白细胞介素-4、13及其基因多态性与动脉粥样硬化性脑梗死关系的研究
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摘要
研究背景：脑梗死发病率、致死率和致残率均高，严重危害人类的健康。动脉粥样硬化是其主要病因之一，近来研究发现炎症和免疫反应在动脉粥样硬化形成中发挥关键作用。白细胞介素-4和13(IL-4和IL-13)是一种生物活性相似的多效细胞因子，具有抗炎作用，脑梗死后其变化目前研究较少，且有争议。同时，IL-4和IL-13参与动脉粥样硬化形成，IL-4与IL-13及其受体基因有多个影响其生物活性的基因多态位点，这些位点的基因多态性与脑梗死的相关性目前国内外鲜有报道。
第一部分白细胞介素-4、13与动脉粥样硬化性脑梗死的关系
目的：动态观察脑梗死后血清IL-4和IL-13的变化，以明确IL-4和IL-13是否参与脑梗死的病理生理过程。
方法：采用病例对照研究设计，纳入28例动脉粥样硬化性脑梗死患者和151例对照者，其中对照组分为有颈动脉粥样硬化和无颈动脉粥样硬化两个亚组。脑梗死病人分别在第1、3、7和14天收集血标本，对照组收集一次血标本。采用ELISA方法测定血清IL-4、IL-13水平。
结果：
1．对照组中有颈动脉粥样硬化和无颈动脉粥样硬化两个亚组血清IL-4水平无差别。与对照组相比，脑梗死后第1天血清IL-4水平无变化(p＞0.05)；第3天开始增高，第7天时达高峰，为基础水平的3.4倍；14天时仍高于对照组(p＜0.01)。同时，脑梗死后第3、7和14天的血清IL-4水平均高于对照组中的颈动脉粥样硬化亚组(p＜0.01)。
2．对照组中有颈动脉粥样硬化和无颈动脉粥样硬化两个亚组IL-13水平无差别。与对照组相比，脑梗死后第1天血清IL-13水平无变化(p＞0.05)；第3天开始增高，第7天时达高峰，为基础水平的2倍，14天时仍高于对照组(p＜0.01)。同时，脑梗死后第3、7和14天的血清IL-13水平均高于对照组中的颈动脉粥样硬化亚组(p＜0.01)。
结论：
脑梗死后，血清IL-4和13水平升高，可能抑制脑梗死后的炎症反应，减轻脑损伤。
第二部分白细胞介素-4、13及其受体基因多态性与动脉粥样硬化性脑梗死的关系
目的：1．探讨IL-4 C-590T和C+33T、IL-13 C+1923T基因多态性与血清IL-4、IL-13水平的关系。2．探讨IL-4 C-590T和C+33T、IL-4RQ576R、IL-13 C+1923T基因多态性与动脉粥样硬化性脑梗死发病的关系。
方法：采用病例对照研究设计，纳入159例动脉粥样硬化性脑梗死患者和151例对照者。采用PCR-限制性片段长度多态性(PCR-RFLP)方法检测对照组人群、动脉粥样硬化性脑梗死患者IL-4 C-590T和C+33T、IL-4R Q576R、IL-13 C+1923T基因的单核苷酸多态性。
结果：
1．IL-4 C-590T和C+33T位点呈连锁不平衡，TT基因型的IL-4血清水平高于TC和CC基因型，TC基因型高于CC基因型。其基因型和等位基因频率在两组中分布无差异。
2．IL-13 C+1923T基因的TC型和TT型的血清IL-13水平无统计学差异，两者的血清IL-13水平均高于CC型。其基因型和等位基因频率在两组中分布无差异。
3．IL-4R Q576R的各种基因型及其等位基因频率在两组中分布无差异。
4．脑梗死组中携带IL-4 590T／IL-4R 576R或IL-4 33T／IL-4R 576R基因型的比例较对照组高；IL-13 1923T／IL-4R 576R基因型在两组间无显著性差异。
结论：
1．IL-4 C-590T与C+33T位点呈连锁不平衡，T等位基因与高血清IL-4水平有关，IL-4 C-590T与C+33T基因多态与中国湖南汉族人动脉粥样硬化性脑梗死的发病无关。
2．IL-13+1923T基因与高血清IL-13水平相关，IL-13 C+1923T基因多态与中国湖南汉族人动脉粥样硬化性脑梗死的发病无关。
3．IL-4R Q576R基因多态与中国湖南汉族人动脉粥样硬化性脑梗死的发病无关。
4．IL-4 590T／IL-4R 576R和IL-4 33T／IL-4576R基因型可作为中国湖南汉族人动脉粥样硬化性脑梗死的独立预知因子。
Background: Cerebral infarction is a common cerebrovascular diseasewith high disease incidence, morbidity and mortality. Atherosclerosis isone of the main causes of cerebral infarction. It has been known thatinflammation plays a key role in atherosclerosis. Interleukin 4 (IL-4) andIL-13(IL-13) are pleiotropic cytokines exerting similar biological activity.As an anti-inflammation cytokine, the change of IL-4 and IL-13 in braininfarction is controversy. Meanwhile, IL-4 and IL-13 play an importantrole in atherogenesis. There are several genetic polymorphisms locus inIL-4, IL-13 and their receptor which alter their biological activity.Unfortunately, the association of those gene polymorphisms with braininfarction hasn't been reported almost.
Part 1The association of IL-4 and IL-13 with atherothrombotic cerebralinfarction
Objects:
To be comprehensive understanding the alternation of the IL-4 andIL-13 serum level in the patients with cerebral infarction, the serialchanges of serum IL-4 and IL-13 in atherothrombotic cerebral infarctionpatients will be measured.
Methods: A case-control study was carded out in this research, in which28 patients with atherothrombotic cerebral infarction, as well as 151control subjects were recruited. Control subjects with or without carotidartery atherosclerosis were divided into 2 subgroups. 28 cerebralinfarction patients' blood was serially obtained at four times: within 24hours, at day 3, at day 7 and at day 14. The control subjects' blood was collected only once. IL-4 and IL-13 levels in serum samples weredetermined with ELISA method using human IL-4 and IL-13immunoassay kit.
Results:
1. The serum level of IL-4 was not different among subjects with carotidartery atherosclerosis and no- carotid artery atherosclerosis (P＞0.05).Compared with the control value, the serum IL-4 level obtained at day1 was not increase (P＞0.05). It began to increase at day 3, and peakedat day 7 (3.4 times of control value). The high level of IL-4 lasted today 14(P＜0.01). Meanwhile, the serum levels of IL-4 obtained at day3, 7, and 14 in patients with cerebral infarction were significantlyhigher than the control subjects with carotid atherosclerosis (P＜0.01).
2. The serum level of IL-13 was not different among subjects withcarotid artery atherosclerosis and no- carotid artery atherosclerosis(P＞0.05). Compared with the control value, the serum IL-13 levelobtained at day 1 was not increase (P＞0.05). It began to increase atday 3, and peaked at day 7 (2 times of control value). The high levellasted to day 14(P＜0.01). Meanwhile, the serum levels of IL-4obtained at day 3, 7, and 14 in patients with cerebral infarction weresignificantly higher than the control subjects with carotidatherosclerotic (P＜0.01).
Conclusion:
The serum levels of IL-4 and IL-13 are elevated after cerebralinfarction. This supposes that IL-4 and IL-13 play an anti-inflammationrole in brain ischemic injury and ameliorate brain ischemic injury.
Part 2The association of gene polymorphisms of IL-4, IL-13 and IL-4Rwith atherothrombotic cerebral infarction
Objects:
1. To elucidate the associations of genetic polymorphism of IL-4 C-590Tand C+33T, IL-13 C+1923T with the serum levels of IL-4 and IL-13.
2. To elucidate the associations ofgene polymorphisms of C-590T andC+33T in IL-4, C+1923T in IL-13 and Q576R in IL-4R withatherothrombotic cerebral infarction.
Methods: A case-control study was carried out in this research, in which159 patients with atherothrombotic cerebral infarction, as well as 151control subjects were recruited. Genotyping among study subjects wascarried out by polymerase chain reaction (PCR)-restriction fragmentlength polymorphism (RFLP).
Results:
1. The IL-4 C+33T was in strong linkage disequilibrium with C-590T.The serum IL-4 level in TT genotype was higher than TC and CCgenotype, TC genotype higher than CC genotype. But those genotypesand allele frequencies in IL-4 were found no difference amongpatients with cerebral infarction and control subjects.
2. The serum IL-13 level in TT genotype of IL-13 C+1923Tpolymorphism was not different from TC genotype. The serum IL-13level in TT and TC genotype were higher than CC genotype. But thosegenotypes and allele frequencies were found no difference amongpatients with cerebral infarction and control subjects.
3. IL-4R Q576R polymorphisms were found no difference amongpatients with cerebral infarction and control subjects.
4. The genotype of IL-4 590T/IL-4R 576R and IL-4 33T/IL-4 576R butnot IL-13 1923T/IL-4R 576R had a significantly increased risk forcerebral infarction.
Conclusion:
1. IL-4 C+33T is in strong linkage disequilibrium with C-590T. T allelewas associated with high serum IL-4 level. The C-590T and C+33Tpolymorphism are not associated with the risk of atherothromboticcerebral infarction in Chinese Han population.
2. The serum IL-13 level depends on IL-13 C+1923T polymorphism, Tallele was associated with high serum IL-13 level. The IL-13C+1923T polymorphism is not associated with the risk ofatherothrombotic cerebral infarction in Chinese Han population.
3. The IL-4R Q576R polymorphism is not associated with the risk ofatherothrombotic cerebral infarction in Chinese Han population.
4. The genotype of IL-4 590T/IL-4R 576R and IL-4 33T/IL-4 576R arefound to be independent predictors of atherothrombotic cerebralinfarction in Chinese Han population.
第一部分白细胞介素-4、13与动脉粥样硬化性脑梗死的关系
目的：动态观察脑梗死后血清IL-4和IL-13的变化，以明确IL-4和IL-13是否参与脑梗死的病理生理过程。
方法：采用病例对照研究设计，纳入28例动脉粥样硬化性脑梗死患者和151例对照者，其中对照组分为有颈动脉粥样硬化和无颈动脉粥样硬化两个亚组。脑梗死病人分别在第1、3、7和14天收集血标本，对照组收集一次血标本。采用ELISA方法测定血清IL-4、IL-13水平。
结果：
1．对照组中有颈动脉粥样硬化和无颈动脉粥样硬化两个亚组血清IL-4水平无差别。与对照组相比，脑梗死后第1天血清IL-4水平无变化(p＞0.05)；第3天开始增高，第7天时达高峰，为基础水平的3.4倍；14天时仍高于对照组(p＜0.01)。同时，脑梗死后第3、7和14天的血清IL-4水平均高于对照组中的颈动脉粥样硬化亚组(p＜0.01)。
2．对照组中有颈动脉粥样硬化和无颈动脉粥样硬化两个亚组IL-13水平无差别。与对照组相比，脑梗死后第1天血清IL-13水平无变化(p＞0.05)；第3天开始增高，第7天时达高峰，为基础水平的2倍，14天时仍高于对照组(p＜0.01)。同时，脑梗死后第3、7和14天的血清IL-13水平均高于对照组中的颈动脉粥样硬化亚组(p＜0.01)。
结论：
脑梗死后，血清IL-4和13水平升高，可能抑制脑梗死后的炎症反应，减轻脑损伤。
第二部分白细胞介素-4、13及其受体基因多态性与动脉粥样硬化性脑梗死的关系
目的：1．探讨IL-4 C-590T和C+33T、IL-13 C+1923T基因多态性与血清IL-4、IL-13水平的关系。2．探讨IL-4 C-590T和C+33T、IL-4RQ576R、IL-13 C+1923T基因多态性与动脉粥样硬化性脑梗死发病的关系。
方法：采用病例对照研究设计，纳入159例动脉粥样硬化性脑梗死患者和151例对照者。采用PCR-限制性片段长度多态性(PCR-RFLP)方法检测对照组人群、动脉粥样硬化性脑梗死患者IL-4 C-590T和C+33T、IL-4R Q576R、IL-13 C+1923T基因的单核苷酸多态性。
结果：
1．IL-4 C-590T和C+33T位点呈连锁不平衡，TT基因型的IL-4血清水平高于TC和CC基因型，TC基因型高于CC基因型。其基因型和等位基因频率在两组中分布无差异。
2．IL-13 C+1923T基因的TC型和TT型的血清IL-13水平无统计学差异，两者的血清IL-13水平均高于CC型。其基因型和等位基因频率在两组中分布无差异。
3．IL-4R Q576R的各种基因型及其等位基因频率在两组中分布无差异。
4．脑梗死组中携带IL-4 590T／IL-4R 576R或IL-4 33T／IL-4R 576R基因型的比例较对照组高；IL-13 1923T／IL-4R 576R基因型在两组间无显著性差异。
结论：
1．IL-4 C-590T与C+33T位点呈连锁不平衡，T等位基因与高血清IL-4水平有关，IL-4 C-590T与C+33T基因多态与中国湖南汉族人动脉粥样硬化性脑梗死的发病无关。
2．IL-13+1923T基因与高血清IL-13水平相关，IL-13 C+1923T基因多态与中国湖南汉族人动脉粥样硬化性脑梗死的发病无关。
3．IL-4R Q576R基因多态与中国湖南汉族人动脉粥样硬化性脑梗死的发病无关。
4．IL-4 590T／IL-4R 576R和IL-4 33T／IL-4576R基因型可作为中国湖南汉族人动脉粥样硬化性脑梗死的独立预知因子。
Background: Cerebral infarction is a common cerebrovascular diseasewith high disease incidence, morbidity and mortality. Atherosclerosis isone of the main causes of cerebral infarction. It has been known thatinflammation plays a key role in atherosclerosis. Interleukin 4 (IL-4) andIL-13(IL-13) are pleiotropic cytokines exerting similar biological activity.As an anti-inflammation cytokine, the change of IL-4 and IL-13 in braininfarction is controversy. Meanwhile, IL-4 and IL-13 play an importantrole in atherogenesis. There are several genetic polymorphisms locus inIL-4, IL-13 and their receptor which alter their biological activity.Unfortunately, the association of those gene polymorphisms with braininfarction hasn't been reported almost.
Part 1The association of IL-4 and IL-13 with atherothrombotic cerebralinfarction
Objects:
To be comprehensive understanding the alternation of the IL-4 andIL-13 serum level in the patients with cerebral infarction, the serialchanges of serum IL-4 and IL-13 in atherothrombotic cerebral infarctionpatients will be measured.
Methods: A case-control study was carded out in this research, in which28 patients with atherothrombotic cerebral infarction, as well as 151control subjects were recruited. Control subjects with or without carotidartery atherosclerosis were divided into 2 subgroups. 28 cerebralinfarction patients' blood was serially obtained at four times: within 24hours, at day 3, at day 7 and at day 14. The control subjects' blood was collected only once. IL-4 and IL-13 levels in serum samples weredetermined with ELISA method using human IL-4 and IL-13immunoassay kit.
Results:
1. The serum level of IL-4 was not different among subjects with carotidartery atherosclerosis and no- carotid artery atherosclerosis (P＞0.05).Compared with the control value, the serum IL-4 level obtained at day1 was not increase (P＞0.05). It began to increase at day 3, and peakedat day 7 (3.4 times of control value). The high level of IL-4 lasted today 14(P＜0.01). Meanwhile, the serum levels of IL-4 obtained at day3, 7, and 14 in patients with cerebral infarction were significantlyhigher than the control subjects with carotid atherosclerosis (P＜0.01).
2. The serum level of IL-13 was not different among subjects withcarotid artery atherosclerosis and no- carotid artery atherosclerosis(P＞0.05). Compared with the control value, the serum IL-13 levelobtained at day 1 was not increase (P＞0.05). It began to increase atday 3, and peaked at day 7 (2 times of control value). The high levellasted to day 14(P＜0.01). Meanwhile, the serum levels of IL-4obtained at day 3, 7, and 14 in patients with cerebral infarction weresignificantly higher than the control subjects with carotidatherosclerotic (P＜0.01).
Conclusion:
The serum levels of IL-4 and IL-13 are elevated after cerebralinfarction. This supposes that IL-4 and IL-13 play an anti-inflammationrole in brain ischemic injury and ameliorate brain ischemic injury.
Part 2The association of gene polymorphisms of IL-4, IL-13 and IL-4Rwith atherothrombotic cerebral infarction
Objects:
1. To elucidate the associations of genetic polymorphism of IL-4 C-590Tand C+33T, IL-13 C+1923T with the serum levels of IL-4 and IL-13.
2. To elucidate the associations ofgene polymorphisms of C-590T andC+33T in IL-4, C+1923T in IL-13 and Q576R in IL-4R withatherothrombotic cerebral infarction.
Methods: A case-control study was carried out in this research, in which159 patients with atherothrombotic cerebral infarction, as well as 151control subjects were recruited. Genotyping among study subjects wascarried out by polymerase chain reaction (PCR)-restriction fragmentlength polymorphism (RFLP).
Results:
1. The IL-4 C+33T was in strong linkage disequilibrium with C-590T.The serum IL-4 level in TT genotype was higher than TC and CCgenotype, TC genotype higher than CC genotype. But those genotypesand allele frequencies in IL-4 were found no difference amongpatients with cerebral infarction and control subjects.
2. The serum IL-13 level in TT genotype of IL-13 C+1923Tpolymorphism was not different from TC genotype. The serum IL-13level in TT and TC genotype were higher than CC genotype. But thosegenotypes and allele frequencies were found no difference amongpatients with cerebral infarction and control subjects.
3. IL-4R Q576R polymorphisms were found no difference amongpatients with cerebral infarction and control subjects.
4. The genotype of IL-4 590T/IL-4R 576R and IL-4 33T/IL-4 576R butnot IL-13 1923T/IL-4R 576R had a significantly increased risk forcerebral infarction.
Conclusion:
1. IL-4 C+33T is in strong linkage disequilibrium with C-590T. T allelewas associated with high serum IL-4 level. The C-590T and C+33Tpolymorphism are not associated with the risk of atherothromboticcerebral infarction in Chinese Han population.
2. The serum IL-13 level depends on IL-13 C+1923T polymorphism, Tallele was associated with high serum IL-13 level. The IL-13C+1923T polymorphism is not associated with the risk ofatherothrombotic cerebral infarction in Chinese Han population.
3. The IL-4R Q576R polymorphism is not associated with the risk ofatherothrombotic cerebral infarction in Chinese Han population.
4. The genotype of IL-4 590T/IL-4R 576R and IL-4 33T/IL-4 576R arefound to be independent predictors of atherothrombotic cerebralinfarction in Chinese Han population.
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