MTHFR、IL-10、ALDH2基因多态性与HBV感染后疾病转归的研究
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摘要
人体感染HBV后病程如何演化是宿主和病毒等多种因素共同作用的结果,宿主基因的多态性可能会影响HBV感染后的疾病进程。基因多态性有较强的地域和民族特征,而且其与肝病之间的关系在不同地区和民族之间的研究结果不尽相同。因此,分析MTHFR、IL-10、ALDH2基因多态性对天津地区汉族人感染HBV后疾病进展的影响,有助于对本地区肝病发生的病因学进行深入研究。
研究目的：探讨MTHFR、IL-10、ALDH2基因多态性与HBV感染后疾病转归的关系。
研究方法：收集标本995例,包括205例健康对照、161例自愈者、221例慢乙肝患者、172例乙肝肝硬化患者以及236例HBV相关性肝癌患者。从凝血块中提取基因组DNA,采用TaqMan SNP基因分型和基因测序的方法检测MTHFR 677 C/T、IL-10-1082 A/G、-819 T/C和ALDH2 rs4646778 C/A、rs671 G/A等5个位点的多态性,以χ2检验分析以上位点的基因型、等位基因以及IL-10-1082/-819、ALDH2 rs4646778/rs671单倍型在各组中的分布及差异。
研究结果：1. MTHFR基因：用于本基因研究的805例研究对象677 CT、TT和CC基因型频率分别为47.09%、30.43%和22.48%；等位基因频率：C为46.02%,T为53.98%,显示天津地区汉族人TT基因型和T等位基因频率明显高于以往其它地区或种族的报道。等位基因和基因型分布在各组无统计学差异(P>0.05)。分析不同性别在各组中的分布特征表明,TT基因型在男性各患病组中显示风险度降低,特别在肝硬化组TT和CT的OR值最低；而在女性的自愈、慢乙肝和肝硬化组,TT和CT显示风险度增加,特别在肝硬化组OR值最高,具有统计学差异(P=0.022)。然而,TT和CT在女性肝癌组却显示风险度降低。对不同临床特征包括肝癌和肝硬化组的Child-Pugh肝功能分级、AFP水平以及所有患者HBsAg表达、DNA拷贝数之间的比较未发现统计学差异(P>0.05)。2.IL-10基因：用于本基因研究的700例研究对象-1082位点的基因型分布为AA占82.29%、AG占16.00%、GG占1.71%；等位基因频率：A为90.29%,G为9.71%。-819位点的基因型分布为TT占41.43%、TC占48.14%、CC占10.43%；等位基因频率：T为65.64%,C为34.36%。两位点等位基因和基因型分布在各组之间比较均无统计学差异(P>0.05),以自愈组为对照,-1082 AG基因型和G等位基因对慢乙肝和肝硬化组的风险度降低,-819 TC对肝癌组风险度降低,CC基因型和C等位基因对三个肝病组的风险度均有降低的趋势。分析IL-10-1082／-819单倍型在各组中的分布,以健康和自愈组为对照,AC单倍型对肝硬化和肝癌组的风险度均降低,且以自愈组为对照时降低程度更大；以自愈组为对照,GC单倍型对慢乙肝和肝硬化组的风险度降低。在不同临床特征的组别之间比较发现,对于-819位点,DNA<103拷贝／mL的患者C等位基因频率显著高于DNA≥103拷贝／mL的患者(P=0.025)。对其它各项的比较未发现统计学差异(P<0.05)。3. ALDH2基因：用于本基因研究的180例研究对象rs4646778位点CC、CA和AA基因型频率分别为51.11%、37.78%和11.11%；等位基因频率：C为70.00%,A为30.00%。rs671位点GG、GA和AA的基因型频率分别为72.22%、24.45%和3.33%；等位基因频率：G为84.44%,A为15.56%。两位点等位基因和基因型分布在各组无统计学差异(P>0.05),以健康组为对照,rs4646778 CA基因型对三个肝病组的风险度均降低,C等位基因对肝癌组的风险度降低。分析rs4646778/rs671单倍型在各组中的分布,以健康组为对照,AG和CA单倍型对三个肝病组的风险度均有降低的趋势。在不同临床特征的组别之间比较未发现统计学差异(P>0.05)。
研究结论：1. MTHFR 677在中国天津汉族人中的TT基因型频率明显高于大多数国家和地区的研究结果。同时提示MTHFR 677 TT和CT基因型降低男性HBV感染者患肝硬化的风险和女性HBV感染者患肝癌的风险,而增加女性HBV感染者患肝硬化的风险。2.IL-10-1082AG基因型和G等位基因,-819 TC、CC基因型和C等位基因,-1082/-819AC、GC单倍型对HBV感染后疾病进展有一定的保护作用；-819 C等位基因更有利于HBV感染者病毒的清除。3. ALDH2 rs4646778 CA基因型、C等位基因以及rs4646778/rs671 AG和CA单倍型对HBV感染后疾病进展可能有一定的保护作用。
How the disease evolves after HBV infection is effected by a variety of factors such as host and virus. Host gene polymorphism is likely to influence disease progression after HBV infection. Gene polymorphism has a strong regional and national identity, and the results of studys connerning on the the relationship between polymorphisms and liver disease varied in different regions and ethnics. Thereby, analyzing the influence of MTHFR, IL-10, ALDH2 gene polymorphisms and disease progression after HBV infection in Chinese Han population in Tianjin may contribute to in-depth study on the etiology of liver disease occurrence in this region.
AIM:To investigate the relationship between MTHFR, IL-10, ALDH2 polymorphisms and the outcome of HBV infection.
METHODS:Collect 955 samples as follows:205 healthy control subjects,161 self-limited patients infected with HBV,221 patients with chronic hepatitis B,172 patients with HBV-induced liver cirrhosis and 236 cases with HBV-related HCC. Genome DNA was extracted from clot, TaqMan SNP genotyping and sequencing assays were employed to determine the distribution of genotypes and alleles at five sites in three genes as MTHFR 677 C/T, IL-10-1082 A/G,-819 T/C and ALDH2 rs4646778 C/A, rs671 A/G. Row×Column or revisedχ2 examination were used to analyse genotype and allele at the positions above. IL-10-1082/-819 and ALDH2 rs4646778/rs671 haplotype were also analysisied in all the groups.
RESULTS:1. MTHFR:Of the 805 subjects, genotype CT, TT and CC accounted for 47.09%,30.43% and 22.48%, respectively. The frequency of C allele was 46.02% and T was 53.98% of the total subjects, which are significantly different from other areas and races. Analysis on the distribution of genotypes in different sexes showed that males with TT genotype had a reduced risk with liver diseases. Particularly, the odds ratio (OR) of TT and CT was lowest in the liver cirrhosis group versus self-limited group. In contrast, females with TT and CT genotypes had an increased risk in the self-limited, chronic hepatitis and liver cirrhosis groups. Particularly, the liver cirrhosis group had the highest OR value versus self-limited group. However, females with TT and CT had a reduced risk in HCC group versus self-limited group. There was no significant difference about the genotype and allele distribution in different clinical feature groups such as Child-Pugh liver faction classification, AFP level in liver cirrhosis and HCC patients, HBsAg expression and DNA copies in all patients with liver disease.2. IL-10:Of the 700 subjects, genotype AA, AG and GG of IL-10-1082 accounted for 82.29%,16.00% and 1.71%, respectively, the frequency of A allele was 90.29% and T was 9.71%of the total subjects, while genotype TT, TC and CC of IL-10-819 accounted for 41.43%,48.14%, and 10.43%, respectively, the frequency of T allele was 65.64% and C was 34.36% of the total subjects. There was no significant difference of genotype or allele distribution among different groups at the two positions(P>0.05). Taking self-limited group as control,-1082 AG genotype and G allele decreased the risks of chronic hepatitis B and cirrhosis occurrence,-819 TC genotype decreased the risk of HCC, CC genotype and C allele decreased the risks of all the three liver disease groups. Analyzing distribution of haplotype-1082/-819 in each group showed that AC haplotype decreased the risks of cirrhosis and HCC using healthy or self-limited group as control, and the reduction degree was greater when regarding self-limited group as control, GC haplotype decreased the risks of chronic hepatitis B and cirrhosis occurrence using self-limited group as control. Comparing IL-10 genotype and allele frequencies in different groups with different clinical features revealed that frequency of-819 C was significantly higher in patients with DNA<103 copies/mL than those with DNA≥103 copies/mL(P=0.025). In addition, There was no significant difference about the genotype and allele distribution in other clinical feature groups(P>0.05).3. ALDH2: Of the 180 subjects, genotype CC, CA and AA of ALDH2 rs4646778 accounted for 51.11%,37.78% and 11.11%, respectively, the frequency of C allele was 70.00% and A was 30.00% of the total subjects, while genotype GG, GA and AA of ALDH2 rs671 accounted for 72.22%,24.45%, and 3.33%, respectively, the frequency of G allele was 84.44% and A was 15.56% of the total subjects. There was no significant difference of genotype or allele distribution among different groups at the two positions(P>0.05). Take healthy group as control, rs4646778 CA genotype decreased the risks of all the three liver disease groups, C allele decreased the risks of HCC group. Analyzing distribution of haplotype rs4646778/rs671 in each group showed that AG and CA haplotype decreased the risks of all the three liver disease groups. There was no significant difference about the genotype and allele distribution in different clinical feature groups(P>0.05).
CONCLUSION:1. MTHFR:The TT genotype shows a relatively high frequency in Tianjin, which is significantly different from other country or area. At the same time, MTHFR 677 polymorphism may play a role in influencing disease progression in patients with HBV infection, and the effect is different on different genders.2. IL-10: IL-10-1082 AG genotype and G allele,-819 TC, CC genotype and C allele,-1082/-819 AC, GC haplotype may play a protective role on disease progression after HBV infection.-819 C allele may attribute to virus elimination for HBV infected patients.3. ALDH2:rs4646778 CA genotype, C allele, and rs4646778/rs671 AG and CA haplotype may play a protective role on disease progression after HBV infection.
研究目的：探讨MTHFR、IL-10、ALDH2基因多态性与HBV感染后疾病转归的关系。
研究方法：收集标本995例,包括205例健康对照、161例自愈者、221例慢乙肝患者、172例乙肝肝硬化患者以及236例HBV相关性肝癌患者。从凝血块中提取基因组DNA,采用TaqMan SNP基因分型和基因测序的方法检测MTHFR 677 C/T、IL-10-1082 A/G、-819 T/C和ALDH2 rs4646778 C/A、rs671 G/A等5个位点的多态性,以χ2检验分析以上位点的基因型、等位基因以及IL-10-1082/-819、ALDH2 rs4646778/rs671单倍型在各组中的分布及差异。
研究结果：1. MTHFR基因：用于本基因研究的805例研究对象677 CT、TT和CC基因型频率分别为47.09%、30.43%和22.48%；等位基因频率：C为46.02%,T为53.98%,显示天津地区汉族人TT基因型和T等位基因频率明显高于以往其它地区或种族的报道。等位基因和基因型分布在各组无统计学差异(P>0.05)。分析不同性别在各组中的分布特征表明,TT基因型在男性各患病组中显示风险度降低,特别在肝硬化组TT和CT的OR值最低；而在女性的自愈、慢乙肝和肝硬化组,TT和CT显示风险度增加,特别在肝硬化组OR值最高,具有统计学差异(P=0.022)。然而,TT和CT在女性肝癌组却显示风险度降低。对不同临床特征包括肝癌和肝硬化组的Child-Pugh肝功能分级、AFP水平以及所有患者HBsAg表达、DNA拷贝数之间的比较未发现统计学差异(P>0.05)。2.IL-10基因：用于本基因研究的700例研究对象-1082位点的基因型分布为AA占82.29%、AG占16.00%、GG占1.71%；等位基因频率：A为90.29%,G为9.71%。-819位点的基因型分布为TT占41.43%、TC占48.14%、CC占10.43%；等位基因频率：T为65.64%,C为34.36%。两位点等位基因和基因型分布在各组之间比较均无统计学差异(P>0.05),以自愈组为对照,-1082 AG基因型和G等位基因对慢乙肝和肝硬化组的风险度降低,-819 TC对肝癌组风险度降低,CC基因型和C等位基因对三个肝病组的风险度均有降低的趋势。分析IL-10-1082／-819单倍型在各组中的分布,以健康和自愈组为对照,AC单倍型对肝硬化和肝癌组的风险度均降低,且以自愈组为对照时降低程度更大；以自愈组为对照,GC单倍型对慢乙肝和肝硬化组的风险度降低。在不同临床特征的组别之间比较发现,对于-819位点,DNA<103拷贝／mL的患者C等位基因频率显著高于DNA≥103拷贝／mL的患者(P=0.025)。对其它各项的比较未发现统计学差异(P<0.05)。3. ALDH2基因：用于本基因研究的180例研究对象rs4646778位点CC、CA和AA基因型频率分别为51.11%、37.78%和11.11%；等位基因频率：C为70.00%,A为30.00%。rs671位点GG、GA和AA的基因型频率分别为72.22%、24.45%和3.33%；等位基因频率：G为84.44%,A为15.56%。两位点等位基因和基因型分布在各组无统计学差异(P>0.05),以健康组为对照,rs4646778 CA基因型对三个肝病组的风险度均降低,C等位基因对肝癌组的风险度降低。分析rs4646778/rs671单倍型在各组中的分布,以健康组为对照,AG和CA单倍型对三个肝病组的风险度均有降低的趋势。在不同临床特征的组别之间比较未发现统计学差异(P>0.05)。
研究结论：1. MTHFR 677在中国天津汉族人中的TT基因型频率明显高于大多数国家和地区的研究结果。同时提示MTHFR 677 TT和CT基因型降低男性HBV感染者患肝硬化的风险和女性HBV感染者患肝癌的风险,而增加女性HBV感染者患肝硬化的风险。2.IL-10-1082AG基因型和G等位基因,-819 TC、CC基因型和C等位基因,-1082/-819AC、GC单倍型对HBV感染后疾病进展有一定的保护作用；-819 C等位基因更有利于HBV感染者病毒的清除。3. ALDH2 rs4646778 CA基因型、C等位基因以及rs4646778/rs671 AG和CA单倍型对HBV感染后疾病进展可能有一定的保护作用。
How the disease evolves after HBV infection is effected by a variety of factors such as host and virus. Host gene polymorphism is likely to influence disease progression after HBV infection. Gene polymorphism has a strong regional and national identity, and the results of studys connerning on the the relationship between polymorphisms and liver disease varied in different regions and ethnics. Thereby, analyzing the influence of MTHFR, IL-10, ALDH2 gene polymorphisms and disease progression after HBV infection in Chinese Han population in Tianjin may contribute to in-depth study on the etiology of liver disease occurrence in this region.
AIM:To investigate the relationship between MTHFR, IL-10, ALDH2 polymorphisms and the outcome of HBV infection.
METHODS:Collect 955 samples as follows:205 healthy control subjects,161 self-limited patients infected with HBV,221 patients with chronic hepatitis B,172 patients with HBV-induced liver cirrhosis and 236 cases with HBV-related HCC. Genome DNA was extracted from clot, TaqMan SNP genotyping and sequencing assays were employed to determine the distribution of genotypes and alleles at five sites in three genes as MTHFR 677 C/T, IL-10-1082 A/G,-819 T/C and ALDH2 rs4646778 C/A, rs671 A/G. Row×Column or revisedχ2 examination were used to analyse genotype and allele at the positions above. IL-10-1082/-819 and ALDH2 rs4646778/rs671 haplotype were also analysisied in all the groups.
RESULTS:1. MTHFR:Of the 805 subjects, genotype CT, TT and CC accounted for 47.09%,30.43% and 22.48%, respectively. The frequency of C allele was 46.02% and T was 53.98% of the total subjects, which are significantly different from other areas and races. Analysis on the distribution of genotypes in different sexes showed that males with TT genotype had a reduced risk with liver diseases. Particularly, the odds ratio (OR) of TT and CT was lowest in the liver cirrhosis group versus self-limited group. In contrast, females with TT and CT genotypes had an increased risk in the self-limited, chronic hepatitis and liver cirrhosis groups. Particularly, the liver cirrhosis group had the highest OR value versus self-limited group. However, females with TT and CT had a reduced risk in HCC group versus self-limited group. There was no significant difference about the genotype and allele distribution in different clinical feature groups such as Child-Pugh liver faction classification, AFP level in liver cirrhosis and HCC patients, HBsAg expression and DNA copies in all patients with liver disease.2. IL-10:Of the 700 subjects, genotype AA, AG and GG of IL-10-1082 accounted for 82.29%,16.00% and 1.71%, respectively, the frequency of A allele was 90.29% and T was 9.71%of the total subjects, while genotype TT, TC and CC of IL-10-819 accounted for 41.43%,48.14%, and 10.43%, respectively, the frequency of T allele was 65.64% and C was 34.36% of the total subjects. There was no significant difference of genotype or allele distribution among different groups at the two positions(P>0.05). Taking self-limited group as control,-1082 AG genotype and G allele decreased the risks of chronic hepatitis B and cirrhosis occurrence,-819 TC genotype decreased the risk of HCC, CC genotype and C allele decreased the risks of all the three liver disease groups. Analyzing distribution of haplotype-1082/-819 in each group showed that AC haplotype decreased the risks of cirrhosis and HCC using healthy or self-limited group as control, and the reduction degree was greater when regarding self-limited group as control, GC haplotype decreased the risks of chronic hepatitis B and cirrhosis occurrence using self-limited group as control. Comparing IL-10 genotype and allele frequencies in different groups with different clinical features revealed that frequency of-819 C was significantly higher in patients with DNA<103 copies/mL than those with DNA≥103 copies/mL(P=0.025). In addition, There was no significant difference about the genotype and allele distribution in other clinical feature groups(P>0.05).3. ALDH2: Of the 180 subjects, genotype CC, CA and AA of ALDH2 rs4646778 accounted for 51.11%,37.78% and 11.11%, respectively, the frequency of C allele was 70.00% and A was 30.00% of the total subjects, while genotype GG, GA and AA of ALDH2 rs671 accounted for 72.22%,24.45%, and 3.33%, respectively, the frequency of G allele was 84.44% and A was 15.56% of the total subjects. There was no significant difference of genotype or allele distribution among different groups at the two positions(P>0.05). Take healthy group as control, rs4646778 CA genotype decreased the risks of all the three liver disease groups, C allele decreased the risks of HCC group. Analyzing distribution of haplotype rs4646778/rs671 in each group showed that AG and CA haplotype decreased the risks of all the three liver disease groups. There was no significant difference about the genotype and allele distribution in different clinical feature groups(P>0.05).
CONCLUSION:1. MTHFR:The TT genotype shows a relatively high frequency in Tianjin, which is significantly different from other country or area. At the same time, MTHFR 677 polymorphism may play a role in influencing disease progression in patients with HBV infection, and the effect is different on different genders.2. IL-10: IL-10-1082 AG genotype and G allele,-819 TC, CC genotype and C allele,-1082/-819 AC, GC haplotype may play a protective role on disease progression after HBV infection.-819 C allele may attribute to virus elimination for HBV infected patients.3. ALDH2:rs4646778 CA genotype, C allele, and rs4646778/rs671 AG and CA haplotype may play a protective role on disease progression after HBV infection.
引文
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