Karni A, Kohn Y, Safirman C, Abramsky O, Barcellos L, Oksenberg J R, Kahana E, Karussis D, Chapman J, Brautbar C
Department of Neurology, Hadassah University Hospital, Hebrew University Hadassah Medical School, Jerusalem, Israel.
Mult Scler. 1999 Dec;5(6):410-5. doi: 10.1177/135245859900500i607.
A strong association exists between multiple sclerosis (MS) and the DRB11501 haplotype, in most populations. Linkage of Multiple Sclerosis (MS) with the MHC or HLA region on chromosome 6p21 has previously been observed in DRB11501 positive MS families. A group of 13 Israeli multiplex MS families with a very low frequency of DRB11501 haplotype were examined in this study. Association and a linkage test were performed in order to identify a non-DRB11501 effect of HLA on susceptibility for MS. MS multiplex families and healthy controls were molecularly typed for six highly polymorphic markers located within the MHC region: DRB1, DQA1 and DQB1, BAT-2, MIB and D6S248. Data analyses included: (a) an association study comparing the patient group with both healthy relative, and healthy control groups (b) a transmission test for linkage disequilibrium (TDT) of the MS-associated alleles in the multiplex families, and (c) multipoint non-parametric linkage (NPL) and parametric LOD score analyses using the GENEHUNTER program. The DRB11303 allele was significantly more frequent among the MS patients. There was a trend towards transmission disequilibrium of DRB11303, but was not statistically significant. Allele sharing and LOD score analyses revealed no evidence for linkage. The high frequency of DRB11303 observed in our family patients provides evidence to support the association with this allele that previously described in sporadic non-Ashkenazi MS patients. Thus, DRB11303 may serve as genetic risk factor for MS. Our study exemplifies the genetic heterogeneity in MS as there is a genetic effect of HLA on MS susceptibility in our low frequency DRB1*1501 patients.
在大多数人群中，多发性硬化症（MS）与DRB11501单倍型之间存在密切关联。先前在DRB11501阳性的MS家族中已观察到多发性硬化症（MS）与6号染色体p21上的MHC或HLA区域存在连锁关系。本研究对一组13个以色列MS多位点家族进行了检测，这些家族中DRB11501单倍型的频率非常低。为了确定HLA对MS易感性的非DRB11501效应，进行了关联分析和连锁测试。对MS多位点家族和健康对照进行了位于MHC区域内的六个高度多态性标记的分子分型：DRB1、DQA1和DQB1、BAT-2、MIB和D6S248。数据分析包括：（a）将患者组与健康亲属和健康对照组进行比较的关联研究；（b）对多位点家族中与MS相关等位基因的连锁不平衡进行传递测试（TDT）；（c）使用GENEHUNTER程序进行多点非参数连锁（NPL）和参数LOD评分分析。DRB11303等位基因在MS患者中显著更常见。DRB11303存在传递不平衡的趋势，但无统计学意义。等位基因共享和LOD评分分析未发现连锁证据。我们家族患者中观察到的DRB11303高频率为支持先前在散发性非阿什肯纳兹MS患者中描述的与该等位基因的关联提供了证据。因此，DRB11303可能是MS的遗传危险因素。我们的研究例证了MS中的遗传异质性，因为在我们低频DRB1*1501患者中存在HLA对MS易感性的遗传效应。
