白细胞介素-6及其基因多态性与阻塞性睡眠呼吸暂停综合征的相关性研究
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摘要
第一部分阻塞性睡眠呼吸暂停综合征患者血清白细胞介素-6的研究
目的探讨阻塞性睡眠呼吸暂停综合征(OSAS)患者血清白细胞介素-6的变化及其与睡眠呼吸参数之间的关系。
方法选择经多导睡眠呼吸监测(PSG)确诊的OSAS患者(AHI≥5次/h)100例作为病例组,其中男性88例,女性12例,按AHI将其分为轻度组25例(AHI为5-20次/h)、中度组17例(AHI为21-40次/h)和重度组58例(AHI>40次/h)。选择经PSG检查正常(AHI<5次/h)的18例鼾症患者作为对照组,其中男性14例,女性4例。除重度组外,病例组各组年龄、BMI与对照组匹配。采用酶联免疫吸附法测定各组血清,比较各组间IL-6的差异并将病例组的IL-6与各睡眠呼吸参数进行相关分析。
结果1、100例OSAS组血清IL-6水平为2.3±1.1 pg/ml,明显高于对照组0.9±0.3 pg/ml(p<0.05)。2、将病例组分层后,轻度OSAS组IL-6为1.4±0.3 pg/ml ,中度OSAS组为1.8±0.2 pg/ml,重度OSAS组为2.9±1.1 pg/m;比较各组IL-6水平,结果显示各病例组间及与对照组间均有明显差异(p均<0.05),其中重度组IL-6升高更明显。3、整个OSAS组IL-6与AHI、低氧指数、TRTSAO2<90%呈正相关(r值分别为0.645、0.537、0.452,p均<0.01)。IL-6与平均SaO2、最低SaO2呈负相关(r值分别为-0560、-0.538,p均<0.01)。
结论1、OSAS患者存在血清IL-6升高。2、升高的IL-6与OSAS严重度有较好的相关性,提示OSAS患者存在系统性炎症反应。3、重度OSAS组更高的IL-6可能是OSAS和肥胖共同作用的结果。
第二部分白细胞介素-6的基因变异对阻塞性睡眠呼吸暂停综合征发病风险的影响
目的肥胖及炎症因素均参与阻塞性睡眠呼吸暂停综合征(OSAS)的发病,据报道,IL-6是肥胖及炎症的重要调节因子之一,且与OSAS发病率增加密切相关。本研究旨在探讨IL-6的遗传变异与OSAS易感性的关系。
方法研究对象为中国华东地区151例OSAS患者及75例健康对照者。通过Haploview 4.1选择了IL-6基因上21kb范围内的5个标签单核苷酸多态性位点(tSNPs),它们分别是rs1404008、rs1880242、rs10499563、rs1800796和rs2069837。运用聚合酶链式反应(PCR)扩增上述tSNPs,扩增产物以限制性酶切及凝胶电泳进行基因分型。通过SHEsis程序进行连锁不平衡(LD)分析及单倍型构建。利用回归分析计算优势比(OR)和95%可信区间(95% confidence intervals,95%CI),并对性别、年龄和BMI进行校正。
结果1、上述5个tSNPs位点在OSAS患者及健康对照者中的分布均无差异。2、在非肥胖组(n=117), IL-6单核苷酸多态性位点rs1800796(-572G/C)的G等位基因携带者患OSAS的风险低于C等位基因携带者[优势比(OR)=0.48; 95%可信区间(CI),0.26-0.86, p=0.014];-572G/C多态性的(GG+CG)基因型携带者患OSAS的风险也低于CC基因型携带者(OR=0.38; 95%CI,0.17-0.88, p=0.008)。3、非肥胖者单倍型TG(rs1880242及rs1800796)携带者患OSAS的风险明显低于其它单倍型携带者(OR=0.39; 95%CI,0.20-0.74, p=0.003)。4、非肥胖者睡眠呼吸障碍的严重程度(以AHI表示,次/h)与IL-6 -572G/C的C多态性位点携带率呈线性关系(GG基因型:14.3±5.1,CG基因型:22.0±3.6及CC基因型34.8±3.5;p=0.012)。
结论本研究结果提示在非肥胖者中,IL-6-572G/C多态性中的CC基因型和C等位基因增加了OSAS患病风险,而GG基因型和G等位基因则对OSAS发病有保护作用。一些单倍型对OSAS的易感性也有影响。本研究在国内外首次揭示了IL-6的遗传变异与OSAS易感性有关。IL-6 SNP基因分型可能成为非肥胖人群睡眠呼吸暂停综合征患病风险的检测方法之一。
Part 1 The Investigation of Serum Interleukin-6 in Patients with Obstructive Sleep Apnea Syndrome
Objective To investigate the serum levels of Interleukin-6 (IL-6) in patients with obstructive sleep apnea syndrome( OSAS),and explore the relationship between the IL-6 and OSAS.
Method 100 patients(88 males and 12 females) with OSAS diagnosed by polysomnography(PSG) were selected as patient group(AHI≥5/h).The patient group was classified into three subgroups according to the severity of apnea: mild OSAS group(5≤AHI≤20,n=25),moderate OSAS group(2040,n=58). 18 persons(14 males and 4 females )with snoring were chosen as control group (AHI<5/h).Except the severe group ,all patients and controls were matched for age and body mass index(BMI). Enzyme-linked immunosorbent assay was performed to determine the serum levels of IL-6 of groups mentioned above and to analyse differences between groups as well as correlations between IL-6 and sleep-breathing parameters in patients.
Result 1.Compared with control subjects(0.9±0.3 pg/ml), serum IL-6 was significantly higher in OSAS patients(2.3±1.1 pg/ml ()p<0.05).2. There were significant differences of IL-6 among subgroups of the OSAS patients . The differences also existed between each subgroup and controls(p<0.05).The IL-6 averages of the three subgroups were 1.4±0.3 pg/ml in the mild group, 1.8±0.2 pg/ml in the moderate group and 2.9±1.1 pg/m in the severe group, respectively. And the average level of IL-6 of the severe subgroup was markedly higher than others. 3. The level of IL-6 has a positive correlation with AHI, oxygen desaturation index(ODI)and percentage of sleep time with SaO2 below 90% ( TRTSAO2<90% ) , respectively.(r=0.645, p<0.01;r=0.537, p <0.01;r=0.452, p<0.01),and a negative correlation with the average SaO2 and the lowest SaO2 .(r=-0.560, p <0.01;r=-0.538, p<0.001) in OSAS patients..
Conclusion 1. Levels of IL-6 were elevated in patients with OSAS. 2. The elevated serum levels of IL-6 were proportional to the severity of OSAS which indicated that there existed inflammatory responses in the OSAS patients. 3. OSAS and obesity may both contribute to the highest IL-6 levels of the severe group.
Part 2 Genetic Variants in Interleukin-6 Modified Risk of Obstructive Sleep Apnea Syndrome
Objective Obesity and inflammation has been well known to correlate with the pathogenesis of obstructive sleep apnea syndrome (OSAS). Interleukin (IL-6), an important regulator of obesity and inflammation, was reported to increase phenotypically in patients with OSAS. This study aimed to investigate whether genetic variants in IL-6 could confer susceptibility to OSAS.
Methods The study population consisted of 151 patients with OSAS and 75 healthy controls from the southeast of China. Five haplotype-tagging single nucleotide polymorphisms (tSNPs) were selected across 21 kb of the IL-6 locus using Haploview software V4.1.They were rs1404008、rs1880242、rs10499563、rs1800796 and rs2069837 .The tSNPs were amplified by polymerase chain reaction (PCR) and genotyped by restriction enzyme digestion followed by gelelectrophoresis. Linkage disequilibrium (LD) and haplotypes reconstruction were carried out by means of SHEsis program. Logistic regression was performed to assess odds ratios (OR) and 95% confidence intervals (CI), which were adjusted for gender, age and BMI.
Result 1. No distribution difference of any of five tSNPs between OSAS patients and controls was observed. 2. In non-obese individuals (n = 117), the minor allele -572G decreased risk of OSAS compared with the major allele -572C [odds ratio (OR), 0.48; 95% confidence interval (95% CI), 0.26-0.86; p = 0.014], and the genotype -572(GG+CG) also decreased risk of OSAS compared with the the genotype -572CC(OR=0.38;95%CI,0.17-0.88,p=0.008 ). 3. The haplotype TG (rs1880242, rs1800796) carried by non-obese individuals conferred significantly more decreased risk of OSAS than other haplotypes (OR, 0.39; 95% CI, 0.20-0.74; p = 0.003). 4. The severity of sleep-disordered breathing (measured by AHI,times/h) increased linearly in carriers of the C variant of IL-6 -572G/C polymorphism in non-obese individuals (14.3±5.1, 22.0±3.6 and 34.8±3.5 for GG, CG and CC, respectively; p = 0.012).
Conclusion The study indicated that genotype CC and allele C of -572G/C polymorphism of IL-6 gene in non-obese individuals could increase the risk of OSAS.Oppositely, genotype GG and allele G may have some protective effect to OSAS. Some haplotypes could play various roles in modifying the predisposition of OSAS in Chinese population.To the best of our knowledge, this is the first study to suggest that genetic variants in IL-6 could modify OSAS susceptibility. SNP genotyping of IL-6 gene could be a potential strategy to detect the risk of breathing disordered diseases in non-obese individuals.
目的探讨阻塞性睡眠呼吸暂停综合征(OSAS)患者血清白细胞介素-6的变化及其与睡眠呼吸参数之间的关系。
方法选择经多导睡眠呼吸监测(PSG)确诊的OSAS患者(AHI≥5次/h)100例作为病例组,其中男性88例,女性12例,按AHI将其分为轻度组25例(AHI为5-20次/h)、中度组17例(AHI为21-40次/h)和重度组58例(AHI>40次/h)。选择经PSG检查正常(AHI<5次/h)的18例鼾症患者作为对照组,其中男性14例,女性4例。除重度组外,病例组各组年龄、BMI与对照组匹配。采用酶联免疫吸附法测定各组血清,比较各组间IL-6的差异并将病例组的IL-6与各睡眠呼吸参数进行相关分析。
结果1、100例OSAS组血清IL-6水平为2.3±1.1 pg/ml,明显高于对照组0.9±0.3 pg/ml(p<0.05)。2、将病例组分层后,轻度OSAS组IL-6为1.4±0.3 pg/ml ,中度OSAS组为1.8±0.2 pg/ml,重度OSAS组为2.9±1.1 pg/m;比较各组IL-6水平,结果显示各病例组间及与对照组间均有明显差异(p均<0.05),其中重度组IL-6升高更明显。3、整个OSAS组IL-6与AHI、低氧指数、TRTSAO2<90%呈正相关(r值分别为0.645、0.537、0.452,p均<0.01)。IL-6与平均SaO2、最低SaO2呈负相关(r值分别为-0560、-0.538,p均<0.01)。
结论1、OSAS患者存在血清IL-6升高。2、升高的IL-6与OSAS严重度有较好的相关性,提示OSAS患者存在系统性炎症反应。3、重度OSAS组更高的IL-6可能是OSAS和肥胖共同作用的结果。
第二部分白细胞介素-6的基因变异对阻塞性睡眠呼吸暂停综合征发病风险的影响
目的肥胖及炎症因素均参与阻塞性睡眠呼吸暂停综合征(OSAS)的发病,据报道,IL-6是肥胖及炎症的重要调节因子之一,且与OSAS发病率增加密切相关。本研究旨在探讨IL-6的遗传变异与OSAS易感性的关系。
方法研究对象为中国华东地区151例OSAS患者及75例健康对照者。通过Haploview 4.1选择了IL-6基因上21kb范围内的5个标签单核苷酸多态性位点(tSNPs),它们分别是rs1404008、rs1880242、rs10499563、rs1800796和rs2069837。运用聚合酶链式反应(PCR)扩增上述tSNPs,扩增产物以限制性酶切及凝胶电泳进行基因分型。通过SHEsis程序进行连锁不平衡(LD)分析及单倍型构建。利用回归分析计算优势比(OR)和95%可信区间(95% confidence intervals,95%CI),并对性别、年龄和BMI进行校正。
结果1、上述5个tSNPs位点在OSAS患者及健康对照者中的分布均无差异。2、在非肥胖组(n=117), IL-6单核苷酸多态性位点rs1800796(-572G/C)的G等位基因携带者患OSAS的风险低于C等位基因携带者[优势比(OR)=0.48; 95%可信区间(CI),0.26-0.86, p=0.014];-572G/C多态性的(GG+CG)基因型携带者患OSAS的风险也低于CC基因型携带者(OR=0.38; 95%CI,0.17-0.88, p=0.008)。3、非肥胖者单倍型TG(rs1880242及rs1800796)携带者患OSAS的风险明显低于其它单倍型携带者(OR=0.39; 95%CI,0.20-0.74, p=0.003)。4、非肥胖者睡眠呼吸障碍的严重程度(以AHI表示,次/h)与IL-6 -572G/C的C多态性位点携带率呈线性关系(GG基因型:14.3±5.1,CG基因型:22.0±3.6及CC基因型34.8±3.5;p=0.012)。
结论本研究结果提示在非肥胖者中,IL-6-572G/C多态性中的CC基因型和C等位基因增加了OSAS患病风险,而GG基因型和G等位基因则对OSAS发病有保护作用。一些单倍型对OSAS的易感性也有影响。本研究在国内外首次揭示了IL-6的遗传变异与OSAS易感性有关。IL-6 SNP基因分型可能成为非肥胖人群睡眠呼吸暂停综合征患病风险的检测方法之一。
Part 1 The Investigation of Serum Interleukin-6 in Patients with Obstructive Sleep Apnea Syndrome
Objective To investigate the serum levels of Interleukin-6 (IL-6) in patients with obstructive sleep apnea syndrome( OSAS),and explore the relationship between the IL-6 and OSAS.
Method 100 patients(88 males and 12 females) with OSAS diagnosed by polysomnography(PSG) were selected as patient group(AHI≥5/h).The patient group was classified into three subgroups according to the severity of apnea: mild OSAS group(5≤AHI≤20,n=25),moderate OSAS group(20
Result 1.Compared with control subjects(0.9±0.3 pg/ml), serum IL-6 was significantly higher in OSAS patients(2.3±1.1 pg/ml ()p<0.05).2. There were significant differences of IL-6 among subgroups of the OSAS patients . The differences also existed between each subgroup and controls(p<0.05).The IL-6 averages of the three subgroups were 1.4±0.3 pg/ml in the mild group, 1.8±0.2 pg/ml in the moderate group and 2.9±1.1 pg/m in the severe group, respectively. And the average level of IL-6 of the severe subgroup was markedly higher than others. 3. The level of IL-6 has a positive correlation with AHI, oxygen desaturation index(ODI)and percentage of sleep time with SaO2 below 90% ( TRTSAO2<90% ) , respectively.(r=0.645, p<0.01;r=0.537, p <0.01;r=0.452, p<0.01),and a negative correlation with the average SaO2 and the lowest SaO2 .(r=-0.560, p <0.01;r=-0.538, p<0.001) in OSAS patients..
Conclusion 1. Levels of IL-6 were elevated in patients with OSAS. 2. The elevated serum levels of IL-6 were proportional to the severity of OSAS which indicated that there existed inflammatory responses in the OSAS patients. 3. OSAS and obesity may both contribute to the highest IL-6 levels of the severe group.
Part 2 Genetic Variants in Interleukin-6 Modified Risk of Obstructive Sleep Apnea Syndrome
Objective Obesity and inflammation has been well known to correlate with the pathogenesis of obstructive sleep apnea syndrome (OSAS). Interleukin (IL-6), an important regulator of obesity and inflammation, was reported to increase phenotypically in patients with OSAS. This study aimed to investigate whether genetic variants in IL-6 could confer susceptibility to OSAS.
Methods The study population consisted of 151 patients with OSAS and 75 healthy controls from the southeast of China. Five haplotype-tagging single nucleotide polymorphisms (tSNPs) were selected across 21 kb of the IL-6 locus using Haploview software V4.1.They were rs1404008、rs1880242、rs10499563、rs1800796 and rs2069837 .The tSNPs were amplified by polymerase chain reaction (PCR) and genotyped by restriction enzyme digestion followed by gelelectrophoresis. Linkage disequilibrium (LD) and haplotypes reconstruction were carried out by means of SHEsis program. Logistic regression was performed to assess odds ratios (OR) and 95% confidence intervals (CI), which were adjusted for gender, age and BMI.
Result 1. No distribution difference of any of five tSNPs between OSAS patients and controls was observed. 2. In non-obese individuals (n = 117), the minor allele -572G decreased risk of OSAS compared with the major allele -572C [odds ratio (OR), 0.48; 95% confidence interval (95% CI), 0.26-0.86; p = 0.014], and the genotype -572(GG+CG) also decreased risk of OSAS compared with the the genotype -572CC(OR=0.38;95%CI,0.17-0.88,p=0.008 ). 3. The haplotype TG (rs1880242, rs1800796) carried by non-obese individuals conferred significantly more decreased risk of OSAS than other haplotypes (OR, 0.39; 95% CI, 0.20-0.74; p = 0.003). 4. The severity of sleep-disordered breathing (measured by AHI,times/h) increased linearly in carriers of the C variant of IL-6 -572G/C polymorphism in non-obese individuals (14.3±5.1, 22.0±3.6 and 34.8±3.5 for GG, CG and CC, respectively; p = 0.012).
Conclusion The study indicated that genotype CC and allele C of -572G/C polymorphism of IL-6 gene in non-obese individuals could increase the risk of OSAS.Oppositely, genotype GG and allele G may have some protective effect to OSAS. Some haplotypes could play various roles in modifying the predisposition of OSAS in Chinese population.To the best of our knowledge, this is the first study to suggest that genetic variants in IL-6 could modify OSAS susceptibility. SNP genotyping of IL-6 gene could be a potential strategy to detect the risk of breathing disordered diseases in non-obese individuals.
引文
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1 Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med, 2002, 165(9):1217-1239.
2 Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med, 1993, 328(17):1230-1235.
3 Ovchinsky A, Rao M, Lotwin I, et al. The familial aggregation of pediatric obstructive sleep apnea syndrome. Arch Otolaryngol Head Neck Sury, 2002, 128(7): 815-818.
4 Gislason T, Johannsson JH, Haraldsson A,et al.Familial predisposition and cosegregation analysis of adult obstructive sleep apnea and the sudden infant death syndrome. Am J Respir Crit Care Med, 2002, 166(6): 833-838.
5 Mathur R, Douglas NJ. Family studies in patients with the sleep apneahypopnea syndrome. Ann Intern Med, 1995, 122(3): 174-178.
6 Redline S, Tishler PV, Tosteson TD, et al. The familial aggregation of obstructive sleep apnea. Am J Respir Crit Care M ed, 1995, 151(3):628-687.
7 Douglas NJ, Luke M, Mathur R. Is the sleep apnoea/hypopnoea syndrome inherited? Thorax, 1993, 48(7):719-721.
8 Pillar G and Lavie P. Assessment of the role of inheritance in sleep apnea syndrome. Am J Respir Crit Care Med, 1995, 151(3): 688-691.
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12 Zhang J, Zhao B, Gesongluobu,et al. Angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism in hypertensive patients with different degrees of obstructive sleep apnea. Hypertens Res,2000, 23(5):407-411.
13 Busjahn A, Knoblauch H, Knoblauch M, et al. Angiotensin converting enzyme and angiotensinogen gene polymorphisms, plasma levels, cardiac dimensions: a twin study.Hypertension,1997,29(1pt2):165-170.
14 Barcelo A, Elorza MA, Barbe F, et al. Angiotensin converting enzyme in patients with sleep apnea syndrome: plasma activity and gene polymorphisms. Eur Respir J, 2001, 17(4): 728-732.
15肖毅,黄席珍,邱长春,等.血管紧张素转换酶基因多态性与阻塞性睡眠呼吸暂停综合征.中华结核和呼吸杂志,1998,21(4):489-491.
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