Investigating the HLA component in rheumatoid arthritis: an additive (dominant) mode of inheritance is rejected, a recessive mode is preferred

Genet Epidemiol. 1991;8(3):153-75. doi: 10.1002/gepi.1370080303.


We examined the mode of inheritance of rheumatoid arthritis (RA) and estimated the genetic contribution of the HLA-linked locus to the development of RA using data from 111 multiplex families (54 London, 57 Cleveland), and 43 randomly ascertained patients (Seattle). HLA-DR4 was present in 78 multiplex probands (70%); a further 16 probands who were negative for DR4 were positive for DR1. Both DR4 and DR1 were significantly in excess when compared to control population frequencies (P less than 0.001); an additional finding was an excess of DR7, although the numbers of probands with DR7 were small. Despite the well-established HLA association with RA, neither recessive nor additive (dominant) modes of inheritance, nor any intermediate models have been ruled out using affected sib-pair and antigen genotype frequency among patients (AGFAP) methods. However, in our study the AGFAP data for HLA-DR4 and DR1 were close to recessive expectations (P = ns) while an additive (dominant) mode of inheritance was rejected (P less than 0.001). The same results were obtained by an independent method which considered HLA-DR transmission from affected parents to their affected children. The affected sib-pair haplotype sharing method showed deviation from random expectations but did not allow discrimination between recessive and additive (dominant) modes. The effect of the HLA-linked locus on familiarity accounted for only a 1.61-fold increased risk to sibs over the population prevalence, compared to an observed value of 3.90. This indicated that there could be at least one other non-HLA locus predisposing to RA with a weight that is slightly greater than that of HLA.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Alleles
  • Arthritis, Rheumatoid / genetics*
  • Epidemiologic Methods
  • Epitopes / genetics
  • Genes, Dominant
  • Genes, Recessive*
  • Genetic Linkage
  • HLA-DR Antigens / genetics*
  • Haplotypes
  • Humans
  • Mathematics
  • Middle Aged
  • Models, Genetic
  • Pedigree
  • Random Allocation


  • Epitopes
  • HLA-DR Antigens