Ассоциация развития аутоиммунных полигландулярных синдромов взрослых с полиморфизмом генов HLA II класса и предрасположенность к развитию хронической надпочечниковой недостаточности в рамках этих синдромов
Ассоциация развития аутоиммунных полигландулярных синдромов взрослых с полиморфизмом генов HLA II класса и предрасположенность к развитию хронической надпочечниковой недостаточности в рамках этих синдромов
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Аннотация
Цель исследования – изучение ассоциации предрасполагающих и протективных гаплотипов HLA II класса, полиморфизмов генов CTLA-4 и PTPN-22 с развитием хронической надпочечниковой недостаточности (ХНН) при аутоиммунных полигландулярных синдромах (АПС) взрослых.
Материалы и методы. Проведено исследование методом случай-контроль (78 пациентов с АПС 2, 3, 4-го типов и 109 здоровых лиц). Идентификацию аллелей генов HLA II класса, CTLA-4 и PTPN-22 проводили методом мультипраймерной аллель-специфической полимеразной цепной реакции. Статистический анализ проводился с использованием точного двустороннего критерия Фишера. Степень ассоциации признака с заболеванием определялась величиной отношения шансов (ОШ), значением 95% доверительного интервала (95% ДИ).
Результаты и обсуждение. Подтверждена стойкая ассоциация гаплотипов DR3-DQ2 (OШ=4,06), DR4-DQ8 (OШ=5,78), генотипа DR3/DR4 (OШ=19,7), аллеля DQA1*0301 (OШ=4,27), а также генотипа DQA1*0301/DQA1*0501 (OШ=13,89) с развитием АПС взрослых в целом по сравнению с группой контроля. При разделении групп пациентов с АПС взрослых по наличию ХНН (АПС 2-го и 4-го типов – в одной группе и АПС 3-го типа – в другой группе) выявлено наибольшее влияние на развитие ХНН в составе АПС гаплотипа DR3-DQ2 (DRB1*17-DQA1*0501-DQB1*0201) (OШ=2,6), а также генотипа DR3/DR4 (OШ=4,28). Выявлены протективные гаплотипы в отношении развития ХНН в рамках АПС взрослых – DRB1*01-DQA1*0101-DQB1*0501 (p<0,01; OШ=0,07), а также аллеля DRB1*01 (р<0,01; OШ=0,08).
Заключение. Обследование пациентов с АПС взрослых без ХНН в отношении наличия протективных генов для развития надпочечниковой недостаточности позволит лучше прогнозировать риски развития инвалидизирующего заболевания в рамках синдрома.
Ключевые слова: аутоиммунный полигландулярный синдром 2, 3, 4-го типов, хроническая надпочечниковая недостаточность, гены DRB1, DQA1, DQB1, HLA II класса, протективные гаплотипы.
Materials and methods. The case-control study involved 78 patients with APS 2, 3, 4 types and 109 healthy subjects). Alleles of the HLA class II genes, CTLA-4 and PTPN-22 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 – confidence interval).
Results and discussion. 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 of adults compared to the control group. APS patients were divided into two groups according to the presence of chronic adrenal insufficiency (APS 2 and 4 types – in one group and type 3 APS in the other group). 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 of adults. Protective haplotypes DRB1 * 01-DQA1 * 0101-DQB1 * 0501 (p<0.01, OR = 0.07), as well as the DRB1 * 01 allele (p<0.01, OR = 0.08) have been identified with respect to the development of adrenal insufficiency in adult APS patients.
Conclusion. Examination of patients with APS of adults without chronic adrenal insufficiency 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.
Keywords: autoimmune polyglandular syndrome 2, 3, 4 types, chronic adrenal insufficiency, genes DRB1, DQA1, DQB1 HLA class II, protective haplotypes.
Материалы и методы. Проведено исследование методом случай-контроль (78 пациентов с АПС 2, 3, 4-го типов и 109 здоровых лиц). Идентификацию аллелей генов HLA II класса, CTLA-4 и PTPN-22 проводили методом мультипраймерной аллель-специфической полимеразной цепной реакции. Статистический анализ проводился с использованием точного двустороннего критерия Фишера. Степень ассоциации признака с заболеванием определялась величиной отношения шансов (ОШ), значением 95% доверительного интервала (95% ДИ).
Результаты и обсуждение. Подтверждена стойкая ассоциация гаплотипов DR3-DQ2 (OШ=4,06), DR4-DQ8 (OШ=5,78), генотипа DR3/DR4 (OШ=19,7), аллеля DQA1*0301 (OШ=4,27), а также генотипа DQA1*0301/DQA1*0501 (OШ=13,89) с развитием АПС взрослых в целом по сравнению с группой контроля. При разделении групп пациентов с АПС взрослых по наличию ХНН (АПС 2-го и 4-го типов – в одной группе и АПС 3-го типа – в другой группе) выявлено наибольшее влияние на развитие ХНН в составе АПС гаплотипа DR3-DQ2 (DRB1*17-DQA1*0501-DQB1*0201) (OШ=2,6), а также генотипа DR3/DR4 (OШ=4,28). Выявлены протективные гаплотипы в отношении развития ХНН в рамках АПС взрослых – DRB1*01-DQA1*0101-DQB1*0501 (p<0,01; OШ=0,07), а также аллеля DRB1*01 (р<0,01; OШ=0,08).
Заключение. Обследование пациентов с АПС взрослых без ХНН в отношении наличия протективных генов для развития надпочечниковой недостаточности позволит лучше прогнозировать риски развития инвалидизирующего заболевания в рамках синдрома.
Ключевые слова: аутоиммунный полигландулярный синдром 2, 3, 4-го типов, хроническая надпочечниковая недостаточность, гены DRB1, DQA1, DQB1, HLA II класса, протективные гаплотипы.
________________________________________________
Materials and methods. The case-control study involved 78 patients with APS 2, 3, 4 types and 109 healthy subjects). Alleles of the HLA class II genes, CTLA-4 and PTPN-22 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 – confidence interval).
Results and discussion. 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 of adults compared to the control group. APS patients were divided into two groups according to the presence of chronic adrenal insufficiency (APS 2 and 4 types – in one group and type 3 APS in the other group). 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 of adults. Protective haplotypes DRB1 * 01-DQA1 * 0101-DQB1 * 0501 (p<0.01, OR = 0.07), as well as the DRB1 * 01 allele (p<0.01, OR = 0.08) have been identified with respect to the development of adrenal insufficiency in adult APS patients.
Conclusion. Examination of patients with APS of adults without chronic adrenal insufficiency 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.
Keywords: autoimmune polyglandular syndrome 2, 3, 4 types, chronic adrenal insufficiency, genes DRB1, DQA1, DQB1 HLA class II, protective haplotypes.
Список литературы
1. Дедов И.И., Мельниченко Г.А., редакторы. Эндокринология: Национальное руководство. Москва: ГЭОТАР-Медиа; 2016. С. 1081-1088 [Dedov II, Mel'nichenko GA, editors. Endokrinologiya: natsional'noe rukovodstvo [Endocrinology: National guidelance]. Moscow: GEOTAR-Media; 2016. P. 1081-1088 (In Russ.)]. Available from: http://www.rosmedlib.ru/book/ISBN9785970436820.html
2. Betterle C, Zanchetta R. Update on autoimmune polyendocrine syndromes (APS). Clin Immunol Allergol. 2003;74:9-33.
3. Erichsen M, Lovas K, Skinningsrud B. Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry. J Clin Endocr Metab. 2009;94(12):4882-4890. doi: 10.1210/jc.2009-1368
4. Klein J, Stato A. The HLA System. First of two Parts. N Engl J Med. 2000;343:702-709. doi: 10.1056/nejm200010123431520
5. Klein J, Stato A. The HLA System. Second of two Parts. N Engl J Med. 2000;343:782-786. doi: 10.1056/nejm200011163432020
6. Villano MJB, Huber AK, Greenberg DA, Golden BK, Concepcion E, Tomer Y. Autoimmune thyroiditis and diabetes: dissecting the joint genetic susceptibility in a large cohort of multiplex families. J Clin Endocr Metab. 2009;94:1458-1466. doi: 10.1210/jc.2008-2193
7. Brozzetti A, Marzotti S, Tortoioli C, Bini V, Giordano R, Dotta R, Betterle C, de Bellis A, Arnaldi G, Toscano V, Arvat E, Bellastella A, Mantero F, Falorni A. Cytotoxic T lymphocyte antigen-4 Ala17 polymorphism is a genetic marker of autoimmune adrenal insufficiency: Italian association study and meta-analysis of European studies. Eur J Endocrinol. 2010;162(2):361-369. doi: 10.1530/eje-09-0618
8. Myhre AG, Undelien DA, Lovas K, et al. Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II association related to clinical features. J Clin Endocr Metab. 2002;87:618-623. doi: 10.1210/jc.87.2.618
9. Albergoni P, Gazzola MV, Slanzi E, Carcassi C, Dal Pra C, Moscon A, Betterle C. HLA-DR and DQ associations with autoimmune Addison's disease in Italian patients. Genes Immunity. 2003;4(1):S35.
10. Erichsen M, Løvås K, Skinningsrud B, Wolff A, Undlien D, Svartberg J, Fougner K, Berg T, Bollerslev J, Mella B, Carlson J, Erlich H, Husebye E. Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry. J Clin Endocr Metab. 2009;94(12):4882-4890. doi: 10.1210/jc.2009-1368
11. Huang W, Connor E, Dela Rosa T, Muir A, Schatz D, Silverstein J, Crockett S, She J-X, Maclaren N. Although DR3-DQB1*0201 may be associated with multiple component diseases of the Autoimmune Polyglandular Syndrome,the Human Leukocyte Antigen DR4-DQB1*0302 haplotype is implicated only in beta-cells autoimmunity. J Clin Endocr Metab. 1996;81:2259-2263. doi: 10.1210/jcem.81.7.8675578
12. Wallaschofski H, Meyer A, Tuschy U, Lohmann T. HLA-DQA1*0301-associated susceptibility for autoimmune polyglandular syndrome type II and III. Horm Metab Res. 2003;35(2):120-124. doi: 10.1055/s-2003-39059
13. Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clin Exp Immunol. 2004;137(2):225-233. doi: 10.1111/j.1365-2249.2004.02561.x
14. Baker P, Fain P, Kahles H, Yu L, Hutton J, Wenzlau J, Rewers M, Badenhoop K, Eisenbarth G. Genetic determinants of 21-hydroxylase autoantibodies amongst patients of the Type 1 Diabetes Genetics Consortium. J Clin Endocr Metab. 2012;97(8):E1573-8. doi: 10.1210/jc.2011-2824
15. Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol. 2009;161(1):11-20. doi: 10.1530/eje-09-0044
16. Golden B, Levin L, Ban Y, Concepcion E, Greenberg DA, Tomer Y. Genetic analysis of families with autoimmune diabetes and thyroiditis: evidence for common and unique genes. J Clin Endocr Metab. 2005;90(8):4904-4911. doi: 10.1210/jc.2004-2236
17. Hansen MP, Matheis N, Kahaly GJ. Type 1 diabetes and polyglandular autoimmune syndrome: A review. World J Diabetes. 2015;6(1):67-79. doi: 10.4239/wjd.v6.i1.67
18. Kahles H, Ramos-Lopez E, Lange B, Zwermann O, Reincke M, Badenhoop K. Sex-specific association of PTPN22 1858T with type 1 diabetes but not with Hashimoto’s thyroiditis or Addison’s disease in the German population. Eur J Endocrinol. 2005;153(6):895-899. doi: 10.1530/eje.1.02035
19. Velaga MR, Wilson V, Jennings CE, Owen CJ, Herington S, Donaldson PT, Ball SG, James RA, Quinton R, Perros P, Pearce SH. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J Clin Endocr Metab. 2004;89:5862-5865. doi: 10.1210/jc.2004-1108
2. Betterle C, Zanchetta R. Update on autoimmune polyendocrine syndromes (APS). Clin Immunol Allergol. 2003;74:9-33.
3. Erichsen M, Lovas K, Skinningsrud B. Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry. J Clin Endocr Metab. 2009;94(12):4882-4890. doi: 10.1210/jc.2009-1368
4. Klein J, Stato A. The HLA System. First of two Parts. N Engl J Med. 2000;343:702-709. doi: 10.1056/nejm200010123431520
5. Klein J, Stato A. The HLA System. Second of two Parts. N Engl J Med. 2000;343:782-786. doi: 10.1056/nejm200011163432020
6. Villano MJB, Huber AK, Greenberg DA, Golden BK, Concepcion E, Tomer Y. Autoimmune thyroiditis and diabetes: dissecting the joint genetic susceptibility in a large cohort of multiplex families. J Clin Endocr Metab. 2009;94:1458-1466. doi: 10.1210/jc.2008-2193
7. Brozzetti A, Marzotti S, Tortoioli C, Bini V, Giordano R, Dotta R, Betterle C, de Bellis A, Arnaldi G, Toscano V, Arvat E, Bellastella A, Mantero F, Falorni A. Cytotoxic T lymphocyte antigen-4 Ala17 polymorphism is a genetic marker of autoimmune adrenal insufficiency: Italian association study and meta-analysis of European studies. Eur J Endocrinol. 2010;162(2):361-369. doi: 10.1530/eje-09-0618
8. Myhre AG, Undelien DA, Lovas K, et al. Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II association related to clinical features. J Clin Endocr Metab. 2002;87:618-623. doi: 10.1210/jc.87.2.618
9. Albergoni P, Gazzola MV, Slanzi E, Carcassi C, Dal Pra C, Moscon A, Betterle C. HLA-DR and DQ associations with autoimmune Addison's disease in Italian patients. Genes Immunity. 2003;4(1):S35.
10. Erichsen M, Løvås K, Skinningsrud B, Wolff A, Undlien D, Svartberg J, Fougner K, Berg T, Bollerslev J, Mella B, Carlson J, Erlich H, Husebye E. Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry. J Clin Endocr Metab. 2009;94(12):4882-4890. doi: 10.1210/jc.2009-1368
11. Huang W, Connor E, Dela Rosa T, Muir A, Schatz D, Silverstein J, Crockett S, She J-X, Maclaren N. Although DR3-DQB1*0201 may be associated with multiple component diseases of the Autoimmune Polyglandular Syndrome,the Human Leukocyte Antigen DR4-DQB1*0302 haplotype is implicated only in beta-cells autoimmunity. J Clin Endocr Metab. 1996;81:2259-2263. doi: 10.1210/jcem.81.7.8675578
12. Wallaschofski H, Meyer A, Tuschy U, Lohmann T. HLA-DQA1*0301-associated susceptibility for autoimmune polyglandular syndrome type II and III. Horm Metab Res. 2003;35(2):120-124. doi: 10.1055/s-2003-39059
13. Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clin Exp Immunol. 2004;137(2):225-233. doi: 10.1111/j.1365-2249.2004.02561.x
14. Baker P, Fain P, Kahles H, Yu L, Hutton J, Wenzlau J, Rewers M, Badenhoop K, Eisenbarth G. Genetic determinants of 21-hydroxylase autoantibodies amongst patients of the Type 1 Diabetes Genetics Consortium. J Clin Endocr Metab. 2012;97(8):E1573-8. doi: 10.1210/jc.2011-2824
15. Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol. 2009;161(1):11-20. doi: 10.1530/eje-09-0044
16. Golden B, Levin L, Ban Y, Concepcion E, Greenberg DA, Tomer Y. Genetic analysis of families with autoimmune diabetes and thyroiditis: evidence for common and unique genes. J Clin Endocr Metab. 2005;90(8):4904-4911. doi: 10.1210/jc.2004-2236
17. Hansen MP, Matheis N, Kahaly GJ. Type 1 diabetes and polyglandular autoimmune syndrome: A review. World J Diabetes. 2015;6(1):67-79. doi: 10.4239/wjd.v6.i1.67
18. Kahles H, Ramos-Lopez E, Lange B, Zwermann O, Reincke M, Badenhoop K. Sex-specific association of PTPN22 1858T with type 1 diabetes but not with Hashimoto’s thyroiditis or Addison’s disease in the German population. Eur J Endocrinol. 2005;153(6):895-899. doi: 10.1530/eje.1.02035
19. Velaga MR, Wilson V, Jennings CE, Owen CJ, Herington S, Donaldson PT, Ball SG, James RA, Quinton R, Perros P, Pearce SH. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J Clin Endocr Metab. 2004;89:5862-5865. doi: 10.1210/jc.2004-1108
2. Betterle C, Zanchetta R. Update on autoimmune polyendocrine syndromes (APS). Clin Immunol Allergol. 2003;74:9-33.
3. Erichsen M, Lovas K, Skinningsrud B. Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry. J Clin Endocr Metab. 2009;94(12):4882-4890. doi: 10.1210/jc.2009-1368
4. Klein J, Stato A. The HLA System. First of two Parts. N Engl J Med. 2000;343:702-709. doi: 10.1056/nejm200010123431520
5. Klein J, Stato A. The HLA System. Second of two Parts. N Engl J Med. 2000;343:782-786. doi: 10.1056/nejm200011163432020
6. Villano MJB, Huber AK, Greenberg DA, Golden BK, Concepcion E, Tomer Y. Autoimmune thyroiditis and diabetes: dissecting the joint genetic susceptibility in a large cohort of multiplex families. J Clin Endocr Metab. 2009;94:1458-1466. doi: 10.1210/jc.2008-2193
7. Brozzetti A, Marzotti S, Tortoioli C, Bini V, Giordano R, Dotta R, Betterle C, de Bellis A, Arnaldi G, Toscano V, Arvat E, Bellastella A, Mantero F, Falorni A. Cytotoxic T lymphocyte antigen-4 Ala17 polymorphism is a genetic marker of autoimmune adrenal insufficiency: Italian association study and meta-analysis of European studies. Eur J Endocrinol. 2010;162(2):361-369. doi: 10.1530/eje-09-0618
8. Myhre AG, Undelien DA, Lovas K, et al. Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II association related to clinical features. J Clin Endocr Metab. 2002;87:618-623. doi: 10.1210/jc.87.2.618
9. Albergoni P, Gazzola MV, Slanzi E, Carcassi C, Dal Pra C, Moscon A, Betterle C. HLA-DR and DQ associations with autoimmune Addison's disease in Italian patients. Genes Immunity. 2003;4(1):S35.
10. Erichsen M, Løvås K, Skinningsrud B, Wolff A, Undlien D, Svartberg J, Fougner K, Berg T, Bollerslev J, Mella B, Carlson J, Erlich H, Husebye E. Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry. J Clin Endocr Metab. 2009;94(12):4882-4890. doi: 10.1210/jc.2009-1368
11. Huang W, Connor E, Dela Rosa T, Muir A, Schatz D, Silverstein J, Crockett S, She J-X, Maclaren N. Although DR3-DQB1*0201 may be associated with multiple component diseases of the Autoimmune Polyglandular Syndrome,the Human Leukocyte Antigen DR4-DQB1*0302 haplotype is implicated only in beta-cells autoimmunity. J Clin Endocr Metab. 1996;81:2259-2263. doi: 10.1210/jcem.81.7.8675578
12. Wallaschofski H, Meyer A, Tuschy U, Lohmann T. HLA-DQA1*0301-associated susceptibility for autoimmune polyglandular syndrome type II and III. Horm Metab Res. 2003;35(2):120-124. doi: 10.1055/s-2003-39059
13. Betterle C, Lazzarotto F, Presotto F. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clin Exp Immunol. 2004;137(2):225-233. doi: 10.1111/j.1365-2249.2004.02561.x
14. Baker P, Fain P, Kahles H, Yu L, Hutton J, Wenzlau J, Rewers M, Badenhoop K, Eisenbarth G. Genetic determinants of 21-hydroxylase autoantibodies amongst patients of the Type 1 Diabetes Genetics Consortium. J Clin Endocr Metab. 2012;97(8):E1573-8. doi: 10.1210/jc.2011-2824
15. Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol. 2009;161(1):11-20. doi: 10.1530/eje-09-0044
16. Golden B, Levin L, Ban Y, Concepcion E, Greenberg DA, Tomer Y. Genetic analysis of families with autoimmune diabetes and thyroiditis: evidence for common and unique genes. J Clin Endocr Metab. 2005;90(8):4904-4911. doi: 10.1210/jc.2004-2236
17. Hansen MP, Matheis N, Kahaly GJ. Type 1 diabetes and polyglandular autoimmune syndrome: A review. World J Diabetes. 2015;6(1):67-79. doi: 10.4239/wjd.v6.i1.67
18. Kahles H, Ramos-Lopez E, Lange B, Zwermann O, Reincke M, Badenhoop K. Sex-specific association of PTPN22 1858T with type 1 diabetes but not with Hashimoto’s thyroiditis or Addison’s disease in the German population. Eur J Endocrinol. 2005;153(6):895-899. doi: 10.1530/eje.1.02035
19. Velaga MR, Wilson V, Jennings CE, Owen CJ, Herington S, Donaldson PT, Ball SG, James RA, Quinton R, Perros P, Pearce SH. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J Clin Endocr Metab. 2004;89:5862-5865. doi: 10.1210/jc.2004-1108
________________________________________________
2. Betterle C, Zanchetta R. Update on autoimmune polyendocrine syndromes (APS). Clin Immunol Allergol. 2003;74:9-33.
3. Erichsen M, Lovas K, Skinningsrud B. Clinical, Immunological, and Genetic Features of Autoimmune Primary Adrenal Insufficiency: Observations from a Norwegian Registry. J Clin Endocr Metab. 2009;94(12):4882-4890. doi: 10.1210/jc.2009-1368
4. Klein J, Stato A. The HLA System. First of two Parts. N Engl J Med. 2000;343:702-709. doi: 10.1056/nejm200010123431520
5. Klein J, Stato A. The HLA System. Second of two Parts. N Engl J Med. 2000;343:782-786. doi: 10.1056/nejm200011163432020
6. Villano MJB, Huber AK, Greenberg DA, Golden BK, Concepcion E, Tomer Y. Autoimmune thyroiditis and diabetes: dissecting the joint genetic susceptibility in a large cohort of multiplex families. J Clin Endocr Metab. 2009;94:1458-1466. doi: 10.1210/jc.2008-2193
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Авторы
А.А. Ларина, Е.А. Трошина, О.Н. Иванова
ФГБУ «Национальный медицинский исследовательский центр эндокринологии» Минздрава России, Москва, Россия
National Medical Research Center of Endocrinology, Ministry of Health of Russia, Moscow, Russia
ФГБУ «Национальный медицинский исследовательский центр эндокринологии» Минздрава России, Москва, Россия
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National Medical Research Center of Endocrinology, Ministry of Health of Russia, Moscow, Russia
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