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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Abstract
Objective. To test whether the genotypic distribution of rheumatoid arthritis (RA)–associated DRB1 alleles suggests that the DRB1-a ssociated 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-g roup allele, by any DR4-g roup or DR1-g roup allele, by any DR4-g roup shared-epitope allele, by any DRC-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-a ssociated RA disease-susceptibility gene. Results. 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 (DRB1*0401, *0404, *0405, or *0408), the observed genotype numbers fit the recessive mode best. When DR1-g roup alleles were added to DR4-g roup alleles, or alternatively, when the major shared-epitope DR1 allele (*0101) was added to DR4-g roup 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-a ssociated disease susceptibility gene must be recessive and not additive (dominant).