The genotypic distribution of shared-epitope DRB1 alleles suggests a recessive mode of inheritance of the rheumatoid arthritis disease-susceptibility gene
The genotypic distribution of shared-epitope DRB1 alleles suggests a recessive mode of inheritance of the rheumatoid arthritis disease-susceptibility gene
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DOI：
10.1002/art.1780381208
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发表时间：
1995-12-01
影响因子：
--
通讯作者：
Moxley, G
中科院分区：
文献类型：
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作者：
Evans, TI;Han, JF;Moxley, G
Objective.检测类风湿关节炎（RA）相关DRB 1等位基因的基因型分布是否提示DRB 1相关疾病易感基因具有隐性或加性（显性）遗传模式。白人RA患者和对照组受试者从一个教师门诊实践招募。DRB 1分型是通过几种基于DNA的技术完成的：聚合酶链反应（PCR），然后用序列特异性寡核苷酸进行斑点杂交，常规和基于PCR的限制性片段长度多态性（RFLP），以及多重扩增难治性突变RFLP系统。通过抗原基因型频率分析患者中共享表位DRB 1等位基因的基因型分布。该分析方法假设一个连锁不平衡模型，其中疾病基因座接近标记基因座，标记等位基因与疾病易感性等位基因连锁不平衡。在这种情况下，标记等位基因可选择地由任何DR 4组等位基因、由任何DR 4组或DR 1组等位基因、由任何DR 4组共享表位等位基因、由任何DR 4组共享表位等位基因加上DRB 1 *0101或由任何共享表位DRB 1等位基因定义。将观察到的数字与DRB 1相关RA疾病易感基因的隐性或加性（显性）遗传模式预测的数字进行比较。共享表位DRB 1等位基因的基因型分布（DRB 1 *0401、*0403、*0405、*0408、*0101、*0102或 *1001）符合隐性遗传模式的预测，与加性遗传模式的预测显著不同当分析仅限于共享表位DR 4等位基因时，（DRB 1 *0401、*0404、*0405或 *0408），观察到的基因型数目最适合隐性模式。当DR 1组等位基因被添加到DR 4组等位基因时，或者，当主要共享表位DR 1等位基因（*0101）加到DR 4组共享表位等位基因上时，与加性遗传模式的偏离不太显著。其原因是通过将观察到的基因型频率与Hardy-Weinberg平衡下预期的基因型频率进行比较得出的; DRB 1 *0401，*0101和 *0101，X过量的人存在赤字。共享表位DRB 1标记等位基因的基因型分布表明，DRB 1相关疾病易感基因的遗传方式必须是隐性的，而不是加性（显性）。
Objective. 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.Methods. 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.Results. The genotypic distribution of shared-epitope DRB1 alleles (DRB1*0401, *0403, *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 (DRB1*0401, *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 DRB1*0401, *0101 and an excess of *0101,X.Conclusion. 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).