Investigating the HLA component in rheumatoid arthritis: an additive (dominant) mode of inheritance is rejected, a recessive mode is preferred.
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.
Rigby
A S
AS
Arthritis and Rheumatism Council Epidemiology Research Unit, University of Manchester Medical School, Great Britain.
Silman
A J
AJ
Voelm
L
L
Gregory
J C
JC
Ollier
W E
WE
Khan
M A
MA
Nepom
G T
GT
Thomson
G
G
D000328:Adult; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D004812:Epidemiologic Methods; D000939:Epitopes / Q000235:genetics; D005799:Genes, Dominant; D005808:Genes, Recessive; D008040:Genetic Linkage; D006684:HLA-DR Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008433:Mathematics; D008875:Middle Aged; D008957:Models, Genetic; D010375:Pedigree; D011897:Random Allocation
D000939:Epitopes; D006684:HLA-DR Antigens