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HLA Diversity in Saudi Population: High Frequency of Homozygous HLA Alleles and Haplotypes

ABSTRACT: Human leukocyte antigens (HLA) diversity has a tremendous impact on shaping the transplantation practices, transfusion-associated graft versus host disease prevention strategies, and host–pathogen interactions. Here, we conducted a retrospective study of HLA class I and class II homozygosity at allelic and haplotype levels in unrelated individuals genotyped from 2012 to 2016 in a tertiary hospital in the capital of Saudi Arabia. Among 5,000 individuals, 2,773 individuals meet inclusion criteria and were retrospectively analyzed for HLA-A, -B, -C–DRB1, and -DQB1 homozygosity at allelic and haplotype levels. HLA molecular typing was performed using a commercial reverse sequence-specific oligonucleotide (rSSO) kit. We were able to identify 15 HLA-A, 20 HLA-B, 11 HLA-C, 13 HLA-DRB1, and five HLA-DQB1 homozygous alleles demonstrating a very low genetic diversity in the Saudi population. The highest homozygosity in HLA class I was found in locus C followed by A and B (20.3% > 16.1% > 15.5%; p < 0.001) where the most homozygote alleles were A*02 (9.2%), B*51 and B*50 (5.7% and 3.7%), and C*07, C*06, and C*15 (7.2%, 5.48%, and 3.3%) and in HLA class II, the highest homozygosity was found in locus DQB1 compared to DRB1 (31.71% > 19.2%; p < 0.001), with the most common homozygote alleles being DRB1*07 and DRB1*04 (5.33% and 4.2%) and DQB1*02, DQB1*06, and DQB1*03 (13.55%, 7.92%, and 7.64%). The frequency of finding an individual with one homozygote allele was (24.6%), two homozygote alleles (13.5%), three homozygote alleles (4.7%), four homozygote alleles (3.4%), and five alleles were (4.8%). The most frequent homozygote haplotypes are A*23∼C*06∼B*50∼DRB1*07∼DQB1*02 and A*02∼C*06∼B*50∼DRB1*07∼DQB1*02. This study shows low diversity of both class I and II alleles and haplotypes in the Saudi population, which would have a significant impact on shaping the transplantation practices, transfusion-associated graft versus host disease prevention strategies, and host–pathogen interactions.

SUBMITTER: Chentoufi A

PROVIDER: S-EPMC9218871 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:IntroductionThe human leukocyte antigen (HLA) region on chromosome 6p21 is well known to carry the most important genetic factors in susceptibility to psoriasis. Different HLA alleles and haplotypes have been reported to be associated with psoriasis in different populations. Psoriasis has a variable age of onset and, based on this, it can be classified into two types; type I with age of onset before 40 years of age and type II with age of onset after 40 years of age. The objective of this study was to determine the association of HLA class I and class II alleles and haplotypes with disease and stratification using age of onset in Pakistani psoriatic patients.MethodsA group of 603 individuals (326 cases and 277 controls) were analyzed for HLA class I and II alleles and haplotype association by sequence specific PCR. The association was further analyzed according to the age of onset of the patients.ResultsWe found that HLA alleles B*57 and Cw*06:02, DQB1*03:03:02 are strongly associated with early onset psoriasis, while alleles B*15, DRB1*13:02 and DQB1*03:03:02 are associated with late-onset psoriasis. Cw*06:02 allele was not associated with late-onset psoriasis patients. Allele DQB1*03:03:02 had the highest odds ratio in all patients. We found a novel association specifically with late-onset psoriasis samples with the haplotype HLA-A*11; B*15; Cw*04; DRB1*15; DQB1*05 (Pc = 3.60 × 10-7). We also found strong association with previously reported extended haplotype EH-57.1: HLA-B*57; Cw*06:02; DRB1*07:01; DQB1*03:03:02 in all our patients (Pc = 8.34 × 10-07).ConclusionOur results show that different HLA class I and II alleles and haplotypes are associated with psoriasis at different age of onset. In this study, we have reported novel alleles and haplotype association with late-onset psoriasis. Our data confirm the previous strong associations with HLA alleles and haplotypes and also reports novel alleles and haplotype association in Pakistani psoriasis patients.

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HLA Diversity in Saudi Population: High Frequency of Homozygous HLA Alleles and Haplotypes

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