The genotypic distribution of shared‐epitope DRB1 alleles suggests a recessive mode of inheritance of the rheumatoid arthritis disease‐susceptibility gene

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).