Abstract
The Major Histocompatibility Complex (MHC, 6p21) codes for traditional HLA and other host response related genes. The polymorphic HLA-DRB1 gene in MHC Class II has been associated with several complex diseases. In this study we focus on MHC haplotype structures in the Finnish population. We explore the variability of extended HLA-DRB1 haplotypes in relation to the other traditional HLA genes and a selected group of MHC class III genes. A total of 150 healthy Finnish individuals were included in the study. Subjects were genotyped for HLA alleles (HLA-A, -B, -DRB1, -DQB1, and -DPB1). The polymorphism of TNF, LTA, C4, BTNL2 and HLA-DRA genes was studied with 74 SNPs (single nucleotide polymorphism). The C4A and C4B gene copy numbers and a 2-bp silencing insertion at exon 29 in C4A gene were analysed with quantitative genomic realtime-PCR. The allele frequencies for each locus were calculated and haplotypes were constructed using both the traditional HLA alleles and SNP blocks. The most frequent Finnish A∼B∼DR -haplotype, uncommon in elsewhere in Europe, was A*03∼B*35∼DRB1*01∶01. The second most common haplotype was a common European ancestral haplotype AH 8.1 (A*01∼B*08∼DRB1*03∶01). Extended haplotypes containing HLA-B, TNF block, C4 and HLA-DPB1 strongly increased the number of HLA-DRB1 haplotypes showing variability in the extended HLA-DRB1 haplotype structures. On the contrary, BTNL2 block and HLA-DQB1 were more conserved showing linkage with the HLA-DRB1 alleles. We show that the use of HLA-DRB1 haplotypes rather than single HLA-DRB1 alleles is advantageous when studying the polymorphisms and LD patters of the MHC region. For disease association studies the HLA-DRB1 haplotypes with various MHC markers allows us to cluster haplotypes with functionally important gene variants such as C4 deficiency and cytokines TNF and LTA, and provides hypotheses for further assessment. Our study corroborates the importance of studying population-specific MHC haplotypes.
Highlights
The Major Histocompatibility Complex located on chromosome 6p21 has a complex allelic structure with extended linkage disequilibrium (LD) and polymorphism
Many non-human leukocyte antigen (HLA) genes related to immune responses e.g. tumor necrosis factor (TNF), lymphotoxin-alpha (LTA), complement C4 genes (C4A and C4B) and butyrophilin-like protein 2 (BTNL2), are located in the MHC class III region that resides between the MHC Class I and II regions [1,2,3]
In the Finnish population, two HLA-A alleles accounted for .66% and five HLA-DPB1 alleles for .91% of the variation at the loci
Summary
The Major Histocompatibility Complex located on chromosome 6p21 has a complex allelic structure with extended linkage disequilibrium (LD) and polymorphism. The HLA genes play a critical role in hematopoietic stem cell transplantation, and HLA mismatching has been associated with graft failure and graft-versus-host disease [9,10]. The polymorphic HLA-DRB1 has been associated with several complex and infectious diseases, such as acute coronary syndrome [12], HSV2 related meningitis [13], type I diabetes, celiac disease and multiple sclerosis (reviewed in [14]). As the traditional HLA typing is considered rather expensive and laborious and the analysis of MHC regions is complex, many studies do not probe MHC associations more closely. The functionality of the variants remains uncertain identification of a specific risk HLA allele could help to understand a disease and its causality further
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