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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
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。
KCNJ11 rs5210 polymorphism and genetic susceptibility to nonalcoholic fatty liver disease and coronary artery disease
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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。 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. -
Key words:
- Non-Alcoholic Fatty Liver Disease /
- Coronary Disease /
- Genotype
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非酒精性脂肪性肝病(NAFLD)是一种与胰岛素抵抗和遗传易感密切相关的代谢应激性肝脏损伤[1]，通常被认为是代谢综合征(metabolic syndrome, MetS)的肝脏表现。最近，国际专家组建议将NAFLD改名为代谢性脂肪性肝病(metabolic fatty liver disease, MAFLD)[2]。冠心病(coronary artery disease, CAD)是指在向心脏供应氧气和营养的血管中形成动脉粥样硬化斑块所导致的疾病[3]，有着高发病率及高病死率[4]。MetS包括肥胖、胰岛素抵抗、高血压和血脂异常，这些也是独立的CAD危险因素的组合[5]。越来越多的临床和流行病学证据[6-7]表明，NAFLD与罹患心血管疾病和2型糖尿病(type 2 diabetes, T2DM)的风险增加有关。NAFLD及CAD发病机制目前尚未完全明确。NAFLD具有复杂的疾病特征，环境与易感多基因宿主背景之间的相互作用决定了疾病表型并影响疾病进展。研究[3, 8-10]表明，多种基因与NAFLD或CAD的发病风险具有相关性。
内向整流钾通道蛋白J亚单位11号成员(potassium inwardly rectifying channel subfamily J member 11, KCNJ11)编码内向整流钾通道蛋白Kir6.2。Kir6.2与磺脲类受体共同组成ATP敏感性钾通道，在糖代谢和细胞膜的电生理调节下，影响胰岛素的分泌[11]。KCNJ11在胰腺组织中高表达，并与T2DM的易感性密切相关[12-13]。国内外多项研究证实，KCNJ11基因不同突变位点可导致一系列连续的、不同轻重的糖代谢异常，包括新生儿糖尿病[14]、青少年发病的成人型糖尿病[15]、T2DM、婴儿持续性高胰岛素血症性低血糖症[16]。KCNJ11编码的Kir6.2离子通道的遗传多态性对微血管功能障碍和缺血性心脏病的易感性具有重要的影响[17]。目前，国内外关于KCNJ11 rs5210的研究较少，其中，大部分为与T2DM的相关性研究[12]，尚无同时纳入NAFLD和CAD患者KCNJ11 rs5210的相关研究。鉴于NAFLD、CAD及T2DM同为代谢性疾病，有多种共同的危险因素[18-20]，亦可能具有共同的易感性多态性位点。本研究旨在探讨KCNJ11 rs5210位点多态性与青岛地区汉族人群NAFLD、NAFLD合并CAD的遗传易感相关性，并为NAFLD及CAD的预防和治疗提供新的思路。
1. 资料与方法
1.1 研究对象
NAFLD组为2018年12月—2019年9月青岛市市立医院收治的NAFLD患者，诊断标准参照2010年版《非酒精性脂肪性肝病诊疗指南》[21]；健康对照组为同期体检中心健康体检者，均通过生化指标结合超声检查确认；CAD组为同期经皮冠脉造影，3支大血管至少1支狭窄超过50%且排除NAFLD的患者；合并组为同期确诊为NAFLD合并CAD的患者。所有患者的选择均采取随机法。
1.2 标本采集
各研究对象均在禁食12 h后，于次日早晨，测量身高、体质量，计算BMI=体重(kg)/身高2(m2)。同时采集受试者的年龄、性别等基本临床信息。抽取正中静脉血5 ml，分别置于2个EDTA抗凝管中，其中一管送本院检验科，进行生化学指标检测，包括空腹血糖(FPG)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、ALT、AST、GGT、ALP、TBil; 另一管血液离心后，将血清与全血细胞分离，置于-80 ℃冰箱保存，以备DNA提取。
1.3 基因组DNA提取、基因型鉴定
全血基因组DNA提取采用血液基因组DNA提取试剂盒(博淼生物科技有限公司，北京)。采用多聚酶链反应(polymerase chain reaction, PCR)方法进行KCNJ11目的基因的扩增，并进行多态基因型分析。PCR引物由同一公司设计合成，引物序列为：上游5′-ACGTTGGATGAGTACCTCCCACAGCCTCT-3′，下游5′-ACGTTGGATGATTTTTGTCCCTGCTCCTCC-3′。PCR扩增：首先95 ℃预变性10 min，然后进行35个循环的扩增反应，每个扩增反应的程序为94 ℃变性1 min，60 ℃退火1 min，70 ℃延伸1 min。所得PCR产物在110 V电压下进行2%琼脂糖凝胶电泳30 min。并得到相应大小的条带。KCNJ11 rs5210位点的基因型通过基因测序方法进行鉴定。
1.4 伦理学审查
本研究经由青岛市市立医院伦理委员会批准，批号：2017临审字第20号(快)，受试者知情同意。
1.5 统计学方法
采用SPSS 25.0软件，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用x±s表示，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；不符合正态分布的计量资料用中位数(最小值~最大值)表示，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(95%CI)。P＜0.05为差异有统计学意义。
2. 结果
2.1 一般资料
本研究共纳入905例，其中NAFLD组246例, CAD组201例，合并组116例, 对照组342例。4组患者一般临床资料及相关实验室指标比较的结果见表 1，各指标在不同组间具有不同程度的差异。
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。 NAFLD组、CAD组、合并组、对照组rs5210位点基因型分布均符合基因遗传平衡法则，来自同一群体(NAFLD组: χ2 =1.493, P＞0.05; CAD组: χ2 =0.112, P＞0.05; 合并组: χ2 =0.877, P＞0.05; 对照组: χ2 =0.047, P＞0.05)。
2.2 KCNJ11 rs5210基因型及等位基因的频率分布
经测序发现KCNJ11 rs5210具有AA、GA、GG 3种基因型，统计学分析结果显示, 对照组、NAFLD组、CAD组及合并组之间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)(表 2)。经校正年龄、性别、BMI后，差异亦无统计学意义(P值均＞0.05)。
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) 2.3 携带不同基因型患者各生化指标比较
分析KCNJ11 rs5210位点多态性不同基因型对全部受试人群及各组患者临床特征的影响，结果显示，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)(表 3、4)。在CAD组、合并组及对照组中，KCNJ11 rs5210 G等位基因的携带者与非携带者之间，未观察到临床参数的统计学差异(P值均＞0.05)。
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。 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。 2.4 患病风险因素分析结果
经非条件logistic回归分析表明，BMI升高与NAFLD患病风险相关；HDL降低提示NAFLD患病风险增加；FPG升高、HDL降低提示CAD、NAFLD+CAD患病风险增加(P值均＜0.05)(表 5)。
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 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 3. 讨论
本研究首次在905例样本中探讨KCNJ11基因rs5210位点多态性与青岛地区汉族人群NAFLD或NAFLD合并CAD发病风险的相关性。
多项研究[22-24]证实，KCNJ11基因多态性(包括rs5210)与T2DM易感性有关。KCNJ11多态性的研究[25-27]表明，KCNJ11与心血管疾病有关。在实验性高血压中，敲除KCNJ11基因的小鼠容易发生充血性心力衰竭和死亡[28]。然而目前，国内外尚无研究证实KCNJ11 rs5210多态性与NAFLD、CAD的发病风险相关。本研究亦未发现KCNJ11 rs5210位点多态性与NAFLD或CAD易感性的相关性(P＞0.05)。鉴于KCNJ11基因功能，即该基因多态性可能通过降低ATP敏感性钾通道对于ATP的敏感性，抑制胰岛素释放[22]，从而影响糖代谢，该过程与肝脏脂肪蓄积无明显相关性。而降低了ATP敏感性钾通道对ATP的敏感性，亦有可能诱发心血管疾病，如心脏舒张功能障碍、高血压及心力衰竭等[29]。CAD的潜在发病机制涉及脂质代谢失衡和适应不良的免疫反应，导致动脉壁的慢性炎症[30]。尽管本研究未发现KCNJ11 rs5210与CAD及CAD合并NAFLD发病风险的相关性，但由于KCNJ11 rs5210多态性对于T2DM的影响是确定的，而NAFLD、CAD常与T2DM、肥胖等同时存在，因此，在不同人群中仍不能忽视该基因位点在NAFLD及CAD中的作用。
众所周知，肥胖是NAFLD的危险因素。有研究[31]结果显示，在中国汉族人群中，NAFLD及NAFLD合并CAD患者的BMI水平较高。本研究经非条件logistic回归分析结果显示，BMI升高与NAFLD患病风险相关，与之前的研究结果一致。Zhuang等[32]研究表明，中国汉族人群T2DM患者中，KCNJ11多态性与BMI水平有相关性。然而澳大利亚等多个地区在T2DM患者与健康人群中的研究[22, 33-35]表明，KCNJ11多态性与BMI无明显相关性。KCNJ11多态性与BMI的相关性在不同研究中结论不完全一致。而在本研究中，在NAFLD组，与携带rs5210 AA基因型受试者相比，GA基因型携带者BMI水平更高(P＜0.05)，差异原因可能是研究人群地域分布不同或者人群本身合并基础疾病不同。
NAFLD患者血脂异常的特征为TG升高，HDL降低，这种血脂异常可能与NAFLD患者CAD患病风险增加有关，因为脂质异常与CAD发病率和/或死亡率独立相关[36-37]。本研究非条件logistic回归分析结果显示，HDL降低提示NAFLD患病风险增加；FPG升高、HDL降低提示CAD、NAFLD+CAD患病风险增加，与其他研究结论相一致。目前，尚无研究明确证实KCNJ11基因多态性与血脂水平具有相关性。如印度的一项研究[38]显示，KCNJ11 rs5210 G等位基因携带与T2DM患者的BMI、FPG、HDL、LDL等生化指标无明显相关性。本研究亦未发现G等位基因携带对TG、TC等其他血脂水平的影响。鉴于NAFLD和CAD的发生均与脂质代谢异常有关，该结果与前文所述KCNJ11 rs5210多态性与NAFLD和CAD多态性无明显相关性的结论相一致。
综上所述，本研究首次探讨了KCNJ11 rs5210多态性与青岛地区汉族人群NAFLD及CAD发病风险的相关性，结果表明，KCNJ11 rs5210位点基因型和等位基因与NAFLD及CAD发病风险无明显相关性，且未发现G等位基因携带者对于TG、TC等其他血脂水平的影响。然而，NAFLD患者KCNJ11 rs5210 GA基因型携带者比AA基因型携带者具有更高的BMI，该基因位点对NAFLD及CAD发病风险的影响仍不能忽视。此外，本研究存在一些局限性，将来可继续扩大样本量并扩大地域范围，而且KCNJ11 rs5210多态性与BMI之间相关机制还需要进一步研究。
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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 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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