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

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Abstract
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 < 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 < 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.