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

• Published in: Genetic epidemiology Vol. 20; no. 2; pp. 271 - 283
• Main Authors: Bitti, P.P., Murgia, B.S., Ticca, A., Ferrai, R., Musu, L., Piras, M.L., Puledda, E., Campo, S., Durando, S., Montomoli, C., Clayton, D.G., Mander, A.P., Bernardinelli, L.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 01.02.2001; Wiley-Liss
• Subjects: Alleles; Biological and medical sciences; Case-Control Studies; case-control study; conditional independence; EM algorithm; Ethnic Groups - genetics; Fundamental and applied biological sciences. Psychology; Gene Frequency; Genetics of eukaryotes. Biological and molecular evolution; haplotype analysis; haplotype analysis, conditional independence, log‐linear modeling; Haplotypes; HLA-A Antigens - genetics; HLA-B Antigens - genetics; HLA-B18 Antigen; HLA-DR3 Antigen - genetics; Human; Humans; Italy - epidemiology; log-linear modeling; malaria; Malaria - epidemiology; Multiple Sclerosis - ethnology; Multiple Sclerosis - genetics; Multiple Sclerosis - immunology; Population genetics, reproduction patterns; Prevalence; Research Design; Statistics as Topic; unknown gametic phase; Sardinia; Italy; Europe; Protozoal disease; Nervous system diseases; Multiple sclerosis; Statistical analysis; Malaria; Major histocompatibility system; Parasitosis; Case control study; Linkage equilibrium; Linear model; Inflammatory disease; Infection; Gene frequency; Epidemiologic genetics; Central nervous system disease; Haplotype
• ISSN: 0741-0395; 1098-2272
• DOI: 10.1002/1098-2272(200102)20:2<271::AID-GEPI9>3.0.CO;2-L

Association and linkage studies have established the importance of the major histocompatibility complex (MHC) in the susceptibility for multiple sclerosis (MS). We carried out a case‐control study to investigate the ancestral haplotype A30B18DR3 and MS in the Nuoro population of Sardinia, which is isolated and genetically distinct from other populations in the Mediterranean basin and characterized by genetic homogeneity, high level of inbreeding, low migration, high prevalence of MS, high frequency of the relevant haplotype, and high past malaria prevalence. Cases and controls were serologically 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 hypothesis comparing different models via a likelihood ratio test. We overcame the complication due to unknown gametic phase using expectation‐maximization (EM) 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 possible stratification in cases and controls; (2) DR3 allele was conditional independent on disease status, given A30B18 haplotype; (3) there was a tendency 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). Genet. Epidemiol. 20:271–283, 2001. © 2001 Wiley‐Liss, Inc.