The Protective Effect of HLA-DRB1 and HLA-DQB1 Alleles to ACPA-Positive and RF-Positive RA in Albanian Population

Main Article Content

Margarita Prifti-Kurti
Genc Sulcebe
Erkena Shyti
Zamira Ylli


BACKGOUND: The prevalence of rheumatoid arthritis (RA) and its specific autoantibodies varies in different populations. This variability depends on the genetic polymorphism of the immune response genes among which the HLA system plays a major role.

AIM: We conducted a preliminary study of the distribution of HLA-DRB1 and HLA-DQB1 first field level alleles in a sample of 100 Albanian patients with RA.

METHODS: In this context, we studied the HLA-DRB1 and HLA-DQB1 first-level allele frequencies in 100 Albanian patients with RA and considering their rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) serologic subgroups. We compared them with the respective frequencies in a population of 191 Albanian individuals without known pathology.

RESULTS: No differences were found between the controls and the RA patient group, but three statistically significant differences were found: an increase in DRB1*04 among ACPA-positive, RF-positive and ACPA-positive/RF-positive patients, a significant decrease in DRB1*11 among ACPA-positive/RF-positive, and also a decrease in DRB1*13 among RF-positive patient subgroups. The frequencies of DRB1 allotypes in ACPA+ and RF+ patients compared to their counterpart ACPA− and RF−patient subgroups showed the predisposing effect of HLA-DRB1*04 for ACPA and RF seropositivity (p, respectively, 0.0008 and 0.0017) and the protective role of HLA-DRB1*11 for ACPA and RF positivity (p, respectively, 0.007 and 0.02). The same protective role from the RF positivity is also found with the HLA-DRB1*13 alleles (p = 0.007). As far as the DQB1 locus is concerned, a protective association has been found between the HLA-DQB1*06 alleles with both RF+ and RF+ ACPA+ positivity (p, respectively, 0.05 and 0.04) when comparing the control group with the respective RA patient subgroups. In ACPA+ and RF+ patients compared to the ACPA− and RF− patient subgroups, the only detected difference was between RF (+) and RF (−) patients (p =0.04).

CONCLUSION: The relatively low frequencies of DRB1*04 and high (DRB1*11 and DRB1*13) in the Albanian population might explain the rather low positivity rate of ACPA and RF antibodies among the Albanian RA patients. Our study demonstrates that DRB1*11, DRB1*13 and DQB1*06 may be negatively associated with RA. Conversely, DRB1*04 may confer susceptibility to RA in Albanian population.


Download data is not yet available.

Article Details

How to Cite
Prifti-Kurti M, Sulcebe G, Shyti E, Ylli Z. The Protective Effect of HLA-DRB1 and HLA-DQB1 Alleles to ACPA-Positive and RF-Positive RA in Albanian Population. SEE J Immunol [Internet]. 2023 Jun. 7 [cited 2023 Sep. 23];6(1):24-8. Available from:
Clinical Immunology


Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res. 2002;4 Suppl 3(Suppl 3):S265-72. PMid:12110146

Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: A systematic review. Semin Arthritis Rheum. 2006;36(3):182-8. PMid:17045630

Klareskog L, Padyukov L, Lorentzen J, Alfredsson L. Mechanisms of disease: Genetic susceptibility and environmental triggers in the development of rheumatoid arthritis. Nat Clin Pract Rheumatol. 2006;2(8):425-33. PMid:16932734

Dadoniene J, Uhlig T, Stropuviene S, Venalis A, Boonen A, Kvien TK. Disease activity and health status in rheumatoid arthritis: A case-control comparison between Norway and Lithuania. Ann Rheum Dis. 2003;62(3):231-5. PMid:12594108

Deighton CM, Walker DJ, Griffiths ID, Roberts DF. The contribution of HLA to rheumatoid arthritis. Clin Genet. 1989;36(3):178-82. PMid:2676268

Ohmura K, Terao C, Mimori T. Recent advances on the genetics of rheumatoid arthritis: Current topics and the future. Inflamm Regen. 2012;32(3):90-8.

Balsa A, Cabezón A, Orozco G, Cobo T, Miranda-Carus E, López-Nevot MA, et al. Influence of HLA DRB1 alleles in the susceptibility of rheumatoid arthritis and the regulation of antibodies against citrullinated proteins and rheumatoid factor. Arthritis Res Ther. 2010;12(2):R62. PMid:20370905

Vallbracht I, Rieber J, Oppermann M, Förger F, Siebert U, Helmke K. Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis. Ann Rheum Dis. 2004;63(9):1079-84. PMid:15308516

Nielen MM, van Schaardenburg D, Reesink HW, van de Stadt RJ, van der Horst-Bruinsma IE, de Koning MH, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: A study of serial measurements in blood donors. Arthritis Rheum. 2004;50(2):380-6. PMid:14872479

Rantapää-Dahlqvist S, de Jong BA, Berglin E, Hallmans G, Wadell G, Stenlund H, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48(10):2741-9. PMid:14558078

van Gaalen FA, van Aken J, Huizinga TW, Schreuder GM, Breedveld FC, Zanelli E, et al. Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis. Arthritis Rheum. 2005;7(3):458-67. PMid:15248208

Kroot EJ, de Jong BA, van Leeuwen MA, Swinkels H, van den Hoogen FH, vant Hof M, et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent onset rheumatoid arthritis. Arthritis Rheum. 2000;43(8):1831-5.<1831:AID- ANR19>3.0.CO;2-6 PMid:10943873

Swart A, Burlingame RW, Gürtler I, Mahler M. Third generation anti-citrullinated peptide antibody assay is a sensitive marker in rheumatoid factor negative rheumatoid arthritis. Clin Chim Acta. 2012;414:266-72. PMid:23022338

van Venrooij WJ, Hazes JM, Visser H. Anticitrullinated protein/ peptide antibody and its role in the diagnosis and prognosis of early rheumatoid arthritis. Neth J. 2002;60(10):383-8.

Niewold TB, Harrison MJ, Paget SA. Anti-CCP antibody testing as a diagnostic and prognostic tool in rheumatoid arthritis. QJM. 2007;100(4):193-201. PMid:17434910

Iain B, McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205-19. PMid:22150039

de Vries RR, Huizinga TW, Toes RE. HLA and RA revisited: Citrullinated food for the SE hypothesis, the DR6 effect, and NIMA. Hum Immunol. 2006;67(6):454-9. PMid:16728269

Barnetche T, Constantin A, Cantagrel A, Cambon-Thomsen A, Gourraud PA. New classification of HLA-DRB1 alleles in rheumatoid arthritis susceptibility: A combined analysis of worldwide samples. Arthritis Res Ther. 2008;10(1):R26. PMid:18307784

de Vries RR, van der Woude D, Houwing JJ, Toes RE. Genetics of ACPA-positive rheumatoid arthritis: The beginning of the end? Ann Rheum Dis. 2011;70 Suppl 1:i51-4. PMid:21339219

Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315-24. PMid:3358796

Bang H, Egerer K, Gauliard A, Lüthke K, Rudolph PE, Fredenhagen G, et al. Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum. 2007;56(8):2503-11. PMid:17665451

Dejaco C, Klotz W, Larcher H, Duftner C, Schirmer M, Herold M. Diagnostic value of antibodies against a modified citrullinated vimentin in rheumatoid arthritis. Arthritis Res Ther. 2006;8(4):R119. PMid:16859519

Nunes JM, Riccio ME, Buhler S, Di D, Currat M, Ries F, et al. Analysis of the HLA population data (AHPD) submitted to the 15th International Histocompatibility/Immunogenetics Workshop byusingtheGene[rate]computertoolsaccommodatingambiguous data (AHPD project report). Tissue Antigens. 2010;76(1):18-30. PMid:20331842

R Development Core Team. R: A Language and Environment for Statistical Computing. Foundation for Statistical Computing, Vienna, Austria; 2008. Available from:

Glantz SA. Primer of Biostatistics. 7th ed. New York: McGraw- Hill; 2005.

van der Helm-van Mil AH, Huizinga TW, Schreuder GM, Breedveld FC, de Vries RR, Toes RE. An independent role of protective HLA class II alleles in rheumatoid arthritis severity and susceptibility. Arthritis Rheum. 2005;52(9):2637-44. PMid:16142711

van der Woude D, Lie BA, Lundström E, Balsa A, Feitsma AL, Houwing-Duistermaat JJ, et al. Protection against anti- citrullinated protein antibody-positive rheumatoid arthritis is predominantly associated with HLA-DRB1*1301: A meta- analysis of HLA-DRB1 associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody- negative rheumatoid arthritis in four European populations. Arthritis Rheum. 2010;62(5):1236-45. PMid:20131291

Laivoranta-Nyman S, Mottonen T, Hermann R, Tuokko J, Luukkainen R, Hakala M, et al. HLA-DR-DQ haplotypes and genotypes in Finish patients with rheumatoid arthritis. Ann Rheum Dis. 2004;63(11):1406-12. PMid:15479890

Rice TK, Schork NJ, Rao DC. Methods for handling multiple testing. Adv Genet. 2008;60:293-308. PMid:18358325