Identical MHC Markers in Non-Jewish Iranian and Ashkenazi Jewish Patients with Pemphigus Vulgaris: Possible Common Central Asian Ancestral Origin

Abstract

ABSTRACT: Previous studies showed that almost all Ashkenazi Jewish patients with pemphigus vulgaris carried the extended haplotype [HLA-B38, SC21, DRB1∗0402, DQB1∗0302] or [HLA-B35, SC31, DRB1∗0402, DQB1∗0302] or class II fragments of them. Non-Jewish patients carried [HLA-B55, SB45, DRB1∗1401, DQB1∗0503] or its class II fragments. In the present study of 20 Iranian patients with pemphigus vulgaris, 17 were found to carry DRB1∗0402, DQB1∗0302 haplotypes, also found among normal Iranian haplotypes and the same as that of the Jews. These findings suggest that the pemphigus MHC susceptibility gene among Iranians derived from the same ancestor as that in the Ashkenazim. The ancient Jews were under Persian domination from 500 B.C. until 300 B.C. and in the 8th century A.D., a Tataric people living in the kingdom of Khazar on the Western shore of the Caspian Sea and the Northern shore of the Black Sea, near Persia, converted to Judaism, providing possible opportunities for gene mixing in two populations that are distinct and separate today.

Introduction

Pemphigus vulgaris (PV) is a blistering disease affecting skin and mucous membranes [1]. Patients have a circulating IgG antibody to a 130 kD protein of the cadherin superfamily of adhesion molecules designated desmoglein III 2, 3. The deposition in vivo of this antibody in the intercellular space of the skin or mucous membranes is a hallmark of the disease 4, 5. The antibody is pathogenetic, since newborns of mothers with PV have antibody in their serum and have transient blisters [6]. Moreover, blisters identical to those in PV develop in newborn mice injected with antibody from patients [7]. The disease has been reported to have a particularly high incidence among Jews 1, 4. Nonetheless, the disease is not limited to the Jewish population but affects other ethnic groups and populations worldwide.

It has been known for some time that certain HLA-Class II alleles 8, 9, 10, 11, 12, particularly HLA-DR4 [8], HLA-DR6 [11] and DQB1.3 (DQB1∗0503) [10], are increased in frequency in PV patients compared with control populations. We found that almost every Ashkenazi Jewish patient with PV carried the extended haplotype [HLA-B38, SC21, DR4,DQ8], [HLA-B35, SC31, DR4, DQ8], or the DR4, DQ8 portion of the whole haplotypes with other class I alleles or complotypes [13]. Almost all patients with DR4, DQ8 (DQB1∗0302) were heterozygotes and the distribution of this haplotype among patients was consistent with dominant expression of a class II region susceptibility gene. Non-Jewish patients sometimes had the same markers but more often had [HLA-B55, SB45,DR6, DQ5] or its class II fragments [14]. There were thus two distinct susceptibility marker haplotypes for PV. The DR4, DQ8-marked susceptibility gene probably arose in an ancestor of modern Ashkenazi Jews and spread to other populations. The HLA-DR6, DQ5 haplotype marks the second mutation in primarily southern European populations. Using a sensitive immunoblotting technique, low levels of the PV antibody could be demonstrated in about 50% of immediate relatives of PV patients [15]. On formal linkage analysis, it was shown that the presence of antibody was highly significantly linked to the previously identified susceptibility MHC haplotypes and was expressed as a dominant trait.

In the present study, we have determined class II alleles and haplotypes in Iranian patients with PV. We hoped to determine whether the disease susceptibility genes in the Iranian patients were similar to those of either the Ashkenazi Jewish patients or the non-Jewish, primarily southern European patients, or were unrelated.