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微粒体甘油三酯转运蛋白基因rs1800591变异与老年人群非酒精性脂肪性肝病发生风险的关系
DOI: 10.3969/j.issn.1001-5256.2023.03.011
伦理学声明：本研究方案于2020年10月26日经由首都医科大学附属北京佑安医院伦理委员会审批，批号：京佑科伦意[2020]-272。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：赵锦涵、张晶负责课题设计，资料分析，论文撰写；张洋负责修改文章关键内容；徐潇艺、勾钰淞、徐航飞、万妍参与收集数据，统计分析解释；吴剑负责拟定写作思路，指导撰写文章及最后定稿。赵锦涵和张晶对本文贡献等同，同为第一作者。
Association between the rs1800591 variation of the microsomal triglyceride transfer protein gene and the risk of nonalcoholic fatty liver disease in the elderly population
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摘要:
目的 探讨老年人群微粒体甘油三酯转运蛋白(MTTP)基因rs1800591多态性与非酒精性脂肪性肝病(NAFLD)发病风险的关系。 方法 本研究的临床队列建立在北京京煤集团总医院门矿医院，2020年1月11日—2021年9月30日在北京门头沟社区共招募参加健康体检1098例老年志愿者，其中NAFLD患者614例，非NAFLD患者484例，采用基因芯片法检测MTTP rs1800591基因型，收集人口学资料并检测受试者的血液生化指标。符合正态分布的计量资料两组间比较采用独立样本t检验；对非正态分布的计量资料两组间比较采用Mann-Whitney U检验；计数资料两组间比较采用χ2检验。应用χ2检验分析基因型频率的分布是否符合Hardy-Weinberg (H-W) 平衡检验以确认样本的群体代表性。以非条件Logistic回归模型计算比值比(OR)及其95%CI以评估基因多态性与NAFLD发生风险及其他合并症的关系。 结果 两组间性别、年龄差异均有统计学意义(P值均＜0.05)。相比于非NAFLD组，NAFLD组的BMI、腰臀比、TG、ALT、AST、CAP、LSM水平均显著提高，而HDL明显降低(P值均＜0.05)。NAFLD组中高血压、糖尿病、肥胖及代谢综合征患者的比例也均高于非NAFLD组(P值均＜0.05)。MTTP rs1800591多态性在对照组基因型频率分布符合Hardy-Weinberg平衡(χ2=1.097，P=0.29)。MTTP rs1800591不同基因型及等位基因分布在NAFLD患者与对照组中均有显著性差异(P值均＜0.001)。总人群中T等位基因(GT+TT，n=351)携带率在男性中比例偏低，而BMI和CAP值显著高于非携带者(GG，n=747)(P值均＜0.001)。相比于非携带者，T等位基因携带者(GT+TT，n=232)中肥胖患者比例明显提高，但NFS评分却显著降低(P值均＜0.05)。在NAFLD受试者中，T等位基因携带者男性比例和腰臀比显著降低, T等位基因携带者HDL高于非携带者(GG，n=382)，T等位基因携带者NFS评分仍明显低于非携带者(P值均＜0.05)。非条件Logistic回归分析表明，在校正性别、年龄、BMI混杂因素后，MTTP rs1800591 GT+TT型仍显著增加了NAFLD的发生风险(OR=1.643, 95%CI：1.226~2.203, P=0.001)，而T等位基因携带则增加了总人群中肥胖的发生风险(OR=1.371, 95%CI：1.051~1.788, P=0.02)。 结论 老年人群中MTTP rs1800591多态性与NAFLD的发生有关，T等位基因携带者可能促进了NAFLD肝脏脂肪变性，增加肥胖症发生风险，但可能抑制了肝纤维化进展。 Abstract:Objective To investigate the association between the polymorphism of the microsomal triglyceride transport protein (MTTP) gene at rs1800591 locus and the risk of nonalcoholic fatty liver disease (NAFLD) in the elderly population. Methods The clinical cohort of this study was established in Menkuang Hospital, Beijing Jingmei Group General Hospital. A total of 1098 healthy elderly volunteers were recruited for physical examination in communities in Mentougou District of Beijing, China, from January 11, 2020 to September 30, 2021, among whom there were 614 patients with NAFLD and 484 individuals without NAFLD. Gene microarray was used to determine the genotypes of MTTP rs1800591; demographic data were collected, and blood biochemical parameters were measured. The independent samples t-test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. The chi-square test was used to investigate whether the distribution of genotype frequency was in accordance with Hardy-Weinberg equilibrium. The unconditional logistic regression model was used to calculate odds ratio (OR) and its 95% confidence interval (CI) to investigate the association of gene polymorphism with the risk of NAFLD and other comorbidities. Results There were significant differences in sex and age between the two groups (P < 0.05). Compared with the non-NAFLD group, the NAFLD group had significantly higher levels of body mass index (BMI), waist-hip ratio, triglyceride, alanine aminotransferase, aspartate aminotransferase, controlled attenuation parameter (CAP), and liver stiffness measurement and a significantly lower level of high-density lipoprotein (HDL) (all P < 0.05). Compared with the non-NAFLD group, the NAFLD group had a significantly higher proportion of patients with hypertension, diabetes, obesity, and metabolic syndrome (all P < 0.05). The distribution of genotype frequency at MTTP rs1800591 locus was in accordance with Hardy-Weinberg equilibrium in the control group (χ2=1.097, P=0.29). There were a significant differences in the genotype and the distribution of alleles at MTTP rs1800591 locus between the patients with NAFLD and the control group (all P < 0.001). In the total population, there was a significantly lower carrying rate of T allele (GT+TT, n=351) in male individuals, and the individuals carrying T allele had significantly higher BMI and CAP than those carrying GG allele (n=747) (P < 0.001). Compared with the individuals who did not carry T allele, the individuals carrying T allele (GT+TT, n=232) had a significantly higher proportion of patients with obesity and a significantly lower NFS score (P < 0.05). As for the individuals with NAFLD, the individuals carrying T allele had a significantly lower proportion of male individuals, a significantly lower waist-hip ratio, and a significantly higher level of HDL compared with those who did not carry T allele (GG, n=382), and the GT+TT group had a significantly lower NFS score than the GG group (all P < 0.05). The non-conditional logistic regression analysis showed that after adjustment for the confounding factors of sex, age, and BMI, the GT+TT genotype at MTTP rs1800591 locus significantly increased the risk of NAFLD (OR=1.643, 95%CI: 1.226-2.203, P=0.001), and carrying T allele also increased the risk of obesity in the total population (OR=1.371, 95%CI: 1.051-1.788, P=0.02). Conclusion MTTP rs1800591 polymorphism is associated with the development of NAFLD in the elderly population, and carrying T allele may promote hepatic steatosis and increase the risk of obesity in NAFLD, while it may inhibit the progression of liver fibrosis. -
Key words:
- Non-alcoholic Fatty Liver Disease /
- Genes /
- Aged
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图 1 MTTP rs1800591等位基因(GT+TT和GG)与NAFLD相关疾病发病风险分析
Figure 1. Analysis of MTTP rs1800591 alleles (GT+TT and GG) and risk of NAFLD-related disease
表 1 研究人群基线资料和代谢指标比较
Table 1. Comparison of baseline information and metabolic indicators in the study population
项目 非NAFLD组(n=484) NAFLD组(n=614) 统计值 P值 年龄(岁) 71.21±5.17 70.15±4.99 t=3.418 ＜0.001 男[例(%)] 163(33.68) 156(25.41) χ2=8.982 0.003 BMI(kg/m2) 24.44±2.79 26.89±3.05 t=-13.857 ＜0.001 腰臀比 0.89±0.05 0.91±0.05 t=-5.346 ＜0.001 TG(mmol/L) 1.16(0.85~1.61) 2.03(1.52~2.78) Z=-8.789 ＜0.001 TC(mmol/L) 4.81±1.16 4.83±1.28 t=-0.236 0.814 HDL(mmol/L) 1.21±0.27 1.12±0.23 t=5.774 ＜0.001 LDL(mmol/L) 3.34±1.06 3.36±1.16 t=-0.265 0.791 ALT(U/L) 17.50±7.60 21.56±10.15 t=-7.567 ＜0.001 AST(U/L) 17.36±5.62 19.42±8.56 t=-4.775 ＜0.001 CAP(dB/m) 243.11±43.34 294.92±41.06 t=-18.521 ＜0.001 LSM(kPa) 4.50±1.77 5.47±2.04 t=-7.737 ＜0.001 NFS -0.79(-1.54~0.03) -0.73(-1.40~0.03) Z=-0.358 0.720 高血压[例(%)] 355(73.35) 480(78.18) χ2=5.349 0.021 糖尿病[例(%)] 173(35.74) 283(46.09) χ2=11.561 ＜0.001 肥胖症[例(%)] 198(40.91) 441(71.82) χ2=106.326 ＜0.001 MS[例(%)] 371(76.65) 560(91.21) χ2=44.444 ＜0.001 
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表 2 基因型及等位基因在NAFLD组与对照组中的分布
Table 2. Distribution of genotypes and alleles in NAFLD group and control group
组别 例数 基因型[例(%)] 等位基因[(例(%)] GG GT TT G T NAFLD组 614 382(62.21) 216(35.18) 16(2.61) 980(79.80) 248(20.20) 非NAFLD组 484 365(75.41) 107(22.11) 12(2.48) 837(86.47) 131(13.53) χ2值 22.668 16.826 P值 ＜0.001 ＜0.001
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表 3 总人群中MTTP rs1800591 T等位基因携带者与非携带者临床资料比较
Table 3. Comparison of clinical data of MTTP rs1800591 T allele carriers and non-carriers in the total population
项目 GG(n=747) GT+TT(n=351) 统计值 P值 年龄(岁) 70.59±5.09 70.68±5.12 t=-0.287 0.774 男[例(%)] 260(34.81) 59(16.81) χ2=37.522 ＜0.001 BMI(kg/m2) 25.62±3.12 26.20±3.29 t=-2.798 0.005 腰臀比 0.90±0.05 0.90±0.04 t=1.928 0.075 TG(mmol/L) 1.29(0.92~1.79) 1.40(1.02~1.89) Z=-1.407 0.160 TC(mmol/L) 4.79±1.16 4.90±1.35 t=-1.382 0.167 HDL(mmol/L) 1.15±0.25 1.18±0.26 t=-2.055 0.040 LDL(mmol/L) 3.33±1.05 3.39±1.24 t=-0.945 0.345 ALT(U/L) 19.47±9.46 20.40±9.03 t=-1.547 0.122 AST(U/L) 18.33±7.78 18.89±6.77 t=-1.174 0.241 NFS -0.68(-1.45~0.09) -0.91(-1.48~-0.20) Z=-2.182 0.029 CAP(dB/m) 268.84±50.31 281.16±45.87 t=-3.701 ＜0.001 LSM(kPa) 5.04±2.04 5.09±1.87 t=-0.348 0.728 高血压[例(%)] 563(75.37) 272(77.49) χ2=0.586 0.444 糖尿病[例(%)] 300(40.16) 156(44.44) χ2=1.713 0.191 肥胖[例(%)] 416(55.69) 223(63.53) χ2=6.038 0.014 MS[例(%)] 626(83.80) 305(86.89) χ2=1.771 0.183
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表 4 NAFLD人群中MTTP rs1800591 T等位基因携带者与非携带者临床资料比较
Table 4. Comparison of clinical data of MTTP rs1800591 T allele carriers and non-carriers in NAFLD population
项目 GG(n=382) GT+TT(n=232) 统计值 P值 年龄(岁) 70.13±4.99 70.19±5.00 t=-0.152 0.880 男[例(%)] 125(32.72) 31(13.36) χ2=28.547 ＜0.001 BMI(kg/m2) 26.83±3.06 26.99±3.05 t=-0.622 0.534 腰臀比 0.91±0.05 0.90±0.04 t=2.718 0.007 TG(mmol/L) 1.52(1.08~2.06) 1.50(1.12~1.99) Z=-0.985 0.324 TC(mmol/L) 4.78±1.19 4.92±1.41 t=-1.296 0.195 HDL(mmol/L) 1.10±0.22 1.16±0.23 t=-3.208 0.001 LDL(mmol/L) 3.32±1.06 3.42±1.31 t=-1.081 0.280 ALT(U/L) 21.48±10.54 21.70±9.49 t=-0.262 0.793 AST(U/L) 19.40±9.27 19.44±7.26 t=-0.056 0.956 NFS -0.67(-1.36~0.09) -0.84(-1.50~-0.20) Z=-2.079 0.038 CAP(dB/m) 293.81±42.02 296.71±39.50 t=-0.790 0.430 LSM(kPa) 5.51±2.12 5.41±1.89 t=0.588 0.557 高血压[例(%)] 293(76.70) 187(80.60) χ2=0.317 0.251 糖尿病[例(%)] 172(45.03) 111(47.84) χ2=0.462 0.497 肥胖[例(%)] 271(70.94) 170(73.28) χ2=0.388 0.533 MS[例(%)] 348(91.10) 212(91.38) χ2=0.014 0.906
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表 5 MTTP rs1800591等位基因(GT+TT vs GG) 与NAFLD发病风险分析
Table 5. Analysis of MTTP rs1800591 allele (GT+TT vs GG) and risk of NAFLD
项目 B值 标准误 Wald P值 OR 95%CI 性别 0.394 0.150 6.929 0.008 1.483 1.106~1.988 年龄 -0.050 0.013 14.259 ＜0.001 0.951 0.927~0.976 BMI 0.301 0.026 135.573 ＜0.001 1.351 1.284~1.421 MTTP rs1800591 (GG为参照) 0.497 0.150 11.033 0.001 1.643 1.226~2.203 常量 4.737 1.119 17.929 ＜0.001 0.009
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