Ramagopalan Sreeram V, Byrnes Jake K, Dyment David A, Guimond Colleen, Handunnetthi Lahiru, Disanto Giulio, Yee Irene M, Ebers George C, Sadovnick A Dessa
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
J Hum Genet. 2009 Sep;54(9):547-9. doi: 10.1038/jhg.2009.69. Epub 2009 Jul 24.
Multiple sclerosis (MS) is a complex neurological trait. Allelic variation in the MHC class II region exerts the single strongest effect on MS genetic risk. The clinical onset of the disease is extremely variable, and can range from the first to the ninth decade of life. Epidemiological studies have suggested a modest genetic component to the age of onset (AO) of MS. Previous studies have shown that HLA-DRB11501 may be associated with a younger AO. Here, we sought to uncover any effect of HLA-DRB11501 on the AO of MS in a large Canadian cohort. A total of 1816 MS patients were genotyped for HLA-DRB1. Patients carrying HLA-DRB11501 were shown to have a small, but significantly lower, AO than patients without the allele (P=0.03). HLA-DRB11501 was also shown to reduce the mean AO in both progressive and relapsing forms of the disease. An investigation of parent-of-origin effects indicated that the lower AO for HLA-DRB11501 patients arises from maternally transmitted HLA-DRB11501 haplotypes (maternal HLA-DRB11501 mean AO=28.4 years, paternal=30.3 years; P=0.009). HLA-DRB11501 exerts a modest, but significant effect on the AO of all forms of MS. Parent-of-origin effects at the MHC are further implicated in MS disease pathogenesis.
多发性硬化症（MS）是一种复杂的神经学特征。MHC II类区域的等位基因变异对MS遗传风险产生单一最强的影响。该疾病的临床发病极为多变，可发生于人生的第一个十年至第九个十年。流行病学研究表明，MS发病年龄（AO）存在适度的遗传因素。先前的研究表明，HLA - DRB11501可能与较年轻的AO相关。在此，我们试图在一个大型加拿大队列中揭示HLA - DRB11501对MS的AO的任何影响。总共对1816例MS患者进行了HLA - DRB1基因分型。携带HLA - DRB11501的患者与不携带该等位基因的患者相比，AO虽小但显著更低（P = 0.03）。HLA - DRB11501在疾病的进展型和复发型中均显示可降低平均AO。对亲本来源效应的研究表明，HLA - DRB11501患者较低的AO源于母系传递的HLA - DRB11501单倍型（母系HLA - DRB11501的平均AO = 28.4岁，父系 = 30.3岁；P = 0.009）。HLA - DRB11501对所有形式的MS的AO均产生适度但显著的影响。MHC处的亲本来源效应进一步涉及MS疾病的发病机制。
