Perçin PAZARCI, Salih ÇETİNER, Gökhan KARACAOĞLAN, Ümit LÜLEYAP, Ayşegül Yolga TAHİROĞLU, Yaşar SERTDEMİR, Gülşah EVYAPAN, Davut ALPTEKİN, Doğa LÜLEYAP, Akgün YAMAN

Determination of the relationship between major histocompatibility complex alleles and childhood onset obsessive-compulsive disorder

Background/aim: About half of the cases of obsessive-compulsive disorder (OCD) occurring in childhood/adolescence occur with similar symptoms both in childhood and adulthood. Immunologic stress is claimed to be a risk factor in the etiology of childhood onset OCD. Our aim was to elucidate the relationship between childhood onset OCD risk and MHC complex I and II alleles. Materials and methods: MHC alleles of 49 OCD children together with 277 healthy children (aged 4–12) were analyzed by PCR. Results were evaluated by using univariate analysis and multivariate logistic regression analysis. Results: A2, A29, C4, DRB3.1, and DRB1*16 alleles were found to increase the risk of OCD. Conclusion: The relationship found between DRB locus and OCD in this study was remarkable since there have been studies on different populations reporting similar relationship between DRB locus and rheumatoid arthritis, which is also an AID. MHC class I and class II alleles were found to increase the risk of OCD in our study, which serves as a suitable model for studies suggesting that MHC genes do not work completely independently. Even though the MHC class I and II genes are considered to have different roles in immune response, in fact they tend to work in cooperation. As in previous studies on AIDs, there is a linear relationship between MHC class II alleles and OCD risk.

PDF

___

1. Boileau B. A review of obsessive-compulsive disorder in children and adolescents. Dialogues in Clinical Neuroscience 2011; 13 (4):401-411. doi: 10.31887/DCNS.2011.13.4/bboileau
2. Abramowitz JS, McKay D, Taylor S. Obsessive-compulsive disorder : subtypes and spectrum conditions. 1st ed. Boston, MA, USA: Elsevier; 2008.
3. American Psychiatric Association. DSM-5 Task Force. Diagnostic and statistical manual of mental disorders : DSM5. 5th ed. Washington, D.C., USA: American Psychiatric Association; 2013.
4. Khramtsova EA, Heldman R, Derks EM, Yu D, Davis LK et al. Sex differences in the genetic architecture of obsessivecompulsive disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2019; 180 (6):351-364. doi: 10.1002/ajmg.b.32687
5. Sadock BJ, Sadock VA, Ruiz P, Kaplan HI. Kaplan & Sadock’s comprehensive textbook of psychiatry, 9th ed. Philadelphia, PA, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009.
6. Asbahr FR, Negrao AB, Gentil V, Zanetta DMT, da Paz JA et al. Obsessive-compulsive and related symptoms in children and adolescents with rheumatic fever with and without chorea: A prospective 6-month study. American Journal of Psychiatry 1998; 155 (8):1122-1124. doi: 10.1176/ajp.155.8.1122
7. Cusick MF, Libbey JE, Fujinami RS. Molecular Mimicry as a Mechanism of Autoimmune Disease. Clinical Reviews in Allergy & Immunology 2012; 42 (1):102-111. doi: 10.1007/ s12016-011-8294-7
8. Leverkus M, McLellan AD, Heldmann M, Eggert AO, Brocker EB et al. MHC class II-mediated apoptosis in dendritic cells: a role for membrane-associated and mitochondrial signaling pathways. International Immunology 2003; 15 (8):993-1006. doi: 10.1093/intimm/dxg099
9. Gough SCL, Simmonds MJ. The HLA region and autoimmune disease: Associations and mechanisms of action. Current Genomics 2007; 8 (7):453-465. doi: 10.2174/138920207783591690
10. Swedo SE, Leonard HL. Childhood Movement-Disorders and Obsessive-Compulsive Disorder. Journal of Clinical Psychiatry 1994; 55:32-37.
11. Özcan ME. Human leukocyte antigen DR1 in Japanese and Turkish patients with schizophrenia. Progress in NeuroPsychopharmacology & Biological Psychiatry 2006; 30 (3):423- 428. doi: 10.1016/j.pnpbp.2005.11.015
12. Wright P, Nimgaonkar VL, Donaldson PT, Murray RM. Schizophrenia and HLA: a review. Schizophrenia Research 2001; 47 (1):1-12. doi: 10.1016/S0920-9964(00)00022-0
13. Pauls DL, Abramovitch A, Rauch SL, Geller DA. Obsessivecompulsive disorder: an integrative genetic and neurobiological perspective. Nature Reviews Neuroscience 2014; 15 (6):410- 424. doi: 10.1038/nrn3746
14. Karno M, Golding JM, Sorenson SB, Burnam MA. The epidemiology of obsessive-compulsive disorder in five US communities. Archives Of General Psychiatry 1988; 45 (12):1094-1099. doi: 10.1001/archpsyc.1988.01800360042006
15. Rasmussen SA, Tsuang MT. The epidemiology of obsessive compulsive disorder. Journal of Clinical Psychiatry 1984; 45 (11):450-457.
16. Grados MA, Riddle MA, Samuels JF, Liang KY, Hoehn-Saric R et al. The familial phenotype of obsessive-compulsive disorder in relation to tic disorders: the Hopkins OCD family study. Biological Psychiatry 2001; 50 (8):559-565. doi: 10.1016/ S0006-3223(01)01074-5
17. Eapen V, Robertson MM, Alsobrook JP, 2nd, Pauls DL. Obsessive compulsive symptoms in Gilles de la Tourette syndrome and obsessive compulsive disorder: differences by diagnosis and family history. American Journal of Medical Genetics 1997; 74 (4):432-438. doi: 10.1002/(sici)1096- 8628(19970725)74:4<432::aid-ajmg15>3.0.co;2-j
18. Swedo SE, Rapoport JL, Leonard H, Lenane M, Cheslow D. Obsessive-compulsive disorder in children and adolescents. Clinical phenomenology of 70 consecutive cases. Archives Of General Psychiatry 1989; 46 (4):335-341. doi: 10.1001/ archpsyc.1989.01810040041007
19. Shiina T, Hosomichi K, Inoko H, Kulski JK. The HLA genomic loci map: expression, interaction, diversity and disease. Journal of Human Genetics 2009; 54 (1):15-39. doi: 10.1038/jhg.2008.5
20. Allen AJ, Leonard HL, Swedo SE. Case study: a new infectiontriggered, autoimmune subtype of pediatric OCD and Tourette’s syndrome. Journal of the American Academy of Child & Adolescent Psychiatry 1995; 34 (3):307-311. doi: 10.1097/00004583-199503000-00015
21. Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. American Journal of Psychiatry 1998; 155 (2):264-271. doi: 10.1176/ajp.155.2.264
22. Miyadera H, Tokunaga K. Associations of human leukocyte antigens with autoimmune diseases: challenges in identifying the mechanism. Journal of Human Genetics 2015; 60 (11):697- 702. doi: 10.1038/jhg.2015.100
23. Cappi C, Brentani H, Lima L, Sanders SJ, Zai G et al. Wholeexome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways. Translational Psychiatry 2016; 6:e764. doi: 10.1038/ tp.2016.30
24. Costas J, Carrera N, Alonso P, Gurriaran X, Segalas C et al. Exon-focused genome-wide association study of obsessivecompulsive disorder and shared polygenic risk with schizophrenia. Translational Psychiatry 2016; 6:e768. doi: 10.1038/tp.2016.34
25. Verreck FA, Termijtelen A, Koning F. HLA-DR beta chain residue 86 controls DR alpha beta dimer stability. European Journal of Immunology 1993; 23 (6):1346-1350. doi: 10.1002/ eji.1830230624
26. Emery P, Mach B, Reith W. The different level of expression of HLA-DRB1 and -DRB3 genes is controlled by conserved isotypic differences in promoter sequence. Human Immunology 1993; 38 (2):137-147. doi: 10.1016/0198-8859(93)90531-5
27. Gough SC, Simmonds MJ. The HLA Region and Autoimmune Disease: Associations and Mechanisms of Action. Current Genomics 2007; 8 (7):453-465. doi: 10.2174/138920207783591690
28. Khankhanian P, Matsushita T, Madireddy L, Lizee A, Din L et al. Genetic contribution to multiple sclerosis risk among Ashkenazi Jews. Bmc Medical Genetics 2015; 16,55. doi: 10.1186/s12881-015-0201-2
29. Zhang YQ, Zhang H, Huang Y, Sun RB, Liu RP et al. Human leukocyte antigen (HLA)-C polymorphisms are associated with a decreased risk of rheumatoid arthritis. Molecular Biology Reports 2014; 41 (6):4103-4108. doi: 10.1007/s11033- 014-3280-9
30. Nordang GBN, Flam ST, Maehlen MT, Kvien TK, Viken MK et al. HLA-C alleles confer risk for anti-citrullinated peptide antibody-positive rheumatoid arthritis independent of HLADRB1 alleles. Rheumatology 2013; 52 (11):1973-1982. doi: 10.1093/rheumatology/ket252
31. Simmonds MJ, Howson JMM, Heward JM, Carr-Smith J, Franklyn JA et al. A novel and major association of HLA-C in Graves’ disease that eclipses the classical HLA-DRB1 effect. Human Molecular Genetics 2007; 16 (18):2149-2153. doi: 10.1093/hmg/ddm165