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HLA haplotype sharing in rheumatoid arthritis sibships: Risk estimates subdivided by proband genotype
Author(s) -
Rigby Alan S.,
MacGregor Alex J.,
Thomson Glenys
Publication year - 1998
Publication title -
genetic epidemiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.301
H-Index - 98
eISSN - 1098-2272
pISSN - 0741-0395
DOI - 10.1002/(sici)1098-2272(1998)15:4<403::aid-gepi6>3.0.co;2-2
Subject(s) - haplotype , proband , genotype , sibling , genetics , rheumatoid arthritis , medicine , heterozygote advantage , biology , mutation , gene , psychology , developmental psychology
There is a well‐known association between rheumatoid arthritis (RA) and HLA‐DR4. Recent research has indicated that both DR4 haplotypes are important in disease predisposition (favoring a recessive mode of inheritance). Others have suggested that certain combinations of genotypes, in particular Dw4/Dw14 heterozygotes, may be more important than others. We examined the mode of inheritance of RA using data from the Arthritis and Rheumatism Council's national repository of family material [Worthington et al. (1994) Br J Rheumatol 33:970–976]. There were 85 affected sibships consisting of 77 sib pairs, 6 trios, 1 quintuplet, and 1 sextuplet. The affected sibs shared two, one, and zero parental HLA haplotypes in a ratio of 0.42:0.43:0.15, which was significantly different from random expectations ( P = 0.00009). Risk estimates for RA to sibs were calculated based on an overall sibling recurrence risk of 3.9%. Risks for those sharing two, one, and zero parental HLA haplotypes were 6.5% [95% confidence interval (CI) = 5.1–7.9%], 3.3% (95% CI = 2.6–4.0%), and 2.5% (95% CI = 1.5–3.5%), respectively. We also examined the risk of RA based on the DRβ1 genotype status of sib and proband. After excluding genotypic combinations with small numbers, the highest genotype‐specific risks were seen for sibs sharing two haplotypes with either a DRβ1*0401/DRβ1*0404 (12.5%, 95% CI = 6.9–15.2%) or a DRβ1*0401/DRβ1*0408 (11.1%, 95% CI = 4.5–15.1%) proband. An independent assessment based on the AGFAP methodology confirmed the increase in risk for these genotypes, in particular for DRβ1*0401/DRβ1*0408. The excess being due to *0401/*0408 rather than to *0401/*0404 may explain why the Dw4/Dw14 effect is not always observed. Genet. Epidemiol. 15:403–418,1998. © 1998 Wiley‐Liss, Inc.