Alaez Carmen, Lin Ling, Flores-A Hilario, Vazquez Miriam, Munguia Andrea, Mignot Emmanuel, Haro Reyes, Baker Harry, Gorodezky Clara
Department of Immunology and Immunogenetics, InDRE, Mexico City, Mexico.
BMC Med Genet. 2008 Aug 15;9:79. doi: 10.1186/1471-2350-9-79.
Narcolepsy-cataplexy is characterized by excessive daytime sleepiness with recurrent episodes of irresistible sleep, cataplexy, hallucinations and sleep paralysis. Its aetiology is unknown, but it is positively associated with the human leukocyte antigens (HLA) in all studied populations. The purpose of the present study was to investigate the association of HLA class II DRB1/DQB1 alleles with narcolepsy-cataplexy in Mexican Mestizo patients.
This is a case-control study of consecutive patients and ethnically matched controls. We included 32 patients diagnosed with typical narcolepsy-cataplexy, of the National Institute of Neurology, of the Institute of Psychiatry and at the Center of Narcolepsy at Stanford University. As healthy controls, 203 Mexican Mestizos were included. DRB1 alleles were identified using sequence based typing. A PCR-SSOP reverse dot blot was used for DQB1 typing. Allele frequency was calculated by direct counting and the significance of the differences was assessed using the Yates Chi square. Odds ratio and confidence intervals were evaluated.
HLA-DRB11501 (OR = 8.2; pc < 0.0001) and DQB10602 (OR = 8.4; pc < 0.0001) were found positively associated with narcolepsy. When deleting DQB10602+ patients from the analysis, DQB10301 was also found increased (OR = 2.7; p = 0.035; pc = NS). DQB10602/DQB10301 genotype was present in 15.6% of the cases (OR = 11.5; p = 0.00035), conferring a high risk. DRB10407 (OR = 0.2; p = 0.016 pc = NS) and DQB10302(OR = 0.4; p = 0.017, pc = NS) were found decreased in the patients. The gender stratification analysis showed a higher risk in females carrying DRB11501 (OR = 15.8, pc < 0.0001) and DQB10602 (OR = 19.8, pc < 0.0001) than in males (OR = 5.0 for both alleles; p = 0.012, pc = NS for DRB1 & p = 0.0012, pc = 0.017 for DQB1). The susceptibility alleles found in Mexicans with narcolepsy are also present in Japanese and Caucasians; DRB1*04 linked protection has also been shown in Koreans. A stronger HLA association is suggested in females, in accordance with the sexual dimorphism claimed previously.
This knowledge may contribute to a better understanding of the disease pathogenesis in different populations. The evaluation of the risk to develop narcolepsy-cataplexy in carriers of the described alleles/genotypes may also be possible. A larger sample should be analysed in Mexican and in other Hispanic patients to confirm these results.
发作性睡病伴猝倒症的特征为日间过度嗜睡，伴有反复出现的不可抗拒的睡眠发作、猝倒、幻觉和睡眠麻痹。其病因不明，但在所有研究人群中均与人类白细胞抗原（HLA）呈正相关。本研究的目的是调查墨西哥梅斯蒂索患者中HLA II类DRB1/DQB1等位基因与发作性睡病伴猝倒症的关联。
这是一项针对连续患者和种族匹配对照的病例对照研究。我们纳入了国立神经病学研究所、精神病学研究所及斯坦福大学发作性睡病中心诊断为典型发作性睡病伴猝倒症的32例患者。作为健康对照，纳入了203名墨西哥梅斯蒂索人。使用基于序列的分型鉴定DRB1等位基因。采用PCR-SSOP反向斑点杂交法进行DQB1分型。通过直接计数计算等位基因频率，并使用耶茨卡方检验评估差异的显著性。评估比值比和置信区间。
发现HLA-DRB11501（OR = 8.2；pc < 0.0001）和DQB10602（OR = 8.4；pc < 0.0001）与发作性睡病呈正相关。从分析中剔除DQB10602+患者后，还发现DQB10301增加（OR = 2.7；p = 0.035；pc = 无显著性差异）。15.6%的病例存在DQB10602/DQB10301基因型（OR = 11.5；p = 0.00035），具有高风险。发现患者中DRB10407（OR = 0.2；p = 0.016，pc = 无显著性差异）和DQB10302（OR = 0.4；p = 0.017，pc = 无显著性差异）减少。性别分层分析显示，携带DRB11501（OR = 15.8，pc < 0.0001）和DQB10602（OR = 19.8，pc < 0.0001）的女性比男性风险更高（两个等位基因的OR均为5.0；DRB1的p = 0.012，pc = 无显著性差异；DQB1的p = 0.0012，pc = 0.017）。在患有发作性睡病的墨西哥人中发现的易感等位基因在日本人和白种人中也存在；在韩国人中也显示出DRB1*04相关的保护作用。根据先前提出的性别二态性，提示女性中HLA关联更强。
这一知识可能有助于更好地理解不同人群中的疾病发病机制。对所述等位基因/基因型携带者发生发作性睡病伴猝倒症的风险评估也可能成为现实。应在墨西哥人和其他西班牙裔患者中分析更大的样本以证实这些结果。
