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

Abstract

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.

Evidence for additional genetic risk indicators of relapse-onset MS within the HLA region

“…As other alleles of this cluster were also associated with relapse-onset MS, our data suggest that C1_3_2*354 might be a marker of this whole haplotype. 1,[31][32][33][34] This study showed that allele C1_3_2*354, encoded within an ancestral haplotype linked to HLA-DR3, was significantly increased among patients with relapse-onset MS as compared with control subjects. 17,25 Because HLA-DR2 has been associated with a cluster (c2) of alleles of microsatellites encoded within the HLA-C to DR region, we tested and confirmed that this cluster is associated with a twofold increased risk for developing relapseonset MS.…”

Evidence for additional genetic risk indicators of relapse-onset MS within the HLA region

“…As other alleles of this cluster were also associated with relapse-onset MS, our data suggest that C1_3_2*354 might be a marker of this whole haplotype. 1,[31][32][33][34] This study showed that allele C1_3_2*354, encoded within an ancestral haplotype linked to HLA-DR3, was significantly increased among patients with relapse-onset MS as compared with control subjects. 17,25 Because HLA-DR2 has been associated with a cluster (c2) of alleles of microsatellites encoded within the HLA-C to DR region, we tested and confirmed that this cluster is associated with a twofold increased risk for developing relapseonset MS.…”

Impact of the Human Leukocyte Antigen Complex on Idiopathic Pulmonary Fibrosis Development and Progression in the Sardinian Population

“…This extended haplotype, commonly found in Sardinia, has been previously associated with autoimmune diseases such as multiple sclerosis, autoimmune type I hepatitis, severe COVID-19, insulin-dependent diabetes mellitus, and celiac disease [ 23 , 26 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. Specifically, this haplotype exhibits the highest frequency (about 14%) in Sardinia and represents the strongest linkage disequilibrium observed globally [ 53 ].…”

High‐resolution analysis of the HLA‐A, ‐B, ‐C and ‐DRB1 alleles and national and regional haplotype frequencies based on 120 926 volunteers from the Italian Bone Marrow Donor Registry

“…This phenomenon is associated with the insular nature of Sardinia, a typical cause of geographic barriers to gene flow and local selective pressure. The most represented haplotype in Sardinia is A*30:02 ~ B*18:01 ~ C*05:01 ~ DRB1*03 .01, which is significantly associated with celiac disease and multiple sclerosis …”

Evidence for additional genetic risk indicators of relapse-onset MS within the HLA region

“…As other alleles of this cluster were also associated with relapse-onset MS, our data suggest that C1_3_2*354 might be a marker of this whole haplotype. 1,[31][32][33][34] This study showed that allele C1_3_2*354, encoded within an ancestral haplotype linked to HLA-DR3, was significantly increased among patients with relapse-onset MS as compared with control subjects. 17,25 Because HLA-DR2 has been associated with a cluster (c2) of alleles of microsatellites encoded within the HLA-C to DR region, we tested and confirmed that this cluster is associated with a twofold increased risk for developing relapseonset MS.…”

Impact of the Human Leukocyte Antigen Complex on Idiopathic Pulmonary Fibrosis Development and Progression in the Sardinian Population

“…This extended haplotype, commonly found in Sardinia, has been previously associated with autoimmune diseases such as multiple sclerosis, autoimmune type I hepatitis, severe COVID-19, insulin-dependent diabetes mellitus, and celiac disease [ 23 , 26 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. Specifically, this haplotype exhibits the highest frequency (about 14%) in Sardinia and represents the strongest linkage disequilibrium observed globally [ 53 ].…”

High‐resolution analysis of the HLA‐A, ‐B, ‐C and ‐DRB1 alleles and national and regional haplotype frequencies based on 120 926 volunteers from the Italian Bone Marrow Donor Registry

“…This phenomenon is associated with the insular nature of Sardinia, a typical cause of geographic barriers to gene flow and local selective pressure. The most represented haplotype in Sardinia is A*30:02 ~ B*18:01 ~ C*05:01 ~ DRB1*03 .01, which is significantly associated with celiac disease and multiple sclerosis …”

Evidence for additional genetic risk indicators of relapse-onset MS within the HLA region

“…As other alleles of this cluster were also associated with relapse-onset MS, our data suggest that C1_3_2*354 might be a marker of this whole haplotype. 1,[31][32][33][34] This study showed that allele C1_3_2*354, encoded within an ancestral haplotype linked to HLA-DR3, was significantly increased among patients with relapse-onset MS as compared with control subjects. 17,25 Because HLA-DR2 has been associated with a cluster (c2) of alleles of microsatellites encoded within the HLA-C to DR region, we tested and confirmed that this cluster is associated with a twofold increased risk for developing relapseonset MS.…”

Impact of the Human Leukocyte Antigen Complex on Idiopathic Pulmonary Fibrosis Development and Progression in the Sardinian Population

“…This extended haplotype, commonly found in Sardinia, has been previously associated with autoimmune diseases such as multiple sclerosis, autoimmune type I hepatitis, severe COVID-19, insulin-dependent diabetes mellitus, and celiac disease [ 23 , 26 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. Specifically, this haplotype exhibits the highest frequency (about 14%) in Sardinia and represents the strongest linkage disequilibrium observed globally [ 53 ].…”

High‐resolution analysis of the HLA‐A, ‐B, ‐C and ‐DRB1 alleles and national and regional haplotype frequencies based on 120 926 volunteers from the Italian Bone Marrow Donor Registry

“…This phenomenon is associated with the insular nature of Sardinia, a typical cause of geographic barriers to gene flow and local selective pressure. The most represented haplotype in Sardinia is A*30:02 ~ B*18:01 ~ C*05:01 ~ DRB1*03 .01, which is significantly associated with celiac disease and multiple sclerosis …”