Major histocompatibility complex haplotypes in Spanish immunoglobulin A deficiency patients: a comparative fine mapping microsatellite study

Abstract

The most consistent finding in Immunoglobulin A deficiency (IgAD) genetics is the presence of susceptibility factors located in the major histocompatibility complex (MHC). We have described the existence of at least two distinct susceptibility genes in the MHC present in different haplotypes. The aim of the present study was to locate with precision the susceptibility genes present in DR1- and DR7-positive haplotypes, taking advantage of their structural diversity, as opposed to the conserved nature of the DR3-extended susceptibility haplotype (DR3/B8), that hampers a more exhaustive scrutiny. A detailed analysis with 20 markers along the MHC in the 400 haplotypes present in 100 IgAD families, with special density at Class II locations, was performed to define the minimal shared susceptibility region present in all haplotypes carrying DR1 and, on the other hand, in all DR7-positive haplotypes. A comparison of the fine microsatellite allele structure of DR-extended haplotypes in the Spanish population with those described for Swedish and British families revealed no difference in DRB1*0101 and DRB1*0102 haplotypes between both populations. Our data suggest that the etiologic mutation present in DRB1*0101 and DRB1*0102 in North Europe (Sweden and UK) is missing in the Spanish DRB1*0101 haplotypes but is present in the DQB1/DRB1 region in DRB1*0102 haplotypes. The results obtained also indicated that the most likely susceptibility gene in the DR7 haplotypes is either DQA1 or DRB1.

Immunoglobulins and complement factor C4 in adult rhinosinusitis

“…C4 nulls and low subclass levels were not associated in our patient groups [9,42,43]. Total IgG4 deficiency has been found previously together with total C1, C4, C2 and C3 deficiencies, but we found it exclusively in patients without C4A nulls (data not shown) [42,44].…”

Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis

“…The location of this DIP is consistent with literature evidence of a complex series of deletions and insertions in the region between DRB1 and DQA1 26 and a null allele of the microsatellite D6S2664, which also lies in this region. 27 We could find no evidence that this DIP affected or biased the distribution of alleles in samples that were successfully genotyped for this SNP.…”

MSH5 is not a genetic predisposing factor for immunoglobulin A deficiency but marks the HLA-DRB1*0102 subgroup carrying susceptibility

“…Based on the observation that similar susceptibility effects in partially different haplotypes are due to the region shared among them, a previous study of our group [15] pointed out the region between G51152 and 8105224 microsatellites (the only shared region among all the haplotypes carrying DRB1*0102) as the one harboring the causal gene. However, with the inclusion of the MSH5 L85F polymorphism in the study, it is observed that only a subgroup of those DRB1*0102-carrying haplotypes increases the risk to IgAD and therefore that common region (between G51152 and 8105224) can be ruled out as the carrier of the susceptibility factor.…”

“…DRB1 was typed by polymerase chain reaction (PCR), followed by hybridization with allele-specific probes [3] and DRB1*1501 and HLA-B*08 by TaqMan technology using the highly correlated SNPs rs3135388 (DRB1*1501), rs6457374, and rs2844535 (HLA-B*08). Moreover, information from additional HLA markers or loci, obtained in our laboratory as previously described [3,15], was used for the available samples (83 trios). These additional markers include 16 microsatellites located in (or close to) different genes located in major histocompatibiliy complex (MHC) class III and class II: MICA, TNFa, TNFb, BAT2, D6S273, 9N2, MN6S1424, D6S2670, D3A, NOTCH4, 8105224, D6S2665, D6S2664, DQCARII, DQCAR, G51152, and the polymorphic genes HLA-B (class I) and DQA1 and DQB1 (class II).…”