摘要：

目的 观察重症肌无力患者白细胞介素-2 受体β亚单位（IL-2Rβ）基因rs228942、rs228941和rs743777 位点多态性，探讨其与重症肌无力易感性和严重程度的关联性。方法 采用SNPscan^TM 技术对480 例重症肌无力患者和487 例正常对照者IL-2Rβ基因rs228942、rs228941 和rs743777 位点进行基因分型，根据性别、发病年龄、抗乙酰胆碱受体（AChR）抗体、伴与不伴胸腺瘤、发病后2 年最严重临床分型和疾病最严重时Oosterhuis 评分将重症肌无力患者分为不同亚组，比较重症肌无力组与对照组、重症肌无力各亚组与对照组、重症肌无力各亚组间等位基因频率，并在共显性、加性和过显性遗传模型下比较基因型频率。结果 重症肌无力组IL-2Rβ基因rs228942 位点T 等位基因频率高于对照组（χ² = 4.692，P = 0.030，OR = 1.242，95%CI：1.021 ~ 1.511），基因型频率在加性遗传模型下差异有统计学意义（P = 0.036，OR = 1.230，95%CI：1.010 ~ 1.480）。重症肌无力组rs228942 和rs228941 位点组成的单倍域中GT单倍型频率高于对照组（χ² = 4.286，P = 0.038），GG 单倍型频率低于对照组（χ² = 5.333，P = 0.021）。rs228942 位点T 等位基因频率在15 ~ 50 岁亚组（χ² = 7.474，P = 0.006，OR = 1.380，95%CI：1.095 ~ 1.740）、不伴胸腺瘤亚组（χ² = 4.700，P = 0.030，OR = 1.261，95%CI：1.022 ~ 1.555）和发病后2 年最严重全身型重症肌无力亚组（χ² = 4.715，P = 0.030，OR = 1.287，95%CI：1.025 ~ 1.617）均高于对照组。多因素前进法Logistic 回归分析显示，发病年龄15 ~ 50 岁（OR = 9.026，95%CI：4.225 ~ 19.284；P = 0.000）和> 50 岁（OR = 9.956，95%CI：4.475 ~ 22.149；P = 0.000）、伴胸腺瘤（OR = 2.578，95%CI：1.393 ~ 4.773；P = 0.003）和抗AChR 抗体阳性（OR = 1.946，95%CI：1.179 ~ 3.214；P = 0.009）均是发病后2 年最严重临床分型的独立危险因素，而基因型不是独立危险因素。结论 IL-2Rβ基因rs228942 位点可能与重症肌无力易感性相关，但未发现与其严重程度相关；亦未发现rs228941 和rs743777 位点多态性与重症肌无力易感性和严重程度相关。

关键词: 白细胞介素类, 多态现象, 遗传, 重症肌无力, 基因, 等位基因, 回归分析

Abstract:

Objective To explore the association of three single nucleotide polymorphisms (SNPs; rs228942, rs228941 and rs743777) in interleukin-2 receptor β subunit (IL-2Rβ) gene with the susceptibility and severity of myasthenia gravis (MG). Methods There were 480 MG patients and 487 normal controls enrolled in this study, and their three SNPs (rs228942, rs228941 and rs743777) in IL - 2Rβ gene were evaluated through SNPscan^TM technique. Subgroups were classified by gender, age of onset, anti - acetylcholine receptor antibodies (AChR-Ab), thymus status, maximal involvement after 2 years of onset and maximal Oosterhuis score. Frequencies of alleles and genotypes were compared between MG group and control group, between MG subgroups and control group, and among subgroups under codominant, log - additive and overdominant models. Results The frequency of T allele of rs228942 in MG group was significantly higher than that in control group (χ² = 4.692, P = 0.030, OR = 1.242, 95%CI: 1.021-1.511). There was significant difference in the frequency of rs228942 genotype between MG group and control group under log-additive model (P = 0.036, OR = 1.230, 95%CI: 1.010-1.480). The rs278942/rs228941 GT haplotype frequency in MG group was higher than that in control group (χ² = 4.286, P = 0.038), while GG haplotype frequency in MG group was lower than that in control group ( χ² = 5.333, P = 0.021). The frequencies of T allele of rs228942 was significantly higher in MG subgroups of onset age 15-50 years (χ² = 7.474, P = 0.006, OR = 1.380, 95%CI: 1.095-1.740), non-thymoma (χ² = 4.700, P = 0.030, OR = 1.261, 95%CI: 1.022-1.555) and maximal generalized involvement ( χ² = 4.715, P = 0.030, OR = 1.287, 95% CI:1.025-1.617) than those in control group. Multivariate forward Logistic regression analysis found that onset age 15-50 years (OR = 9.026, 95%CI: 4.225-19.284; P = 0.000), onset age > 50 years (OR = 9.956, 95%CI:4.475-22.149; P = 0.000), thymoma (OR = 2.578, 95%CI: 1.393-4.773; P = 0.003) and positive AChR-Ab (OR = 1.946, 95%CI: 1.179-3.214; P = 0.009) were the independent risk factors for maximal involvement, while genotypes were not. Conclusions The rs228942 polymorphisms of IL-2Rβ gene may be associated with the susceptibility of MG, but not with the severity of MG. The rs228941 and rs743777 polymorphisms were not found to be associated with the susceptibility and severity of MG.

Key words: Interleukins, Polymorphism, genetic, Myasthenia gravis, Genes, Alleles, Regression analysis