Association between the ancestral haplotype HLA A30B18DR3 and multiple sclerosis in Central Sardinia

Association and linkage studies have established the importance of the majo r histocompatibility complex (MHC) in the susceptibility for multiple scler osis (MS). We carried out a case-control study to investigate the ancestral haplotype A30B18DR3 and MS in the Nuoro population of Sardinia, which is i solated and genetically distinct from other populations in the Mediterranea n basin and characterized by genetic homogeneity, high level of inbreeding, low migration, high prevalence of MS, high frequency of the relevant haplo type, and high past malaria prevalence. Cases and controls were serological ly typed for the currently recognized HLA-A, B, and DR antigens. We used a log-linear approach to fit a wide class of models. We tested our hy pothesi s comparing different models via a likelihood ratio test. We overcame the c omplication due to unknown gametic phase using expectation-maximization GEM ) algorithm as the estimation method. We estimated confidence intervals for odds ratio by using a profile likelihood approach. We found that: (1) the ancestral haplotype A30B18DR3 was associated to MS after allowing for a pos sible stratification in cases and controls; (2) DR3 allele was conditional independent on disease status, given A30B18 haplotype; (3) there was a tend ency for ORs for the high-risk haplotypes to;be higher in the high malaria strata; however, this indication did not achieve statistical significance ( P = 0.11). (C) 2001 Wiley-Liss, Inc.