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 ar thritis (RA)-associated DRB1 alleles suggests that the DRB1-associated disease-susceptibility gene has a recessive or additive (dominant) mo de of inheritance. Methods. Caucasian patients with RA and control sub jects were recruited from a faculty outpatient practice. DRB1 typing w as done by several DNA-based techniques: polymerase chain reaction (PC R), followed by dot-blot hybridization with sequence-specific oligonuc leotides, conventional and PCR-based restriction fragment length polym orphisms (RFLPs), and a multiplex amplification-refractory mutation RF LP system. The genotypic distribution of shared-epitope DRB1 alleles w as analyzed by antigen genotype frequency among patients. The analytic al method postulates a linkage-disequilibrium model with a disease loc us close to a marker locus and a marker allele in linkage disequilibri um with the disease-susceptibility allele. In this instance, the marke r 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 DRB10101, or by any shared- epitope DRB1 allele. Observed numbers were compared with those predict ed for recessive mode or additive (dominant) mode of inheritance of th e DRB1-associated RA disease-susceptibility gene. Results. The genotyp ic distribution of shared-epitope DRB1 alleles (DRB10401, *0403, *040 5, 0408, *0101, *0102, or *1001) fit that predicted for a recessive m ode 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-gr oup alleles were added to DR4-group alleles, or alternatively, when th e major shared-epitope DR1 allele (0101) was added to DR4 group share d-epitope alleles, there was a less significant deviation from the add itive mode of inheritance. The reason for this was derived by comparis on of observed genotype frequencies to those expected under Hardy-Wein berg equilibrium; there was a deficit of persons with DRB10401, *0101 and an excess of 0101,X. Conclusion. The genotypic distribution of s hared-epitope DRB1 marker alleles suggests that the mode of inheritanc e of the DRB1-associated disease susceptibility gene must be recessive and not additive (dominant).