Goris An, Pauwels Ine, Gustavsen Marte W, van Son Brechtje, Hilven Kelly, Bos Steffan D, Celius Elisabeth Gulowsen, Berg-Hansen Pål, Aarseth Jan, Myhr Kjell-Morten, D'Alfonso Sandra, Barizzone Nadia, Leone Maurizio A, Martinelli Boneschi Filippo, Sorosina Melissa, Liberatore Giuseppe, Kockum Ingrid, Olsson Tomas, Hillert Jan, Alfredsson Lars, Bedri Sahl Khalid, Hemmer Bernhard, Buck Dorothea, Berthele Achim, Knier Benjamin, Biberacher Viola, van Pesch Vincent, Sindic Christian, Bang Oturai Annette, Søndergaard Helle Bach, Sellebjerg Finn, Jensen Poul Erik H, Comabella Manuel, Montalban Xavier, Pérez-Boza Jennifer, Malhotra Sunny, Lechner-Scott Jeannette, Broadley Simon, Slee Mark, Taylor Bruce, Kermode Allan G, Gourraud Pierre-Antoine, Sawcer Stephen J, Andreassen Bettina Kullle, Dubois Bénédicte, Harbo Hanne F
1 Laboratory for Neuroimmunology, Section of Experimental Neurology, Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium
1 Laboratory for Neuroimmunology, Section of Experimental Neurology, Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium.
Brain. 2015 Mar;138(Pt 3):632-43. doi: 10.1093/brain/awu405. Epub 2015 Jan 22.
Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640A-rs6457617G haplotype, correlated with HLA-DRB11501, and rs34083746G, correlated with HLA-DQA10301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640A-rs6457617G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.
多发性硬化症的免疫学特征包括中枢神经系统中抗体的产生，表现为寡克隆带的出现和/或免疫球蛋白G指数升高（脑脊液中免疫球蛋白G水平与血清中免疫球蛋白G水平的比值）。然而，多发性硬化症患者中寡克隆带阳性和阴性患者之间的潜在差异以及免疫球蛋白G指数变化的原因尚不清楚。为了确定影响多发性硬化症患者脑脊液中抗体水平变化的遗传因素，我们对来自9个国家的患者进行了全基因组关联筛查，针对两个特征：有无寡克隆带（n = 3026）和免疫球蛋白G指数水平（n = 938），随后在另外3891名患者中进行了重复验证。我们重复了先前在主要组织相容性复合体区域中关于寡克隆带状态的关联信号，即与HLA-DRB11501相关的rs9271640A-rs6457617G单倍型，以及与HLA-DQA10301相关的rs34083746G（比较两个单倍型的P值 = 8.88×10⁻¹⁶）。此外，我们在ELAC1/SMAD4基因附近发现了一个与寡克隆带状态相关的新关联信号rs9807334（P = 8.45×10⁻⁷）。先前报道的免疫球蛋白重链基因座与免疫球蛋白G指数的关联在该数据集中达到了很强的关联证据（P = 3.79×10⁻³⁷）。我们在主要组织相容性复合体区域中发现了两个与免疫球蛋白G指数相关的新关联：与寡克隆带状态共享的rs9271640A-rs6457617G单倍型（P = 1.59×10⁻²²），以及rs6457617G的额外独立效应（P = 3.68×10⁻⁶）。本研究中鉴定出的变体在寡克隆带阳性几率上造成了高达2倍的差异，在免疫球蛋白G指数变化中占7.75%。这两个特征都与疾病的临床特征相关，如女性性别、发病年龄和严重程度。这是迄今为止针对多发性硬化症患者脑脊液中抗体水平的遗传影响进行研究的最大样本量，共纳入6950名患者。我们证实遗传因素是这些抗体水平的基础，并确定主要组织相容性复合体和免疫球蛋白重链区域为主要决定因素。
