(0.58~3.60)	1.18(0.66~2.58)¹⁾	1.03(0.62~2.28)¹⁾²⁾	1.01(0.35~6.90)¹⁾²⁾	H=181.92	＜0.01
LDL(mmol/L)	3.08(1.65~5.55)	3.31(1.20~15.37)	2.64(0.70~5.20)¹⁾²⁾	2.66(0.87~9.82)¹⁾²⁾	H=67.77	＜0.01
ALT(U/L)	18.00(6.00~287.17)	23.80(5.63~325.69)¹⁾	22.25(7.00~153.00)¹⁾	20.97(1.20~305.02)¹⁾²⁾	H=52.53	＜0.01
AST(U/L)	20.30(10.00~524.75)	22.28(1.81~87.85)¹⁾	22.42(0.74~438.66)¹⁾	22.45(10.13~381.84)¹⁾	H=22.24	＜0.01
GGT(U/L)	20.00(7.00~374.50)	30.52(10.23~1043.56)¹⁾	26.44(9.05~902.84)¹⁾	27.11(9.47~171.78)¹⁾	H=80.61	＜0.01
ALP(U/L)	66.16(15.00~182.29)	76.11(1.60~499.84)¹⁾	82.41(44.45~509.41)¹⁾²⁾	83.14(28.72~234.74)¹⁾	H=93.97	＜0.01
TBil(μmol/L)	13.47(5.60~55.50)	11.90(5.00~40.80)¹⁾	13.47(5.50~52.70)	13.30(2.50~63.90)	H=12.12	＜0.01
注：与对照组相比，1)P＜0.05；与NAFLD组相比，2)P＜0.05。

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表 2 KCNJ11 rs5210位点等位基因和基因型频率分布

项目	对照组(n=342)	NAFLD组(n=246)	合并组(n=116)	CAD组(n=201)	χ²值	P值
基因型[例(%)]					4.63	0.59
AA	84(24.6)	59(24.0)	25(21.6)	55(27.4)
GA	173(50.6)	113(45.9)	63(54.3)	98(48.8)
GG	85(24.9)	74(30.1)	28(24.1)	48(23.9)
等位基因[例(%)]					2.16	0.54
A	341(49.9)	231(47.0)	113(48.7)	208(51.7)
G	343(50.1)	261(53.0)	119(51.3)	194(48.3)
隐性模型[例(%)]					3.04	0.39
GA+AA	257(75.1)	172(69.9)	88(75.9)	153(76.1)
GG	85(24.9)	74(30.1)	28(24.1)	48(23.9)
显性模型[例(%)]					1.46	0.69
AA	84(24.6)	59(24.0)	25(21.6)	55(27.4)
GG+GA	258(75.4)	187(76.0)	91(78.4)	146(72.6)

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表 3 全部受试人群KCNJ11 rs5210位点多态性不同基因型之间各指标比较

指标	AA(n=223)	GA(n=447)	GG(n=235)	统计值	P值
年龄(岁)	55.00(20.00~75.00)	54.00(23.00~75.00)	53.00(21.00~75.00)	H=0.99	0.61
女/男(例)	88/135	173/274	108/127	χ²=3.57	0.17
BMI(kg/m²)	24.65(16.44~32.87)	24.81(15.24~38.54)	24.66(17.13~34.35)	H=1.86	0.40
FPG(mmol/L)	4.81(2.90~17.60)	4.84(2.90~18.30)	4.89(1.80~15.60)	H=0.33	0.85
TC(mmol/L)	5.07(0.94~13.90)	5.03(0.84~18.50)	4.94(0.99~9.01)	H=0.72	0.70
TG(mmol/L)	1.27(0.41~8.33)	1.33(0.05~40.38)	1.32(0.33~10.32)	H=1.52	0.47
HDL(mmol/L)	1.18(0.54~3.60)	1.16(0.35~6.90)	1.16(0.40~3.49)	H=0.44	0.80
LDL(mmol/L)	3.12(0.87~8.37)	3.04(1.20~15.37)	2.97(0.74~11.37)	H=1.34	0.51
ALT(U/L)	20.21(5.70~325.69)	21.63(1.20~305.02)	19.18(6.00~156.66)	H=5.05	0.08
AST(U/L)	21.35(1.81~381.84)	21.45(0.80~524.75)	20.83(0.74~427.83)	H=2.91	0.23
GGT(U/L)	24.40(7.52~610.35)	25.66(7.00~902.84)	24.69(8.00~1043.56)	H=1.03	0.60
ALP(U/L)	76.34(30.00~327.90)	73.51(15.00~509.41)¹⁾	74.07(1.60~499.84)	H=6.23	0.04
TBil(μmol/L)	13.22(3.00~64.00)	13.41(3.00~55.00)	13.22(6.00~53.00)	H=1.54	0.46
注：与AA相比，1)P＜0.05。

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表 4 NAFLD组KCNJ11 rs5210位点多态性不同基因型之间各指标比较

指标	AA(n=59)	GA(n=113)	GG(n=74)	统计值	P值
年龄(岁)	47.00(24.00~72.00)	45.00(25.00~73.00)	46.00(28.00~72.00)	H=3.77	0.15
女/男(例)	30/29	47/66	32/42	χ²=1.39	0.50
BMI(kg/m²)	25.39(20.20~32.87)	26.40(20.06~34.72)¹⁾	26.06(20.20~34.35)	H=6.39	0.04
FPG(mmol/L)	4.81(3.27~16.11)	4.66(2.88~13.20)	4.89(3.55~15.62)	H=0.98	0.61
TC(mmol/L)	5.42(3.12~13.90)	5.25(2.60~8.77)	5.21(3.11~9.01)	H=1.19	0.55
TG(mmol/L)	1.64(0.53~6.07)	1.51(0.62~32.34)	1.53(0.62~10.32)	H=0.18	0.92
HDL(mmol/L)	1.21(0.70~2.13)	1.16(0.72~2.58)	1.13(0.66~1.93)	H=3.57	0.17
LDL(mmol/L)	3.35(1.74~8.37)	3.32(1.20~15.37)	3.30(1.82~11.37)	H=0.54	0.76
ALT(U/L)	22.76(11.51~325.69)	26.86(5.63~277.92)	22.80(10.31~111.54)	H=1.70	0.43
AST(U/L)	22.71(1.81~87.85)	22.06(12.02~68.91)	21.83(11.62~55.35)	H=0.19	0.91
GGT(U/L)	27.74(14.37~610.35)	33.01(10.23~165.61)	29.14(10.70~1043.56)	H=2.31	0.32
ALP(U/L)	82.35(41.61~327.90)	73.02(41.33~163.10)	77.50(1.60~499.84)	H=5.82	0.05
TBil(μmol/L)	11.00(5.00~33.10)	13.10(6.50~40.80)	11.95(5.90~23.90)	H=11.62	0.003
注：与AA相比，1)P＜0.05。

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表 5 NAFLD、CAD及NAFLD+CAD危险因素的logistic回归分析结果

指标	NAFLD			CAD			NAFLD+CAD
指标	OR	95%CI	P值	OR	95%CI	P值	OR	95%CI	P值
BMI	1.35	1.25~1.45	＜0.01	1.05	0.98~1.12	0.18	1.08	0.99~1.18	0.10
FPG	1.08	0.94~1.24	0.30	1.51	1.29~1.76	＜0.01	1.46	1.20~1.78	＜0.01
TC	1.02	0.87~1.18	0.85	0.91	0.75~1.10	0.33	1.02	0.84~1.25	0.82
TG	1.07	0.92~1.24	0.36	0.94	0.75~1.17	0.58	1.11	0.91~1.35	0.32
HDL	0.33	0.16~0.71	＜0.01	0.11	0.05~0.26	＜0.01	0.06	0.02~0.18	＜0.01
LDL	1.20	0.98~1.46	0.07	0.69	0.50~0.95	0.02	0.61	0.40~0.92	0.02
rs 5210 G等位基因携带	0.87	0.57~1.35	0.55	0.97	0.61~1.54	0.90	1.07	0.60~1.92	0.82

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