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Research Article | DOI: https://doi.org/10.31579/2640-1045/035
1* Associate fellow of Russian Academy of Sciences, professor, deputy director of Institute of clinical endocrinology, head of therapeutic endocrinological department, Endocrinology Research Centre.
2 Candidate of therapeutic endocrinology, Endocrinology Research Centre, Moscow, Russia.
*Corresponding Author: Troshina E.A, Associate fellow of Russian Academy of Sciences, professor, deputy director of Institute of clinical endocrinology, head of therapeutic endocrinological department, Endocrinology Research Centre.
Citation: Troshina E.A, (2018). Association of polymorphism of HLA II genes with chronic adrenal insufficiency in APS 2,3,4 types – protective and predisposing genes. J. Endocrinology and Disorders. Doi:10.31579/2640-1045/035
Copyright: © 2018 Troshina E.A . This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 29 October 2018 | Accepted: 05 November 2018 | Published: 12 November 2018
Keywords: Autoimmune polyglandular syndrome 2, 3, 4 types, chronic adrenal insufficiency, genes DRB1, DQA1, DQB1 HLA class II, protective haplotypes
Endocrinology Research Centre, Moscow, Russian Federation.
This research was conducted under the research grant RSF “Autoimmune endocrinopathies multiple organ failure that are genomic, postgenomic and metabolic markers. Genetic risk prediction, monitoring, early predictors, personalized correction and rehabilitation.” Project number is 17-75-30035.
Introduction
The aim of the study was to determine the association of chronic adrenal insufficiency with polymorphism of HLA II genes among patients with APS 2,3,4 types. The focus of the study was on the revealing of protective genes for Addison’s disease in APS 3 type patients.
Materials and methods
The case-control study involved 78 patients with APS 2, 3, 4 types and 109 healthy subjects. Alleles of the HLA II class genes, CTLA4 and PTPN22 were identified by the multiprimer allele-specific PCR method. The statistical analysis was carried out using the exact two-sided Fisher test. The association of the chronic adrenal insufficiency in patients with APS was determined by the value of the odds ratio (OR - odd's ratio), the value of 95% confidence interval (95% CI).
Results
Haplotypes DR3-DQ2 (OR = 4.06), DR4-DQ8 (OR = 5.78), genotype DR3/DR4 (OR = 19.7), DQA1*0301 allele (OR = 4.27), as well as genotype DQA1*0301/DQA1*0501 (OR = 13.89) predispose to the development of APS type 2, 3 and 4 in adults compared to the control group. APS patients were divided into two groups according to the presence of Addison’s disease (APS 2 and 4 types - and type 3 APS). Haplotype DR3-DQ2 (DRB1*17-DQA1*0501-DQB1*0201) (OR = 2.6), as well as the genotype DR3/DR4 (OR = 4.28) found the strongest association with the development of adrenal insufficiency in patients with APS.
Haplotypes DRB1*01-DQA1*0101-DQB1*0501 (OR = 0.07), as well as DRB1*01 (OR = 0.08) have been determined as protective for the development of Addison’s disease.
Conclusion
Examination of APS type 3 patients without Addison’s disease for the presence of protective genes for the development of adrenal insufficiency will allow better predicting the risks of developing of the disease within the syndrome.
Autoimmune polyglandular syndromes (APS) are the combinations of a variety of autoimmune endocrine and non-endocrine diseases represented by the two main types – APS type 1 and APS type 2. Another two types - APS type 3 and APS type 4 are relating to APS of adults according to classification of clinical character [1, 5].
Nowadays in Russian practice there is no enough focus on diagnostic risks of development the new components of syndrome in APS type 3 patients. Such patients have a combination of autoimmune thyroid disorders with endocrine and non-endocrine autoimmune diseases –Type 1 Diabetes or LADA, vitiligo, alopecia, coeliacia, autoimmune atrophic gastritis, systemic lupus erythematosus, etc. excluding Addison’s disease.
The regular examination for the autoimmune markers of the new components of APS, and also revealing of predisposal and protective genes for Addison’s disease (HLA DR3, DR4) allow to predict the risk of sudden onset of complications within the syndrome (adrenal crisis and heavy forms of hypoglycemia at the onset of chronic adrenal insufficiency) [6].
The Aim of the study was to determine the association of chronic adrenal insufficiency with polymorphism of HLA II genes among patients with APS 2,3,4 types. The focus of the study was on the revealing of protective genes for Addison’s disease in APS 3 type patients.
Sera of 78 patients with APS type 2, 3, 4 and 109 healthy subjects were screened for HLA II genes’ polymorphism. APS patients were at the age of 18-78 years, women – 74,4 %, men-– 25,6 %. The control healthy group was at the age of 18-58, among them women - 64,2 %, men - 35,8 %/ The difference between two groups was not statistically significant on gender (р=0,154).
Molecular-genetic examination of HLA II genes was conducted for all patients. DNA from the whole blood of the person was carried out by set of QIAamp DNA Blood Mini Kit (QIAGEN). The method of multyprimer allele-specified polymerase chain reaction was used.
Statistical analysis was carried out by STATISTICA 10, SPSS Statistics with the use of precise two-sided Fisher’s test. The differences were considered significant with р<0> 1, inverse association with the disease - with ОR and 95 % CI <1>
Addison’s disease occurred in 46,2
A strong association of haplotypes DR3-DQ2, DR4-DQ8, especially of genotype DR3/DR4, allele DQA1*0301, and also of genotype DQA1*0301/DQA1*0501, with the development of APS of adults was confirmed.
When the groups were divided into APS with the chronic adrenal insufficiency (APS 2 and 4 types) and APS without it (APS type 3), the strongest influence on the risk of the development of chronic adrenal insufficiency in APS had haplotype DR3-DQ2 (DRB1 * 17-DQA1 * 0501-DQB1 * 0201), as well as genotype DR3 / DR4. This fact can serve as an unfavorable prognostic sign for the development of chronic adrenal insufficiency in APS type 3 and require more thorough regular screening in such patients and their relatives with autoimmune diseases.
Herewith the presence of protective haplotype DRB1*01-DQA1*0101-DQB1*0501, and also allele DRB1*01 and DRB1*13, in relation to development of chronic adrenal insufficiency in APS of adults oppositely allows to predict more favorable course of the syndrome.
Screening for the development of chronic adrenal insufficiency in APS type 3 patients is possible in standard terms - 1 time in 5 years.
Information about financing and conflict between interests.
The authors emphasize about absence of express or implied conflicts of interests, connected with conducting of this research and publication of this article.
Author contribution statement.
Troshina E.A. - formulation of the purpose and objectives of the study, development of the research concept, checking the text of the article Larina A.A. - patient recruitment, static processing of received data, writing an article
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