幽门螺杆菌感染与PPARγ2基因Pro12Ala、GPx-1基因Pro198Leu多态性的交互作用和非酒精性脂肪性肝病的关系
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摘要
目的探讨幽门螺杆菌(H. pylori)感染与过氧化物酶体增殖物激活受体γ2(PPARγ2)基因Pro12Ala、谷胱甘肽过氧化物酶-1(GPx-1)基因Pro198Leu多态性的交互作用和非酒精性脂肪性肝病(NAFLD)及其严重程度的关系。方法选择2011年3月-2015年7月新乡医学院第一附属医院门诊和病房收治的非酒精性单纯性脂肪肝(NAFL)、非酒精性脂肪性肝炎(NASH)和非酒精性脂肪性肝硬化(NAFHC)患者各750例,以750例健康体检者作为对照组,以上述各组患者的外周血白细胞为样本,利用PCRRFLP技术检测了Pro12Ala和Pro198Leu多态性。采用14C-尿素呼气试验法检测受检者H. pylori与14C结合的每分钟衰变数(DPM)以判断H. pylori感染情况;对每位研究对象进行面对面的问卷调查。计量资料2组间比较采用t检验;计数资料组间比较采用χ2检验。采用多因素logistic回归模型对资料进行分析,估算PPARγ2基因Pro12Ala和GPx-1基因Pro198Leu多态性和H. pylori感染与NAFLD发病风险的调整比值比(OR)及95%可信区间,并分析Pro12Ala、Pro198Leu多态性与H. pylori感染的交互作用。结果 Pro12Ala(PA)、Pro12Ala(AA)、Pro198Leu(PL)和Pro198Leu(LL)基因型者患NAFLD的风险均显著增加(OR分别为5. 7324、5. 973 2、6. 360 5、6. 165 7,P值均<0. 01)。基因突变的协同分析发现在Pro12Ala(PA)和Pro198Leu(PL)之间、Pro12Ala(PA)和Pro198Le(LL)之间、Pro12Ala(AA)和Pro198Leu(PL)及Pro12Ala(AA)和Pro198Leu(LL)之间均存在正向交互作用(γ值均> 1)。100≤DPM <500和DPM≥500的H. pylori感染者患NAFLD的风险性均明显增高(OR_(NAFL)=2. 064 1,OR_(NASH)=4. 448 5,OR_(NAFHC)=10.969 5; OR_(NAFL)=3. 130 5,OR_(NASH)=8. 024 6,OR_(NAFHC)=21. 461 4),而DPM≥500的H. pylori感染者患NAFLD的风险性则又明显高于100≤DPM <500的H. pylori感染者(P <0. 01)。H. pylori感染与Pro12Ala(PA)、Pro12Ala(AA)、Pro198Leu(PL)和Pro198Leu(LL)基因型均有正向交互作用(γ值均>1)。结论携带Pro12Ala(PA)、Pro12Ala(AA)、Pro198Leu(PL)和Pro198Leu(LL)基因型的个体属NAFLD高危险人群,这些基因型和H. pylori感染的交互作用促进了NAFLD的发生、发展,应当采取根除H. pylori或调控基因表达的措施以达到有效预防NAFLD的目的。
Objective To investigate the interaction between Helicobacter pylori infection and polymorphisms of PPAR-γ2 gene Pro12 Ala and GPx-1 gene Pro198 Leu and its association with nonalcoholic fatty liver disease( NAFLD). Methods A total of 750 patients with nonalcoholic fatty liver( NAFL),750 patients with nonalcoholic steatohepatitis( NASH),and 750 patients with nonalcoholic fatty hepatic cirrhosis( NAFHC) who were treated or hospitalized in The First Affiliated Hospital of Xinxiang Medical University from March 2011 to July2015 were enrolled,and 750 individuals who underwent physical examination were enrolled as control group. Peripheral blood leukocytes were collected for each group,and PCR-RFLP was used to detect the polymorphisms of Pro12 Ala and Pro198 Leu. The14 C-urea breath test was used to measure disintegration per minute( DPM) of Helicobacter pylori binding to14 C,in order to evaluate the degree of Helicobacter pylori infection. A face-to-face questionnaire survey was performed for each subject. The t-test was used for comparison of continuous data between two groups,the chi-square test was used for comparison of categorical data between groups. The multivariate logistic regression model was used for data analysis. The adjusted odds ratio( OR) and 95% confidence interval of Pro12 Ala polymorphism,Pro198 Leu polymorphism,and Helicobacter pylori infection for the risk of NAFLD were calculated,and the interaction between Helicobacter pylori infection and polymorphism of PPAR-γ2 gene Pro12 Ala and GPx-1 gene Pro198 Leu was analyzed. Results The patients with the genotypes of Pro12 Ala( PA),Pro12 Ala( AA),Pro198 Leu( PL),and Pro198 Leu( LL) had a significant increase in the risk of NAFLD( OR = 5. 732 4,5. 973 2,6. 360 5,and 6. 165 7,all P < 0. 01). The combined analysis of the polymorphisms showed positive interactions between Pro12 Ala( PA) and Pro198 Leu( PL),between Pro12 Ala( PA) and Pro198 Leu( LL),between Pro12 Ala( AA) and Pro198 Leu( PL),and between Pro12 Ala( AA) and Pro198 Leu( LL)( all γ > 1). The Helicobacter pylori infection patients with 100≤DPM < 500 or DPM≥500 had a significant increase in the risk of NAFLD( 100≤DPM < 500: OR_(NAFL)= 2. 064 1,OR_(NASH)= 4. 448 5,OR_(NAFHC)= 10. 969 5;DPM≥500: OR_(NAFL)= 3. 130 5,OR_(NASH)= 8. 024 6,OR_(NAFHC)= 21. 461 4),and the patients with DPM≥500 had a significantly higher risk of NAFLD than those with 100 ≤ DPM < 500( P < 0. 01). There were positive interactions between Helicobacter pylori infection and Pro12 Ala( PA),Pro12 Ala( AA),Pro198 Leu( PL),and Pro198 Leu( LL)( all γ > 1). Conclusion The carriers of Pro12 Ala( PA),Pro12 Ala( AA),Pro198 Leu( PL),and Pro198 Leu( LL) genotypes may have a high risk of NAFLD,and the interaction between these genotypes and Helicobacter pylori infection promotes the development and progression of NAFLD. Therefore,effective prevention measures including Helicobacter pylori eradication and gene expression regulation should be adopted to prevent NAFLD.
Objective To investigate the interaction between Helicobacter pylori infection and polymorphisms of PPAR-γ2 gene Pro12 Ala and GPx-1 gene Pro198 Leu and its association with nonalcoholic fatty liver disease( NAFLD). Methods A total of 750 patients with nonalcoholic fatty liver( NAFL),750 patients with nonalcoholic steatohepatitis( NASH),and 750 patients with nonalcoholic fatty hepatic cirrhosis( NAFHC) who were treated or hospitalized in The First Affiliated Hospital of Xinxiang Medical University from March 2011 to July2015 were enrolled,and 750 individuals who underwent physical examination were enrolled as control group. Peripheral blood leukocytes were collected for each group,and PCR-RFLP was used to detect the polymorphisms of Pro12 Ala and Pro198 Leu. The14 C-urea breath test was used to measure disintegration per minute( DPM) of Helicobacter pylori binding to14 C,in order to evaluate the degree of Helicobacter pylori infection. A face-to-face questionnaire survey was performed for each subject. The t-test was used for comparison of continuous data between two groups,the chi-square test was used for comparison of categorical data between groups. The multivariate logistic regression model was used for data analysis. The adjusted odds ratio( OR) and 95% confidence interval of Pro12 Ala polymorphism,Pro198 Leu polymorphism,and Helicobacter pylori infection for the risk of NAFLD were calculated,and the interaction between Helicobacter pylori infection and polymorphism of PPAR-γ2 gene Pro12 Ala and GPx-1 gene Pro198 Leu was analyzed. Results The patients with the genotypes of Pro12 Ala( PA),Pro12 Ala( AA),Pro198 Leu( PL),and Pro198 Leu( LL) had a significant increase in the risk of NAFLD( OR = 5. 732 4,5. 973 2,6. 360 5,and 6. 165 7,all P < 0. 01). The combined analysis of the polymorphisms showed positive interactions between Pro12 Ala( PA) and Pro198 Leu( PL),between Pro12 Ala( PA) and Pro198 Leu( LL),between Pro12 Ala( AA) and Pro198 Leu( PL),and between Pro12 Ala( AA) and Pro198 Leu( LL)( all γ > 1). The Helicobacter pylori infection patients with 100≤DPM < 500 or DPM≥500 had a significant increase in the risk of NAFLD( 100≤DPM < 500: OR_(NAFL)= 2. 064 1,OR_(NASH)= 4. 448 5,OR_(NAFHC)= 10. 969 5;DPM≥500: OR_(NAFL)= 3. 130 5,OR_(NASH)= 8. 024 6,OR_(NAFHC)= 21. 461 4),and the patients with DPM≥500 had a significantly higher risk of NAFLD than those with 100 ≤ DPM < 500( P < 0. 01). There were positive interactions between Helicobacter pylori infection and Pro12 Ala( PA),Pro12 Ala( AA),Pro198 Leu( PL),and Pro198 Leu( LL)( all γ > 1). Conclusion The carriers of Pro12 Ala( PA),Pro12 Ala( AA),Pro198 Leu( PL),and Pro198 Leu( LL) genotypes may have a high risk of NAFLD,and the interaction between these genotypes and Helicobacter pylori infection promotes the development and progression of NAFLD. Therefore,effective prevention measures including Helicobacter pylori eradication and gene expression regulation should be adopted to prevent NAFLD.
引文
[1]NEOKOSMIDIS G,TZIOMALOS K.Role of cenicriviroc in the management of nonalcoholic fatty liver disease[J].World JGastroenterol,2018,24(48):5415-5417.
[2]SHARPTON SR,YONG GJM,TERRAULT NA,et al.Gut microbial metabolism and nonalcoholic fatty liver disease[J].Hepatol Commun,2018,3(1):29-43.
[3]ZHANG XX,XU HT,XU YQ.The natural history and clinical features of nonalcoholic fatty liver disease-related cirrhosis[J].J Clin Hepatol,2018,34(1):24-26.(in Chinese)张霞霞,徐宏团,徐有青.非酒精性脂肪性肝病相关肝硬化的自然史与临床特点[J].临床肝胆病杂志,2018,34(1):24-26.
[4]SUN YG,DU XF,ZHENG Q,et al.Relationship between helicobacter pylori infection and inflammatory bowel disease[J].Clin J Med Offic,2017,45(3):232-233.(in Chinese)孙永刚,杜选峰,郑倩,等.幽门螺杆菌感染与炎症性肠病相关性研究[J].临床军医杂志,2017,45(3):232-233.
[5]WIJARNPREECHA K,THONGPRAYOON C,PANJAWATANANP,et al.Helicobacter pylori and risk of nonalcoholic fatty liver disease:A systematic review and Meta-analysis[J].J Clin Gastroenterol,2018,52(5):386-391.
[6]HE C,CHENG D,WANG H,et al.Helicobacter pylori infection aggravates diet-induced nonalcoholic fatty liver in mice[J].Clin Res Hepatol Gastroenterol,2018,42(4):360-367.
[7]PARK S,YOO S,KIM J.14-3-3βandγdifferentially regulate peroxisome proliferator activated receptorγ2 transactivation and hepatic lipid metabolism[J].Biochim Biophys Acta,2015,1849(10):1237-1247.
[8]HUANG JQ,ZHOU JC,WU YY,et al.Role of glutathione peroxidase 1 in glucose and lipid metabolism-related diseases[J].Free Radic Biol Med,2018,127:108-115.
[9]Fatty Liver and Alcoholic Liver Disease Study Group of the Chinese Liver Disease Association.Guidelines for diagnosis and treatment of nonalcoholic fatty liver disease[J].J Clin Hepatol,2010,26(2):120-124.(in Chinese)中华医学会肝脏病学分会脂肪肝和酒精性肝病学组.非酒精性脂肪性肝病诊疗指南[J].临床肝胆病杂志,2010,26(2):120-124.
[10]REY JW,NOETEL A,HARDT A,et al.Pro12Ala polymorphism of the peroxisome proliferator-activated receptorγ2 in patients with fatty liver diseases[J].World J Gastroenterol,2010,16(46):5830-5837.
[11]SUZEN HS,GUCYENER E,SAKALLI O,et al.CAT C-262Tand GPX1 Pro198Leu polymorphisms in a Turkish population[J].Mol Biol Rep,2010,37(1):87-92.
[12]WALLACE HM.A model of gene-gene and gene-environment interactions and its implications for targeting environmental interventions by genotype[J].Theor Biol Med Model,2006,3:35.
[13]ZHAO X,XUE J,WANG XL,et al.Involvement of hepatic peroxisome proliferator-activated receptorα/γin the therapeutic effect of osthole on high-fat and high-sucrose-induced steatohepatitis in rats[J].Int Immunopharmacol,2014,22(1):176-181.
[14]RAHIMI Z,CHAMAIE-NEJAD F,SAEIDI S,et al.The association of PPARγPro12Ala and C161T polymorphisms with polycystic ovary syndrome and their influence on lipid and lipoprotein profiles[J].Int J Fertil Steril,2018,12(2):147-151.
[15]SAEIDI S,CHAMAIE-NEJAD F,EBRAHIMI A,et al.PPARγPro12Ala and C161T polymorphisms in patients with acne vulgaris:Contribution to lipid and lipoprotein profile[J].Adv Med Sci,2018,63(1):147-151.
[16]BECER E,CRAKOGRAKO LU A.Effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptorγ2 gene on lipid profile and adipokines levels in obese subjects[J].Balkan J Med Genet,2017,20(1):71-80.
[17]LI XL,ZHANG L,LI YN,et al.Relationship of polymorphism of Pro12Ala of PPARγ2 with blood lipid of patients with type 2diabetes and their first-degree relatives[J].J Xi'an Jiaotong Univ:Med Sci,2013,34(5):632-636.(in Chinese)李秀丽,章琳,李影娜,等.PPARγ2基因Pro12Ala多态性与2型糖尿病及其一级亲属血脂的相关性研究[J].西安交通大学学报:医学版,2013,34(5):632-636.
[18]SHIN SK,CHO HW,SONG SE,et al.Catalase and nonalcoholic fatty liver disease[J].Pflugers Arch,2018,470(12):1721-1737.
[19]ALSHAMMARI GM,BALAKRISHNAN A,CHINNASAMY T.Butein protects the nonalcoholic fatty liver through mitochondrial reactive oxygen speciesattenuation in rats[J].Biofactors,2018,44(3):289-298.
[20]SPAHIS S,DELVIN E,BORYS JM,et al.Oxidative stress as a critical factor in nonalcoholic fatty liver disease pathogenesis[J].Antioxid Redox Signal,2017,26(10):519-541.
[21]CAO M,MU X,JIANG C,et al.Single-nucleotide polymorphisms of GPX1 and Mn SOD and susceptibility to bladder cancer:A systematic review and meta-analysis[J].Tumour Biol,2014,35(1):759-764.
[22]HABYARIMANA T,BAKRI Y,MUGENZI P,et al.Association between glutathione peroxidase 1 codon 198 variant and the occurrence of breast cancer in Rwanda[J].Mol Genet Genomic Med,2018,6(2):268-275.
[23]HADAMI K,AMEZIANE EI HASSANI R,AMEUR A,et al.Association between GPX1 Pro189Leu polymorphism and the occurrence of bladder cancer in Morocco[J].Cell Mol Biol(Noisy-le-grand),2016,62(14):38-43.
[24]KIM TJ,SINN DH,MIN YW,et al.A cohort study on Helicobacter pylori infection associated with nonalcoholic fatty liver disease[J].J Gastroenterol,2017,52(11):1201-1210.
[25]TANG DM,KUMAR S.The association between helicobacter pylori infection and nonalcoholic fatty liver disease[J].Curr Gastroenterol Rep,2017,19(2):5.
[26]BUTCHER LD,DEN HARTOG G,ERNST PB,et al.Oxidative stress resulting from helicobacter pylori infection contributes to gastric carcinogenesis[J].Cell Mol Gastroenterol Hepatol,2017,3(3):316-322.
[27]YANAKA A.Role of sulforaphane in protection of gastrointestinal tract against H.pylori and NSAID-induced oxidative stress[J].Curr Pharm Des,2017,23(27):4066-4075.
[28]WANG H,TENG T,WANG L,et al.Research of advances in the pathogenesis of nonalcoholic fatty liver disease[J].J Clin Hepatol,2017,33(4):769-773.(in Chinese)王虎,滕田,王莉,等.非酒精性脂肪性肝病发病机制的研究进展[J].临床肝胆病杂志,2017,33(4):769-773.
[2]SHARPTON SR,YONG GJM,TERRAULT NA,et al.Gut microbial metabolism and nonalcoholic fatty liver disease[J].Hepatol Commun,2018,3(1):29-43.
[3]ZHANG XX,XU HT,XU YQ.The natural history and clinical features of nonalcoholic fatty liver disease-related cirrhosis[J].J Clin Hepatol,2018,34(1):24-26.(in Chinese)张霞霞,徐宏团,徐有青.非酒精性脂肪性肝病相关肝硬化的自然史与临床特点[J].临床肝胆病杂志,2018,34(1):24-26.
[4]SUN YG,DU XF,ZHENG Q,et al.Relationship between helicobacter pylori infection and inflammatory bowel disease[J].Clin J Med Offic,2017,45(3):232-233.(in Chinese)孙永刚,杜选峰,郑倩,等.幽门螺杆菌感染与炎症性肠病相关性研究[J].临床军医杂志,2017,45(3):232-233.
[5]WIJARNPREECHA K,THONGPRAYOON C,PANJAWATANANP,et al.Helicobacter pylori and risk of nonalcoholic fatty liver disease:A systematic review and Meta-analysis[J].J Clin Gastroenterol,2018,52(5):386-391.
[6]HE C,CHENG D,WANG H,et al.Helicobacter pylori infection aggravates diet-induced nonalcoholic fatty liver in mice[J].Clin Res Hepatol Gastroenterol,2018,42(4):360-367.
[7]PARK S,YOO S,KIM J.14-3-3βandγdifferentially regulate peroxisome proliferator activated receptorγ2 transactivation and hepatic lipid metabolism[J].Biochim Biophys Acta,2015,1849(10):1237-1247.
[8]HUANG JQ,ZHOU JC,WU YY,et al.Role of glutathione peroxidase 1 in glucose and lipid metabolism-related diseases[J].Free Radic Biol Med,2018,127:108-115.
[9]Fatty Liver and Alcoholic Liver Disease Study Group of the Chinese Liver Disease Association.Guidelines for diagnosis and treatment of nonalcoholic fatty liver disease[J].J Clin Hepatol,2010,26(2):120-124.(in Chinese)中华医学会肝脏病学分会脂肪肝和酒精性肝病学组.非酒精性脂肪性肝病诊疗指南[J].临床肝胆病杂志,2010,26(2):120-124.
[10]REY JW,NOETEL A,HARDT A,et al.Pro12Ala polymorphism of the peroxisome proliferator-activated receptorγ2 in patients with fatty liver diseases[J].World J Gastroenterol,2010,16(46):5830-5837.
[11]SUZEN HS,GUCYENER E,SAKALLI O,et al.CAT C-262Tand GPX1 Pro198Leu polymorphisms in a Turkish population[J].Mol Biol Rep,2010,37(1):87-92.
[12]WALLACE HM.A model of gene-gene and gene-environment interactions and its implications for targeting environmental interventions by genotype[J].Theor Biol Med Model,2006,3:35.
[13]ZHAO X,XUE J,WANG XL,et al.Involvement of hepatic peroxisome proliferator-activated receptorα/γin the therapeutic effect of osthole on high-fat and high-sucrose-induced steatohepatitis in rats[J].Int Immunopharmacol,2014,22(1):176-181.
[14]RAHIMI Z,CHAMAIE-NEJAD F,SAEIDI S,et al.The association of PPARγPro12Ala and C161T polymorphisms with polycystic ovary syndrome and their influence on lipid and lipoprotein profiles[J].Int J Fertil Steril,2018,12(2):147-151.
[15]SAEIDI S,CHAMAIE-NEJAD F,EBRAHIMI A,et al.PPARγPro12Ala and C161T polymorphisms in patients with acne vulgaris:Contribution to lipid and lipoprotein profile[J].Adv Med Sci,2018,63(1):147-151.
[16]BECER E,CRAKOGRAKO LU A.Effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptorγ2 gene on lipid profile and adipokines levels in obese subjects[J].Balkan J Med Genet,2017,20(1):71-80.
[17]LI XL,ZHANG L,LI YN,et al.Relationship of polymorphism of Pro12Ala of PPARγ2 with blood lipid of patients with type 2diabetes and their first-degree relatives[J].J Xi'an Jiaotong Univ:Med Sci,2013,34(5):632-636.(in Chinese)李秀丽,章琳,李影娜,等.PPARγ2基因Pro12Ala多态性与2型糖尿病及其一级亲属血脂的相关性研究[J].西安交通大学学报:医学版,2013,34(5):632-636.
[18]SHIN SK,CHO HW,SONG SE,et al.Catalase and nonalcoholic fatty liver disease[J].Pflugers Arch,2018,470(12):1721-1737.
[19]ALSHAMMARI GM,BALAKRISHNAN A,CHINNASAMY T.Butein protects the nonalcoholic fatty liver through mitochondrial reactive oxygen speciesattenuation in rats[J].Biofactors,2018,44(3):289-298.
[20]SPAHIS S,DELVIN E,BORYS JM,et al.Oxidative stress as a critical factor in nonalcoholic fatty liver disease pathogenesis[J].Antioxid Redox Signal,2017,26(10):519-541.
[21]CAO M,MU X,JIANG C,et al.Single-nucleotide polymorphisms of GPX1 and Mn SOD and susceptibility to bladder cancer:A systematic review and meta-analysis[J].Tumour Biol,2014,35(1):759-764.
[22]HABYARIMANA T,BAKRI Y,MUGENZI P,et al.Association between glutathione peroxidase 1 codon 198 variant and the occurrence of breast cancer in Rwanda[J].Mol Genet Genomic Med,2018,6(2):268-275.
[23]HADAMI K,AMEZIANE EI HASSANI R,AMEUR A,et al.Association between GPX1 Pro189Leu polymorphism and the occurrence of bladder cancer in Morocco[J].Cell Mol Biol(Noisy-le-grand),2016,62(14):38-43.
[24]KIM TJ,SINN DH,MIN YW,et al.A cohort study on Helicobacter pylori infection associated with nonalcoholic fatty liver disease[J].J Gastroenterol,2017,52(11):1201-1210.
[25]TANG DM,KUMAR S.The association between helicobacter pylori infection and nonalcoholic fatty liver disease[J].Curr Gastroenterol Rep,2017,19(2):5.
[26]BUTCHER LD,DEN HARTOG G,ERNST PB,et al.Oxidative stress resulting from helicobacter pylori infection contributes to gastric carcinogenesis[J].Cell Mol Gastroenterol Hepatol,2017,3(3):316-322.
[27]YANAKA A.Role of sulforaphane in protection of gastrointestinal tract against H.pylori and NSAID-induced oxidative stress[J].Curr Pharm Des,2017,23(27):4066-4075.
[28]WANG H,TENG T,WANG L,et al.Research of advances in the pathogenesis of nonalcoholic fatty liver disease[J].J Clin Hepatol,2017,33(4):769-773.(in Chinese)王虎,滕田,王莉,等.非酒精性脂肪性肝病发病机制的研究进展[J].临床肝胆病杂志,2017,33(4):769-773.