Multiple Sclerosis Center, Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
PLoS One. 2013 Apr 8;8(4):e59790. doi: 10.1371/journal.pone.0059790. Print 2013.
We performed a case-control study in 2,555 multiple sclerosis (MS) Sardinian patients and 1,365 healthy ethnically matched controls, analyzing the interactions between HLA-DRB1-DQB1 haplotypes and defining a rank of genotypes conferring a variable degree of risk to the disease. Four haplotypes were found to confer susceptibility (*13:03-*03:01 OR = 3.3, Pc 5.1 × 10(-5), *04:05-*03:01 OR = 2.1, Pc 9.7 × 10(-8), *15:01-*06:02 OR = 2.0, Pc = 9.1 × 10(-3), *03:01-*02:01 OR = 1.7 Pc = 7.9 × 10(-22)) and protection (*11, OR = 0.8, Pc = 2.7 × 10(-2), *16:01-*05:02 OR = 0.6, Pc = 4.8 × 10(-16), *14:01-4-*05:031 = OR = 0.5, Pc = 9.8 × 10(-4) and *15:02-*06:01 OR = 0.4, Pc = 5.1 × 10(-4)). The relative predispositional effect method confirms all the positively associated haplotypes and showed that also *08 and *04 haplotypes confers susceptibility, while the *11 was excluded as protective haplotype. Genotypic ORs highlighted two typologies of interaction between haplotypes: i) a neutral interaction, in which the global risk is coherent with the sum of the single haplotype risks; ii) a negative interaction, in which the genotypic OR observed is lower than the sum of the OR of the two haplotypes. The phylogenic tree of the MS-associated DRB1 alleles found in Sardinian patients revealed a cluster represented by *14:01, *04:05, *13∶03, *08:01 and *03:01 alleles. Sequence alignment analysis showed that amino acids near pocket P4 and pocket P9 differentiated protective from predisposing alleles under investigation. Furthermore, molecular dynamics simulation performed on alleles revealed that position 70 is crucial in binding of MBP 85-99 peptide. All together, these data suggest that propensity to MS observed in Sardinian population carried by the various HLA-DRB1-DQB1 molecules can be due to functional peculiarity in the antigen presentation mechanisms.
我们在 2555 名多发性硬化症（MS）撒丁岛患者和 1365 名具有相同种族匹配的健康对照中进行了病例对照研究，分析了 HLA-DRB1-DQB1 单倍型之间的相互作用，并定义了一系列赋予疾病不同程度风险的基因型等级。发现四个单倍型具有易感性（*13:03-*03:01 OR = 3.3，Pc 5.1 × 10(-5)，*04:05-*03:01 OR = 2.1，Pc 9.7 × 10(-8)，*15:01-*06:02 OR = 2.0，Pc = 9.1 × 10(-3)，*03:01-*02:01 OR = 1.7 Pc = 7.9 × 10(-22)) 和保护作用（*11，OR = 0.8，Pc = 2.7 × 10(-2)，*16:01-*05:02 OR = 0.6，Pc = 4.8 × 10(-16)，14:01-4-05:031 = OR = 0.5，Pc = 9.8 × 10(-4) 和 15:02-06:01 OR = 0.4，Pc = 5.1 × 10(-4)）。相对易感性效应方法证实了所有与正相关的单倍型，并表明08 和04 单倍型也具有易感性，而11 则被排除为保护性单倍型。基因型 OR 突出了单倍型之间两种类型的相互作用：i）中性相互作用，其中整体风险与单个单倍型风险的总和一致；ii）负相互作用，其中观察到的基因型 OR 低于两个单倍型的 OR 之和。在撒丁岛患者中发现的与 MS 相关的 DRB1 等位基因的系统发育树显示了一个由14:01、*04:05、*13∶03、08:01 和03:01 等位基因组成的聚类。序列比对分析表明，口袋 P4 和口袋 P9 附近的氨基酸区分了研究中具有易感性和易感性的等位基因。此外，对等位基因进行的分子动力学模拟表明，位置 70 在结合 MBP 85-99 肽中至关重要。所有这些数据表明，撒丁岛人群中观察到的 MS 倾向与各种 HLA-DRB1-DQB1 分子有关，这可能归因于抗原呈递机制中的功能特殊性。
