Evans T I, Han J, Singh R, Moxley G
Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, VA 23249, USA.
Arthritis Rheum. 1995 Dec;38(12):1754-61. doi: 10.1002/art.1780381208.
To test whether the genotypic distribution of rheumatoid arthritis (RA)-associated DRB1 alleles suggests that the DRB1-associated disease-susceptibility gene has a recessive or additive (dominant) mode of inheritance.
Caucasian patients with RA and control subjects were recruited from a faculty outpatient practice. DRB1 typing was done by several DNA-based techniques: polymerase chain reaction (PCR), followed by dot-blot hybridization with sequence-specific oligonucleotides, conventional and PCR-based restriction fragment length polymorphisms (RFLPs), and a multiplex amplification-refractory mutation RFLP system. The genotypic distribution of shared-epitope DRB1 alleles was analyzed by antigen genotype frequency among patients. The analytical method postulates a linkage-disequilibrium model with a disease locus close to a marker locus and a marker allele in linkage disequilibrium with the disease-susceptibility allele. In this instance, the marker allele was defined alternatively by any DR4-group allele, by any DR4-group or DR1-group allele, by any DR4-group shared-epitope allele, by any DR4-group shared-epitope allele plus DRB1*0101, or by any shared-epitope DRB1 allele. Observed numbers were compared with those predicted for recessive mode or additive (dominant) mode of inheritance of the DRB1-associated RA disease-susceptibility gene.
The genotypic distribution of shared-epitope DRB1 alleles (DRB1*0401, *0404, *0405, *0408, *0101, *0102, or 1001) fit that predicted for a recessive mode of inheritance and was significantly different from that predicted for an additive (dominant) mode. When the analysis was restricted to shared-epitope DR4 alleles alone (DRB10401, *0404, *0405, or *0408), the observed genotype numbers fit the recessive mode best. When DR1-group alleles were added to DR4-group alleles, or alternatively, when the major shared-epitope DR1 allele (0101) was added to DR4-group shared-epitope alleles, there was a less significant deviation from the additive mode of inheritance. The reason for this was derived by comparison of observed genotype frequencies to those expected under Hardy-Weinberg equilibrium; there was a deficit of persons with DRB10401, *0101 and an excess of *0101,X.
The genotypic distribution of shared-epitope DRB1 marker alleles suggests that the mode of inheritance of the DRB1-associated disease susceptibility gene must be recessive and not additive (dominant).
检测类风湿关节炎（RA）相关DRB1等位基因的基因型分布是否提示与DRB1相关的疾病易感性基因具有隐性或加性（显性）遗传模式。
从医院门诊招募白种人RA患者和对照受试者。采用多种基于DNA的技术进行DRB1分型：聚合酶链反应（PCR），随后用序列特异性寡核苷酸进行点杂交、传统的和基于PCR的限制性片段长度多态性（RFLP），以及多重扩增不应性突变RFLP系统。通过患者中的抗原基因型频率分析共享表位DRB1等位基因的基因型分布。该分析方法假定一个连锁不平衡模型，其中疾病位点靠近标记位点，且标记等位基因与疾病易感性等位基因处于连锁不平衡状态。在这种情况下，标记等位基因可交替定义为任何DR4组等位基因、任何DR4组或DR1组等位基因、任何DR4组共享表位等位基因、任何DR4组共享表位等位基因加DRB1*0101，或任何共享表位DRB1等位基因。将观察到的数量与DRB1相关RA疾病易感性基因隐性模式或加性（显性）模式遗传所预测的数量进行比较。
共享表位DRB1等位基因（DRB1*0401、*0404、*0405、*0408、0101、0102或1001）的基因型分布符合隐性遗传模式的预测，且与加性（显性）模式的预测有显著差异。当分析仅限于共享表位DR4等位基因（DRB10401、*0404、0405或0408）时，观察到的基因型数量最符合隐性模式。当将DR1组等位基因添加到DR4组等位基因中，或者将主要共享表位DR1等位基因（0101）添加到DR4组共享表位等位基因中时，与加性遗传模式的偏差较小。其原因是通过将观察到的基因型频率与哈迪-温伯格平衡预期的频率进行比较得出的；DRB10401、0101的个体数量不足，而0101,X的个体数量过多。
共享表位DRB1标记等位基因的基因型分布提示，与DRB1相关的疾病易感性基因的遗传模式必定是隐性的，而非加性（显性）的。
