G.P.63 High-resolution analysis of HLA-DRB1 alleles and diplotypes in an Australian inclusion body myositis cohort

Abstract

In Caucasians, susceptibility to sporadic inclusion body myositis (s-IBM) is associated with the HLA-DR3 serotype and the HLA-DRB1∗0301 allele which encodes it, and with the extended 8.1 MHC ancestral haplotype. Most previous HLA studies in s-IBM have used serological typing or low-resolution (2-digit) genotyping to identify disease-associated alleles, and the contribution of alleles other than HLA-DRB1∗0301 and of the complementary in trans allele at the HLA-DRB1 locus has received little attention. In the present study we performed high-resolution (4-digit) HLA-DRB1 genotyping in an Australian cohort of 105 s-IBM patients and 189 controls from the Busselton Population Study and analysed risk-associated alleles and effects on age-at-onset (AAO) of the disease. Case–control logistic regression analysis showed that, apart from the strongly associated HLA-DRB1∗0301 allele (OR 13.6), HLA-DRB1∗0101 (OR 3.65) and HLA-DRB1∗1301 (OR 3.31) are independent risk alleles. A number of other alleles, HLA-DRB1∗0401, ∗0404, ∗0701, ∗0901, ∗1101 and ∗1501 were reduced in frequency in s-IBM cases and may be protective. We evaluated the influence of allele combinations on disease risk and found that the strongest estimated risk is with the HLA-DRB1∗0301/∗0101 diplotype, while other allele combinations have diminishing risk effects. HLA-DRB1∗0301 was associated with an AAO 4.3 years earlier than other alleles and DRB1∗1301 with an AAO 4.5 years later, despite it being a risk factor. The findings indicate that the influence of HLA-DRB1 in s-IBM is complex, influencing both disease risk and AAO, and that allelic interactions at the HLA-DRB1 locus contribute to disease susceptibility.