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

A. S. Rigby, A. J. Silman, L. Voelm, J. C. Gregory, W. E R Ollier, M. A. Khan, G. T. Nepom, G. Thomson

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    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.
    Original languageEnglish
    Pages (from-to)153-175
    Number of pages22
    JournalGenetic Epidemiology
    Issue number3
    Publication statusPublished - 1991




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