HLA class II DRB1, DQA1, DQB1 loci in patients with HIV infection and tuberculosis in a Latvian cohort group.

Introduction: Until the COVID-19 pandemic, tuberculosis (TB) was the leading cause of death from a single infectious agent, ranking above HIV/AIDS. It is also the key cause of death among people infected with HIV. Tuberculosis incidence in Latvia has decreased by 25% during the last 30 years, but the mortality level of TB remains significant. The HLA class II genes are responsible for antigen presentation and regulation of immune responses, which plays an important role in individual susceptibility to infection disease. Whether or not differential HLA polymorphism contributes to TB with HIV infection and TB without HIV infection in Latvian patients is unknown. Material and methods: For the detection of HLA class II DQA1, DQB1, and DRB1 alleles a total of 616 subjects were enrolled, including 80 primary active TB (PATB) patients, 168 HIV-1/TB patients, 168 HIV-1 patients and 200 HC individuals. Results: For immunodeficiency caused by TB, HIV-1 or HIV-1/TB coinfection, alleles DRB1*12:01, 14:01, 16:01, DQA1*01:02, 01:03, 02:01, 06:01, DQB1*03:03, 06:01 are identified as protective, but DRB1*07:01, 11:01, 15:01, DQA1*02:01, 03:01, DQB1*03:01, 05:01 are identified as risk alleles. Conclusions: The results of our experimental pilot studies demonstrated that HLA class II genes may contribute to the genetic risk of TB and HIV-1/TB co-infection, possibly by reducing the presentation of protective Mycobacterium tuberculosis antigens to T-helpers. It is necessary to conduct repetitive, multicentre, and large sample studies in order to draw more scientific conclusions and to confirm the relationship between TB, HIV and HIV-1/TB co-infection susceptibility and gene polymorphisms.

HLA-A, -C, -B, -DRB1, -DQA1, and -DQB1 Allele and Haplotype Repertoires in the Albanian Population from Kosovo.

To give new insight into the huge polymorphism of HLA system and supplement the existing data, an analysis of HLA alleles and HLA-A~C~B~DRB1~DQA1~DQB1 haplotype distribution in 124 Albanian individuals from Kosovo was performed. All samples were HLA-typed applying the polymerase chain reaction-sequence specific oligonucleotide probing (PCR-SSOP) method and all ambiguous HLA typing results were additionally confirmed by the standard PCR-Sequence Specific Primers (PCR-SSP) high-resolution protocol. Twenty-two HLA-A, 21 HLA-C, 37 HLA-B, 27 HLA-DRB1, 11 HLA-DQA1 and 14 HLA-DQB1 allele groups were detected. Sixteen out of 172 different six-locus estimated haplotypes were found at a frequency higher than 1.00% with a cumulative frequency of 28.82%. The most prevalent haplotype was found to be HLA-A*02:01~C*07:01~B*18:01~DRB1*11:04~DQA1*05:05~DQB1*03:0(5.2%).A total of 13 haplotypes were observed with higher frequency than in populations reported in HaploStats and The Allele Frequency Net Database. The proposed origin of the most frequent haplotypes reflects a basic Euro-Mediterranean background of Albanians in Kosovo. This is the first report of high-resolution HLA-A~C~B~DRB1~DQA1~DQB1 haplotype distribution among the Albanian population from Kosovo, which provides valuable anthropological data and confirms population-specific characteristics.

HLA Class II Allele and Haplotype Diversity in Libyans and Their Genetic Relationships with Other Populations.

Background: Libya witnessed the succession of many civilizations and ethnic groups throughout history, thereby questioning the origin of present-day Libyans. Indeed, they were considered Africans given the geographical position of the country, Arabs at the cultural level, and Berbers because of the notable presence of Berber tribes. Genetic anthropology studies investigating the origin of Libyans were rarely reported, and thus little was known about the population structure of current Libyans, particularly at autosomic markers level. Methods: We examined HLA class II (DRB1, DQB1) gene profiles of 101 unrelated Libyans, and compared them with Arab-speaking communities and with Sub-Saharan and Mediterranean populations using Neighbour-Joining dendrograms, genetic distances, correspondence, and haplotype analysis. Results: Of the 42 DRB1 alleles identified, DRB1*07:01 (14.36%), DRB1*03:01 (12.38%) were the most frequent, while DQB1*02:01 (24.17%), DQB1*02:02 (13.86%), and DQB1*03:01 (12.38%) were the most frequent of the 17 DQB1 alleles detected. DRB1*03:01-DQB1*02:01 (6.93%), DRB1*07:01-DQB1*02:02 (4.45%), and DRB1*04:03-DQB1*03:02 (3.46%) were the most frequent DRB1-DQB1 haplotypes. Conclusion: Libyans appear to be closely related to North Africans, Saudis, and Iberians, but distinct from Levantine Arabs, East Mediterraneans, and Sub-Saharan Africans. This indicates limited genetic contribution of Levantine Arabs and Sub-Saharans on the makeup of Libyan gene pool. Our study confirmed genetic heterogeneity among Arab populations, with three identified groups. The first comprises North Africans, Saudis, and Kuwaitis who were related to Iberians and West Mediterraneans, while the second consists of Levantine Arabs who were close to East Mediterraneans, and the third contained Sudanese and Comorians, with a close relatedness to Sub-Saharans.

Associative role of HLA-DRB1 SNP genotypes as risk factors for susceptibility and severity of rheumatoid arthritis: A North-east Indian population-based study.

Rheumatoid arthritis (RA) is a complex, multifactorial, systemic autoimmune disease. Reports are suggestive of the role of HLA especially HLA-DRB1 alterations in RA pathogenesis. Existing data involving different geographical populations on the role of alterations in specific locus of HLA-DRB1 in RA susceptibility and severity are equivocal, with no data available from ethnically distinct North-east Indian population, where RA cases are alarmingly increasing. This study aimed to evaluate the association of HLA-DRB1 gene SNPs (rs13192471, rs660895 and rs6457617) with susceptibility and severity of RA in an ethnically distinct North-east Indian population. Whole blood was collected from clinically characterized RA cases (satisfying the American College of Rheumatology 1987 criteria) (n = 123) and community-based age and sex-matched healthy controls (n = 156) with informed consent. The HLA-DRB1 SNP analysis was performed for all the RA and control cases using ARMS-PCR using case and control genomic DNA as template. Statistical analysis was performed by SPSSv13.0 software. The HLA-DRB1 rs660895 showed both wild (AA) and heterozygote (AG) genotype but the heterozygote allele was found to be associated with reduced risk of RA compared to controls [OR = 0.531, p = .024]. The difference in distribution of rs6457617 polymorphism between RA and control cases was comparable [OR = 0.525, p = .079]. Significantly higher distribution of variant rs13192471 genotype was observed in RA cases (69.92%) compared to controls (46.75%) (p < .001) and was associated with increased risk of susceptibility to RA [OR = 2.576, p < .001] compared to controls, as well as progression to severity in RA cases [OR = 2.404, p = .048]. Combinatorially also, the presence of rs13192471 variant genotype was associated with increased risk of RA susceptibility [OR = 8.267, p = .026] and RA severity [OR = 3.647, p = .280]. Alterations in HLA-DRB1 are associated with RA susceptibility. HLA-DRB1 rs13192471 SNP plays a critical role in RA susceptibility and severity in North-east Indian cases and has prognostic significance in RA.

Allelic and haplotype diversity of HLA-A, HLA-B and HLA-DRB1 gene at high resolution in the Nanning Han population.

The distribution of human leucocyte antigen (HLA) allele and haplotype varied among different ethnic populations. In this study, we investigated the allele and haplotype frequencies of HLA-A, HLA-B and HLA-DRB1 loci in the Nanning Han population who live in Guangxi province of China. We identified 26 HLA-A, 56 HLA-B and 31 HLA-DRB1 alleles in 562 Nanning individuals of Han ethnic group by sequence-based typing method. Of these, the three most common alleles in HLA-A, HLA-B and HLA-DRB1 loci, respectively, were A*11:01 (32.12%), A*02:07 (12.54%), A*24:02 (12.01%); B*46:01 (14.41%), B*15:02 (13.61%), B*40:01 (11.48%); DRB1*15:01 (14.15%), DRB1*16:02 (11.57%) and DRB1*12:02 (10.14%). With the exception of HLA-DRB1, the p values of the HLA-A and HLA-B loci showed that the HLA allelic distribution in this population was in accordance with Hardy-Weinberg expectation (p > 0.05). A total of 173 HLA~A-B~DRB1 haplotype with a frequency of >0.1% were presented and the three most common haplotype were HLA-A*33:03~B*58:01~DRB1*03:01 (6.12%), HLA-A*11:01~B*15:02~DRB1*12:02 (3.39%) and HLA-A*11:01~B*15:02~DRB1*15:01 (3.22%). The phylogenetic tree and the principal component analysis suggested that Nanning Han population had a relative close genetic relationship with Chinese Zhuang population and a relative distant genetic relationship with Northern Han Chinese. The information will be useful for anthropological studies, for HLA matching in transplantation and disease association studies in the Chinese population.

The HLA-B landscape of Africa: Signatures of pathogen-driven selection and molecular identification of candidate alleles to malaria protection.

Human leukocyte antigen (HLA) genes play a key role in the immune response to infectious diseases, some of which are highly prevalent in specific environments, like malaria in sub-Saharan Africa. Former case-control studies showed that one particular HLA-B allele, B*53, was associated with malaria protection in Gambia, but this hypothesis was not tested so far within a population genetics framework. In this study, our objective was to assess whether pathogen-driven selection associated with malaria contributed to shape the HLA-B genetic landscape of Africa. To that aim, we first typed the HLA-A and -B loci in 484 individuals from 11 populations living in different environments across the Sahel, and we analysed these data together with those available for 29 other populations using several approaches including linear modelling on various genetic, geographic and environmental parameters. In addition to relevant signatures of populations' demography and migrations history in the genetic differentiation patterns of both HLA-A and -B loci, we found that the frequencies of three HLA alleles, B*53, B*78 and A*74, were significantly associated with Plasmodium falciparum malaria prevalence, suggesting their increase through pathogen-driven selection in malaria-endemic environments. The two HLA-B alleles were further identified, by high-throughput sequencing, as B*53:01:01 (in putative linkage disequilibrium with one HLA-C allele, C*04:01:01:01) and B*78:01 in all but one individuals tested, making them appropriate candidates to malaria protection. These results highlight the role of environmental factors in the evolution of the HLA polymorphism and open key perspectives for functional studies focusing on HLA peptide-binding properties.

Understanding the obstacle of incompatibility at residue 156 within HLA-B*35 subtypes.

Defining permissive and non-permissive mismatches for transplantation is a demanding challenge. Single mismatches at amino acid (AA) position 156 of human leucocyte antigen (HLA) class I have been described to alter the peptide motif, repertoire, or mode of peptide loading through differential interaction with the peptide-loading complex. Hence, a single mismatch can tip the balance and trigger an immunological reaction. HLA-B*35 subtypes have been described to evade the loading complex, 156 mismatch distinguishing B*35:01 and B*35:08 changes the binding groove sufficiently to alter the sequence features of the selected peptide repertoire. To understand the functional influences of residue 156 in B*35 variants, we analyzed the peptide binding profiles of HLA-B*35:01(156Leu), B*35:08(156Arg) and B*35:62(156Trp). The glycoprotein tapasin represents a target for immune evasions and functions within the multimeric peptide-loading complex to stabilize empty class I molecules and promote acquisition of high-affinity peptides. All three B*35 subtypes showed a tapasin-independent mode of peptide acquisition. HLA-B*35-restricted peptides of low- and high-binding affinities were recovered in the presence and absence of tapasin and subsequently sequenced utilizing mass spectrometry. The peptides derived from B*35 variants differ substantially in their features dependent on their mode of recruitment; all peptides were preferentially anchored by Pro at p2 and Tyr, Phe, Leu, or Lys at pΩ. However, the Trp at residue 156 altered the p2 motif to an Ala and restricted the pΩ to a Trp. Our results highlight the importance of understanding the impact of key micropolymorphism and how a single AA mismatch orchestrates the neighboring AAs.

The frequency of HLA alleles in the Romanian population.

Knowledge of human leukocyte antigen (HLA) allele frequencies is essential for bone marrow and kidney donor searches. The Romanian Caucasian population is heterogeneous and information on HLA polymorphism has not been well studied. We characterized the HLA genetic profile and allele frequencies of regional populations in Romania. HLA-A, B and DRB1 alleles were examined in 8252 individuals, belonging to the four main regions of Romania. The most common alleles found in the Romanian population are the following: HLA-A*01, A*02, A*03, A*11, A*24; HLA-B*18, B*35, B*44, B*51 and HLA-DRB1*01, DRB1*03, DRB1*07, DRB1*11, DRB1*13, DRB1*15, DRB1*16. More than half of the alleles are non-homogeneously spread in Romania. These results provide a starting point for future analyses of genetic heterogeneity in Romania.

Polymorphisms of HLA-A, -B, -Cw and DRB1 antigens in Moroccan patients with ankylosing spondylitis and a comparison of clinical features with frequencies of HLA-B*27.

Ankylosing spondylitis (AS) is very often associated with human leukocyte antigen (HLA), particularly HLA-B*27. However, the strength of this association and clinical features may vary in different ethnic groups. Our study aims to assess the distribution of HLA-A, -B, -Cw and DRB1 alleles in Moroccan patients with AS and to compare the clinical features of AS and the frequencies of HLA-B27 in patients from Morocco with other series. Seventy-five patients diagnosed with AS and assessed for clinical manifestations were selected and compared to 100 healthy controls. HLA class I and II antigens were typed by polymerase chain reaction sequence-specific oligonucleotide. HLA-B27 subtypes were studied by polymerase chain reaction amplification with sequence-specific primers. HLA-B27 was found in 64% of patients. It was positively associated with younger age at disease onset, family history, and uveitis while it had a negative association with late onset. Six B*27 subtypes were identified in the AS group. HLA-B*2705 and B*2702 were the most common observed subtypes. Among other HLA genes, a significant increase in the prevalence of HLA-Cw*02 and HLA-DRB*15 was found in AS patients. HLA-B27 is involved in the predisposition of AS in the Moroccan population. HLA-B*2705 and B*2702 were the predominant subtypes supporting previous reports in Caucasian spondyloarthropathies. Other HLA genes, HLA-Cw*02 and HLA-DRB1*15, seem to confer predisposing effect to the disease. However, the lower frequency of HLA-B27 compared to the literature in our study suggests the existence of different genetic and/or environmental factors in Morocco.

Moroccan study of HLA (-A, -B, -C, -DR, -DQ) polymorphism in 647 unrelated controls: Updating data.

The scope of this study is to investigate the HLA (Human Leukocyte Antigen) distribution and polymorphism in a large sample of healthy Moroccans in order to extend and update the available data. 647 unrelated Moroccan controls originating from diverse regions of the country were typed using microlymphocytotoxicity for HLA-A and -B, sequence-specific-primer amplification for -C, -DR, and -DQ and Luminex HD for specific -DR. The most frequent allele groups detected were HLA-A2 (19.2%), -B44 (12.4%), -C*07 (24.4%), -DRB1*03 (16.9%), -DRB1*04 (18.4%), -DQB1*02 (28.7%) and -DQB1*03 (27.8%). The most predominant specific alleles found for DRB1 were: *03:01, *04:02, *04:05, *07:01, *11:01, *13:02 and *15:01. Rare allelic variants were detected, for the first time in Moroccan population, at the DRB1*03 (*03:52, *03:54, *03:56), DRB1*07 (*07:07, *07:11, *07:16) and DRB1*11 (*11:70) locus. The most frequent haplotypes were: A2-B44, A30-B18, A2-C*16, A30-C*06, B14-C*08, B58-C*07, B45-C*06, DRB1*03-DQB1*02, DRB1*04-DQB1*03, DRB1*07-DQB1*02 and DRB1*15-DQB1*06. Comparison of genetic distances and haplotypes with other populations shows that the Moroccans are genetically closer to North Africans and Europeans than to sub-Saharan Africans. Our results reflect the high degree of HLA polymorphism in the Moroccan population and provide a useful baseline of healthy Moroccan controls for disease association and anthropological studies.

Association of HLA gene polymorphisms with Helicobacter pylori related gastric cancer-a systematic review.

The appropriate host cell immune responses for the progression of several diseases, including gastric or stomach cancer (GC), are significantly influenced by HLA polymorphisms. Our objective was to systematically review the evidence linking HLA polymorphisms with the risk of Helicobacter. pylori related GC. We conducted a comprehensive literature search to identify studies published between 2000 and April 2023 on the association of HLA polymorphisms with H. pylori related GC using databases such as Medline through PubMed, Embase, Web of Science (core collection), The Cochrane Library, and Scopus. Two authors independently screened articles, extracted data, and assessed the risk of bias using the Risk of Bias Assessment tool for Non-randomized Studies. From 7872 retrieved studies, 19 met inclusion criteria, encompassing 1656 cases and 16,787 controls across four World Health Organization regions, with Japan contributing the most studies. We explored HLA-A/B/C, HLA-DRB1/DQA1/DQB1, HLA-G, and MICA alleles. Of 29 significant HLA polymorphisms identified, 18 showed a positive association with GC, whereas 11 were negatively associated. HLA-DQB1*06 allele was most frequently associated to susceptibility, as reported in four studies, followed by HLA-DRB1*04 and HLA-DQA1*01, each reported in two studies. Conversely, HLA-G*01, HLA-DQA1*01, HLA-DQA1*05, and HLA-DQB1*03 were identified as protective in two studies each. Additionally, five genotypes and six haplotypes were reported as positive, whereas three genotypes and two haplotypes were negative factors for the disease incidence or mortality. Despite heterogeneity in the study population and types of HLA polymorphisms examined, our analysis indicates certain polymorphisms are associated with H. pylori related GC progression and mortality in specific populations.

The novel HLA-C*06:372 allele, identified in a stem cell donor of an old order mennonite ethnicity.

HLA-C*06:372 differs from HLA-C*06:02:01:01 by a single substitution in exon 4.

The novel HLA-DQA1*05:05:17:03 allele, identified in a potential organ donor.

HLA-DQA1*05:05:17:03 differs from HLA-DQA1*05:05:01:02 by a single base substitution in exon 1 and HLA-DQA1*05:05:17:01 within introns 1 and 2.

The novel HLA-DRB1*08:127 allele, identified in a deceased organ donor of Scandinavian descent.

HLA-DRB1*08:127 differs from HLA-DRB1*08:01:01:01 by a single substitution in exon 4.

Host genetic variants, Epstein-Barr virus subtypes, and the risk of nasopharyngeal carcinoma: Assessment of interaction and mediation.

Epstein-Barr virus (EBV) and human leukocyte antigen (HLA) polymorphisms are well-known risk factors for nasopharyngeal carcinoma (NPC). However, the combined effects between HLA and EBV on the risk of NPC are unknown. We applied a causal inference framework to disentangle interaction and mediation effects between two host HLA SNPs, rs2860580 and rs2894207, and EBV variant 163364 with a population-based case-control study in NPC-endemic southern China. We discovered the strong interaction effects between the high-risk EBV subtype and both HLA SNPs on NPC risk (rs2860580, relative excess risk due to interaction [RERI] = 4.08, 95% confidence interval [CI] = 2.03-6.14; rs2894207, RERI = 3.37, 95% CI = 1.59-5.15), accounting for the majority of genetic risk effects. These results indicate that HLA genes and the high-risk EBV have joint effects on NPC risk. Prevention strategies targeting the high-risk EBV subtype would largely reduce NPC risk associated with EBV and host genetic susceptibility.

Association between human leukocyte antigen (HLA) and end-stage renal disease (ESRD): a meta-analysis.

Objectives: We recently studied the association between various human leukocyte antigen (HLA) alleles and end-stage renal disease (ESRD). According to our analysis, HLA-B*50 and HLA-DQA1*3 alleles were positively associated with ESRD, while B*40, DRB1*12, DRB1*13, and DQA1*6 alleles were negatively associated with ESRD. However, a single case-control study does not have enough statistical power to evaluate the possible impact of genetic polymorphism on any disease. Hence, the main objective of this meta-analysis is to determine the association between these abovementioned HLA alleles and ESRD. Design: MEDLINE/PubMed, EMBASE, Web of Science, and Cochrane databases were searched through December 2020 for case-control studies on the associations between HLA polymorphisms and ESRD. Independent reviewers screened the texts of potentially eligible studies and assessed the risk of bias. The meta-analysis was conducted based on the checklists and guidelines based on PRISMA. Results: We identified 26 case-control studies comprising 1,312 ESRD and 3,842 healthy subjects. A non-significant positive association was observed between HLA-B*50 (OR = 1.02, 95% CI [0.90, 1.24]), HLA-B*40 (OR = 1.75, 95% CI [0.98, 3.2]), HLA-DQA1*3, (OR = 1.17, 95% CI [0.74, 1.84]), DRB1*12 (OR = 1.05, 95% CI [0.94, 1.18]) alleles and ESRD. In addition, a non-significant negative association was observed between HLA-DRB1*13 (OR = 0.90, CI [0.81, 1.01]), HLA-DQB1*6 (OR = 0.79, 95% CI [0.58, 1.07]) alleles and ESRD. Conclusions: Our meta-analysis indicates no significant association between HLA-B*50, HLA-DQA1*3, B*40, DRB1*12, DRB1*13, and DQA1*6 alleles and ESRD. Further studies with larger sample sizes and adjustments for confounders are required to confirm these conclusions.

HLA-targeted sequencing reveals the pathogenic role of HLA-B*15:02/HLA-B*13:01 in albendazole-induced liver failure: a case report and a review of the literature.

Drug-induced liver injury (DILI) is one of the serious adverse drug reactions (ADRs), which belongs to immune-mediated adverse drug reactions (IM-ADRs). As an essential health drug, albendazole has rarely been reported to cause serious liver damage. A young man in his 30 s developed severe jaundice, abnormal transaminases, and poor blood coagulation mechanism after taking albendazole, and eventually developed into severe liver failure. The patient was found heterozygous of HLA-B*15:02 and HLA-B*13:01 through HLA-targeted sequencing, which may have a pathogenic role in the disease. This case report summarizes his presentation, treatment, and prognosis. A useful summary of the diagnosis and associated genetic variant information is provided.

Analysis of somatic mutations and key driving factors of cervical cancer progression.

We investigated the somatic mutations and key driving factors of cervical cancer by whole exome sequencing . We found 22,183 somatic single nucleotide variations (SNVs) in 52 paired samples. Somatic SNVs in cervical cancer were significantly higher than those in high-grade intraepithelial lesion and low-grade squamous intraepithelial lesion groups (P < 0.05). C → T/G accounted for 44.12% of base substitution. Copy number variation (false discovery rate < 0.05) was found in 57 chromosome regions. The three regions with significant differences between cervical cancer and non-cervical cancer groups were 1q21.1, 3q26.33, and 13q33.1, covering genes related to tumor proliferation, differentiation, and apoptosis. The frequency of human papillomavirus (HPV) insertion/integration and the number of "tCw" mutations in the cervical cancer group were significantly higher than those in the non-cervical cancer group (P < 0.05). The total number of mutations was positively correlated with the number of "tCw" mutations (R 2 = 0.7967). HPV insertion/integration (OR = 2.302, CI = 1.523-3.589, P = 0.0005), APOBEC enrichment (OR = 17.875, CI = 2.117-150.937, P = 0.001), and HLA-B*39 in HLA-I (OR = 6.435, CI = 0.823-48.919, P = 0.0042) were risk factors for cervical cancer, while HLA-DQB1*05 in HLA-II was a protective factor (OR = 0.426, CI = 0.197-0.910, P = 0.032). Conclusively, HPV insertion/integration, APOBEC mutagenesis, and HLA polymorphisms are high-risk factors for cervical cancer and may be causes of genome instability and somatic mutations. This study provides experimental data for revealing the molecular mechanism of cervical cancer.

Deciphering Driver of Nasopharyngeal Cancer Development.

A great deal of progress has been made on understanding nasopharyngeal cancer in recent decades. Genomic, transcriptomic, and proteomic studies have enabled us to gain a deeper understanding on the biology of nasopharyngeal cancer, and though this new information is elaborate and detailed, an overall picture of the driver of nasopharyngeal cancer that includes all this information is lacking. This review will focus on providing a broad overview, with plausible and simple language, on nasopharyngeal carcinogenesis based on current updated information. This will help readers to gain a broad understanding, which may be necessary to provide common ground for further research on nasopharyngeal cancer.

Association of HLA gene polymorphism with susceptibility, severity, and mortality of COVID-19: A systematic review.

HLA is crucial for appropriate immune responses in several viral infections, as well as in severe acute respiratory syndrome coronavirus-2 (SARS CoV-2). The unpredictable nature of Coronavirus Disease 19 (COVID-19), observed in both inter-individual and inter-population level, raises the question, to what extent the HLA, as part of host genetic factors, contribute to disease susceptibility and prognosis. We aimed to identify significant HLAs, those were investigated till now, for their association with COVID-19. Three databases were searched (PubMed, Cochrane library, and Web of Science) and articles published between January 2020 and May 2021 were included for in-depth analysis. Two separate teams including four observers independently extracted the summary data, with discrepancies resolved by consensus. This study is registered with PROSPERO (CRD42021251670). Of 1278 studies identified, 36 articles were included consisting of 794,571 participants. Countries from the European region appeared in the highest number of studies and vice versa for countries from South East Asia. Among 117 significantly altered alleles, 85 (72.65%) were found to have a positive correlation with COVID-19 and 33 (27.35%) alleles were observed having a negative correlation. HLA A*02 is the most investigated allele (n = 18) and showed contradictory results. Non-classical HLA E was explored by only one study and it showed that E*01:01 is associated with severity. Both in silico and wet lab data were considered and contrasting results were found from two approaches. Although several HLAs depicted significant association, nothing conclusive could be drawn because of heterogeneity in study designs, HLA typing methods, and so forth. This systematic review shows that, though HLAs play role in COVID-19 susceptibility, severity, and mortality, more uniformly designed, interrelated studies with the inclusion of global data, for use in evidence-based medicine are needed.