中国人群中NOS2基因启动子区（CCTTT）n多态性与偏头痛易感性的关联研究
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摘要
背景以往大量研究表明，遗传因素参与了偏头痛的发生，而且有报道显示与一氧化氮的生成有关的基因与偏头痛易感性存在关联。已有研究探讨了编码不同类型一氧化氮合酶的基因多态与偏头痛的易感性之间的关系，然而大多数研究得到的都是阴性的结果。诱导型一氧化氮合酶（NOS2）的启动子区的五核苷酸重复多态(CCTTT)n的等位基因频率分布在不同的种族间显示高度差异性。因此，不同人群中该基因的五核苷酸重复多态性可能会影响偏头痛的易感性。
目的研究NOS2基因启动子区(CCTTT)n多态与中国人群的偏头痛的易感性之间的关系。
方法在中国汉族人群中，对504例偏头痛患者及512例对照组样本进行病例对照研究，从受试者外周血中提取基因组DNA,采用多聚酶链式反应及聚丙烯酰胺凝胶电泳分析方法对该多态进行基因分型。得出的数据采用逻辑回归分析，必要时使用Monte Carlo预测法及Bonferroni校正法进行统计。
结果偏头痛组中含重复11次的基因型频率显著高于对照组（P=0.0068）。NOS2基因CCTTT串联重复序列的等位基因频率分布在对照组及偏头痛患者间存在显著差异(P=0.0014)。进行多组比较时经过Bonferroni校正后（校正后α=0.00138），重复9次与重复11次的等位基因频率在病例组及对照组间有统计学差异(P=0.00014,OR=0.42，95%CI:0.26-0.68)，重复10次与重复11次的等位基因频率在两组间的差异亦具有统计学意义（P=0.0011, OR=0.62，95%CI：0.46-0.84）。重复9次的等位基因在对照组中更常见（P=0.0073），而重复11次的等位基因在病例组中更常见（P=0.0006）。此外，在统计分析时使用了一种特殊的分析方法，切断法。当经重复次数为9及10的等位基因进行切断时，等位基因频率及基因型频率在偏头痛患者组中及对照者组中的分布具有统计学差异（等位基因频率差异分别为P=0.007，P=0.005；基因型频率差异分别为Ptrend=0.0086，Ptrend=0.0033）。在经重复次数为10的等位基因进行切断时，使用逻辑回归分析发现同质体基因型S/S罹患偏头痛的可能性低于同质体基因型L/L（OR=0.47,95%CI:0.26-0.85）
结论在中国人群中NOS2基因启动子区CCTTT串联重复序列的多态性与偏头痛的易感性相关。但是鉴于该多态在不同种族人群中的差异性，需要更多的重复研究来进一步阐明NOS2多态在偏头痛的发生中的作用。
Background Genes involved in the production of nitric oxide (NO) have beensuggested as genetic factors for migraine. It has been studied whether polymorphisms inthe genes encoding for different types of NO synthase (NOS) could be involved in theliability to migraine; however, most studies yield negative results. The pentanucleotiderepeat microsatellite in the promoter region of inducible NOS (iNOS, NOS2) shows highlysignificant differences in allelic frequencies among ethnically diverse populations. Thus,variation in the number of pentanucleotide repeats may have some significance in thepredisposition to migraine among different human populations.
Objective The aim of this study was to investigate the possible association betweenpentanucleotide repeat polymorphism and the risk for migraine in Chinese population.
Method We studied the genotypic and allelic frequencies of the pentanucleotiderepeat polymorphism in the promoter region of NOS2in504patients with migraine and512healthy controls, using polymerase chain reaction amplification and polyacrylamidegel electrophoresis analyses.
Results Comparison of global allele counts between patients and controls showed thatthe difference was significant (P=0.0014). The carriage of9-repeat and10-repeat alleleswas significantly more common in controls, whereas11-repeat allele was more common inpatients after Bonferroni correction for multiple comparisons. A specific analysis of thedifferent cutoffs for number of repeats showed that allelic and genotypic frequencies forthe9-repeat and10-repeat cutoff were significantly different between cases and controls (P=0.007and P=0.005for allelic frequencies, respectively; P=0.0086and P=0.0033for genotypic frequencies, respectively).
Conclusions Our results implied an association between NOS2pentanucleotide repeatpolymorphism and migraine susceptibility in a Chinese population. Considering thesignificant allelic frequency differences in ethnically diverse populations, furtherreplication studies, especially in ethnically different groups, were necessary to fullyestablish the role of NOS2polymorphism in migraine susceptibility.
目的研究NOS2基因启动子区(CCTTT)n多态与中国人群的偏头痛的易感性之间的关系。
方法在中国汉族人群中，对504例偏头痛患者及512例对照组样本进行病例对照研究，从受试者外周血中提取基因组DNA,采用多聚酶链式反应及聚丙烯酰胺凝胶电泳分析方法对该多态进行基因分型。得出的数据采用逻辑回归分析，必要时使用Monte Carlo预测法及Bonferroni校正法进行统计。
结果偏头痛组中含重复11次的基因型频率显著高于对照组（P=0.0068）。NOS2基因CCTTT串联重复序列的等位基因频率分布在对照组及偏头痛患者间存在显著差异(P=0.0014)。进行多组比较时经过Bonferroni校正后（校正后α=0.00138），重复9次与重复11次的等位基因频率在病例组及对照组间有统计学差异(P=0.00014,OR=0.42，95%CI:0.26-0.68)，重复10次与重复11次的等位基因频率在两组间的差异亦具有统计学意义（P=0.0011, OR=0.62，95%CI：0.46-0.84）。重复9次的等位基因在对照组中更常见（P=0.0073），而重复11次的等位基因在病例组中更常见（P=0.0006）。此外，在统计分析时使用了一种特殊的分析方法，切断法。当经重复次数为9及10的等位基因进行切断时，等位基因频率及基因型频率在偏头痛患者组中及对照者组中的分布具有统计学差异（等位基因频率差异分别为P=0.007，P=0.005；基因型频率差异分别为Ptrend=0.0086，Ptrend=0.0033）。在经重复次数为10的等位基因进行切断时，使用逻辑回归分析发现同质体基因型S/S罹患偏头痛的可能性低于同质体基因型L/L（OR=0.47,95%CI:0.26-0.85）
结论在中国人群中NOS2基因启动子区CCTTT串联重复序列的多态性与偏头痛的易感性相关。但是鉴于该多态在不同种族人群中的差异性，需要更多的重复研究来进一步阐明NOS2多态在偏头痛的发生中的作用。
Background Genes involved in the production of nitric oxide (NO) have beensuggested as genetic factors for migraine. It has been studied whether polymorphisms inthe genes encoding for different types of NO synthase (NOS) could be involved in theliability to migraine; however, most studies yield negative results. The pentanucleotiderepeat microsatellite in the promoter region of inducible NOS (iNOS, NOS2) shows highlysignificant differences in allelic frequencies among ethnically diverse populations. Thus,variation in the number of pentanucleotide repeats may have some significance in thepredisposition to migraine among different human populations.
Objective The aim of this study was to investigate the possible association betweenpentanucleotide repeat polymorphism and the risk for migraine in Chinese population.
Method We studied the genotypic and allelic frequencies of the pentanucleotiderepeat polymorphism in the promoter region of NOS2in504patients with migraine and512healthy controls, using polymerase chain reaction amplification and polyacrylamidegel electrophoresis analyses.
Results Comparison of global allele counts between patients and controls showed thatthe difference was significant (P=0.0014). The carriage of9-repeat and10-repeat alleleswas significantly more common in controls, whereas11-repeat allele was more common inpatients after Bonferroni correction for multiple comparisons. A specific analysis of thedifferent cutoffs for number of repeats showed that allelic and genotypic frequencies forthe9-repeat and10-repeat cutoff were significantly different between cases and controls (P=0.007and P=0.005for allelic frequencies, respectively; P=0.0086and P=0.0033for genotypic frequencies, respectively).
Conclusions Our results implied an association between NOS2pentanucleotide repeatpolymorphism and migraine susceptibility in a Chinese population. Considering thesignificant allelic frequency differences in ethnically diverse populations, furtherreplication studies, especially in ethnically different groups, were necessary to fullyestablish the role of NOS2polymorphism in migraine susceptibility.
引文
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