HLA-DRB1*04 may predict the severity of disease in a group of Iranian COVID-19 patients

Abstract

Human leukocyte antigen (HLA) genes with extreme diversity can make a contribution for individual variations to the immune response against SARS-COV-2 infection. This study aimed to explore the distributions of HLA class II alleles frequencies and their relations with disease severity in a group of Iranian COVID-19 patients. This prospective and case-control study was conducted on 144 COVID-19 patients including 46 cases with moderate form, 54 cases with severe and 44 cases with critical disease. HLA-DRB1 and –DQB1 allele families were determined by PCR-SSP method and compared between three groups of the patients and in comparison to 153 ethnic-matched healthy controls. The patients group showed lower frequencies of HLA-DRB1*15 (OR=0.57, P=0.06), DRB1*15∼DQB1*05 haplotype (P=0.04) and DRB1*15/DRB1*04 genotype (P=0.04) in compare with healthy controls. Moderate COVID-19 patients had higher frequencies of HLA-DRB1*04 (P=0.03), HLA-DRB1*10 (P=0.05) and DRB1*04/DRB1*11 genotype (P=0.01). Also, a higher significantly frequency of HLA-DRB1*03 allele group was observed in the critical patients versus controls (P=0.01). Multiple logistic regression analysis revealed that the presence of DRB1*04 allele group was negatively associated with development of severe and critical disease (OR: 0.289, P=0.005) . Our results indicate a possible contribution of some HLA class II alleles in disease severity and clinical features of COVID-19 disease.

The association of COVID-19 severity and susceptibility and genetic risk factors: A systematic review of the literature

“…HLA-DPA1*02:02 was also found to be linked to higher susceptibility to COVID-19 but did not seem to affect the risk of hospitalization ( Warren and Birol, 2021 ). The presence of HLA-A*11, HLA-C*01, HLA-A*11:01, HLA-C*04:01, HLA-C rs143334143, DQA1*01:02, HLA-DRB1*03 and HLA-DQB1*04 were associated with higher mortality ( Ebrahimi et al, 2021 , Hovhannisyan et al, 2022 , Lorente et al, 2021 , Weiner et al, 2021 ). In a study of 178 Japanese COVID-19 patients, the risk for severe infection was noted to be increased in the presence of the DRB1*09:01 allele compared to pre-existing comorbid conditions like diabetes, hypertension, or cardiovascular diseases ( Anzurez et al, 2021 ).…”

“… ( Ben Shachar et al, 2021 ) HLA-DRB1, -DQB1 HLA-DRB1*03,HLA-DRB1*15, DRB1*15 ∼ DQB1*05, DRB1*15/DRB1*04, HLA- DRB1*04 Iran 144 COVID-19 patients HLA-DRB1*03 was notably higher in severely ill patients.HLA-DRB1*04 was determined to be a protective factor against the development of severe forms of the disease.Frequencies of HLA-DRB1*15, DRB1*15 ∼ DQB1*05, and DRB1*15/DRB1*04 were lower in COVID-19 patients. ( Ebrahimi et al, 2021 ) HLA-DRB1 and HLA-DQB1 HLA- DRB1*04:01, HLA- DQA1*01:01‐DQB1*05:01‐DRB1*01:01 England 147 COVID-19 patients Compared to the asymptomatic group, frequencies of HLA-DRB1*04:01 allele and the haplotype.HLA-DQA1*01:01‐DQB1*05:01‐DRB1*01:01 were drastically lower in severe COVID-19 patients. ( Langton et al, 2021 ) HLA-A, HLA-B, HLA-C, HLA-DRB1 HLA-A*02:05, HLA-B*58:01, HLA-C*07:01, HLA-DRB1*03:01, HLA-DRB1*08 Italy 182 patients, 619 controls HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 haplotype could protect against COVID-19.HLA-DRB1*08 allele was associated with the highest risk for severe COVID-19 illness.…”

“…On the contrary, certain HLA variants such as HLA-A*02:05, HLA-B*58:01, HLA-C*07:01, and HLA- DRB1*03:01 are thought to be protective against critical COVID-19 infection ( Ebrahimi et al, 2021 , Langton et al, 2021 , Littera et al, 2020 , Lorente et al, 2021 , Pisanti et al, 2020 , Tomita et al, 2020 ). Higher frequencies of activating B-telomeric KIR3DS1 (Killer cell immunoglobulin-like receptor 3DL1) in HLA-B*15:01 were linked to less severe infection ( Bernal et al, 2021 ).…”

Susceptibility and Severity of COVID-19 Are Both Associated With Lower Overall Viral–Peptide Binding Repertoire of HLA Class I Molecules, Especially in Younger People

“…For HLA-DRB1*04 , it was suggested to be significantly associated with either susceptibility ( 19 ) or severity ( 54 ) in different population samples, besides our previous report on HLA-DRB1 with the same patients but totally different controls ( 12 ). Such inconsistency among studies has been attributed to various factors including sampling bias due to small sample sizes, inaccuracy of prediction algorithms, and different genetic background of populations ( 12 ). Already noted in previous studies, it also led to the conclusion by some authors that HLA might play a small role in COVID-19 susceptibility ( 20 , 21 ).…”

“…However, among the dozens of case-control studies investigating potential HLA-COVID-19 association, few results have explicitly supported the prediction data. Through frequency comparisons between patients and controls, multiple HLA Class I and Class II alleles were reported as risk or protective factors in these studies, strongly depending on populations, and most results became insignificant after multiple testing corrections (11)(12)(13)(14)(15)(16). In contrast, no significant association between HLA alleles and the disease was observed in studies focusing on South Asia, Brazil, Italy, Spain, and Germany (17)(18)(19)(20).…”