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HLA-DRB1 alleles distribution in patients with rheumatoid arthritis in a tertiary center in the Southeastern Anatolia region of Turkey /Turkiye'nin guneydogu anadolu bolgesinde tersiyer bir merkezdeki romatoid artritli hastalarda HLA-DRB1 alel dagilimi.

Introduction

Rheumatoid arthritis (RA) is a multifactorial disease that occurs due to genetic and environmental factors (1). The genetic predisposition to RA has been supported through the evidence obtained from studies conducted on siblings and twins (2,3). The relationship between HLA class II genes and the genetic predisposition to RA has been clearly defined. The main determinant among the genes causing a predisposition to RA is the HLA-DRB1 alleles (4). This relationship between HLA-DRB1 and RA varies according to different populations. The association between the HLA-DRB1 alleles and RA has been shown in many populations, such as Italian, Caucasian, Finn, Korean and Latin American populations (4-8).

Genetic research has revealed that the HLA-DRB1 alleles code a conserved sequence, which is characterized by the RAA pattern at position 72-74 of the third hypervariable region of different HLA-DR chains. This region in the third hypervariable region of the DRB1 molecule is defined as the 'shared epitope (SE)' and the SE is connected to the occurrence and severity of arthritis (2,3,7,9). Due to the differences in the geographical distribution of the HLA genes, it is yet to be clarified which HLA-DRB1 alleles are protective (10).

Although the relationship between RA and HLA has been evaluated in many populations, there are rather few studies conducted on the Turkish population (11,12). In the present study, our aim was to determine the genotyping of the HLA- DRB1 alleles and certain HLA-DRB1 subgroups (HLA-DRB1*01, *04, *07, *08, *10) among the population in the Southeastern Anatolia Region of Turkey.

Materials and Methods

This study was approved by the Ethics Committee of the Dicle University School of Medicine. Ninety-six patients (78 female, 18 male) who have applied to the physical medicine and rehabilitation outpatient clinic at Dicle University School of Medicine, and were diagnosed with RA according to the 1987 American College of Rheumatology (ACR) classification criteria were enrolled in the study together with 84 healthy individuals (48 female, 36 male) from the same region as the control group. The control group consisted of individuals who applied to the molecular hematology laboratory at Dicle University School of Medicine as donors. Written informed consent was obtained from all the subjects. Data on age and sex and age at disease onset were recorded. All the patients underwent a detailed physical examination. The RF titres were measured through the nephelometric immunoassay method and values above 20 IU/ mL were considered positive. Erythrocyte sedimentation rate was measured by the Westergren method (mm/h), and serum C reactive protein levels were measured by nephelometry (mg/l).

Peripheral blood samples collected from all RA patients and healthy individuals were stored at -30[degrees]C for DNA isolation. The DNA isolation was performed using the GenoM-6 model (Qiagen) isolation robot and the EZ1 DNA blood kit (Qiagen). Polymerase chain reaction (PCR) amplification of the DNA was done through the Thermal Cycler (Corbet Research), and the HLA-DRB1 genotyping was performed using the PCR-SSP HLA-DRB1 Low Resolution gene panel manufactured by Olerup. The HLA-DRB1*01, 04, 07, 08, 10 subtypes were detected using the PCR-SSP HLA-DRB1 High Resolution genotyping panel also manufactured by Olerup.

Computerized statistical analyses were performed using SPSS 15.0 for Windows and MedCalc Version 10.1.6.0 Biostatistics package. The standard distribution, frequency and percentages of the variables were calculated. Fisher's exact Chi- Square test was used for the comparison of proportional variables and the relationships were calculated in odds ratio (OR) and 95% CI (confidence interval). A p value of less than 0.05 was considered statistically significant.

Results

The demographic data and the disease features of the 96 patients diagnosed with RA are presented in Table 1. Extraarticular involvements were diabetes mellitus (DM) (4.2%), hypertension (HT) (23.9%), coroner heart disease (4.1%), hypothyroidism (1.1%), and chronic hepatic disease (1.1%).

When the allele type frequencies were compared between RA-patient group and the control group, the DRB1*10 allele was found to be significantly higher in the RA patient group, while the DRB1*07 and DRB1*11 alleles were significantly lower in patients with RA (p<0.05). When the patient and control groups were compared, no significant difference was observed in the frequencies of the DRB1*01, DRB1*03, DRB1*04, DRB1*08, DRB1*13, DRB1*14, DRB1*15, and DRB1*16 alleles (p>0.05) (Table 2).

The most frequently observed DRB1*04 subtypes were the DRB1*0405, DRB1*0408, DRB1*0403, DRB1*0401, DRB1*0402 and DRB1*0404 in order of frequency (17.5 %, 9.3 %, 8.2 %, 7.2 %, 6.2 %, 6.2 %, respectively). There was no relationship between accompanying systemic disease and DRB1 alleles (p>0.05). When the allele subtype frequencies in the patient group and the control group were compared, the DRB1*0401, DRB1*0408 and DRB1*1001 subtypes were found to be significantly higher (p<0.05) in the RA patient group, while the DRB1*0402, DRB1*0403 and DRB1*0701 subtypes were found to be significantly lower (p<0.05) (Table 3). No significant difference in the frequencies of the DRB1*0101, DRB1*0404, DRB1*0405, DRB1*0801 and DRB1*0804 subtypes were observed between the patient and control groups (p>0.05). There was no relationship between RF seropositivity and DRB1 alleles (p>0.05).

Discussion

In the present study, the distribution of the HLA-DRB1 alleles among patients diagnosed with RA in the Southeastern Anatolia Region of Turkey was investigated. Although the DRB1*04 allele was more frequently observed among the patients with RA compared to controls, the result was not statistically significant.

The association between HLA-DR and RA is attributable to the susceptibility alleles that encode a homologous amino acid sequence in the third hypervariable region of the first domain of the HLA-DR beta chain. This sequence was determined as the ''shared epitope'' (SE) and this epitope is considered to explain the main role of the HLA-DRB1 in susceptibility leading to RA (1-2). Variations among the subtypes related to RA mainly originate from the different distributions of the HLA-DRB1 alleles among the ethnic groups (1).

In this study, the DRB1*10 type and the DRB1*0401, DRB1*0408, DRB1*1001 subtypes were found to be significantly more frequent in the study group. The relationship of the DRB1*0401 alleles with the predisposition to the disease in our study was in compliance with the studies conducted on Spanish (13), Greek (14) and Caucasian (15) populations, as well as the populations in various regions in Turkey (11,12). Similarly, the relationship of the DRB1*0408 subtype with the predisposition to RA in our study was in line with other studies conducted on patients from Northern Hungary (16), Finland (6) and the Caucasus (15). However, the DRB1*01, DRB1*04, DRB1*0404 and DRB1*0405 alleles were not observed to have a statistically significant relationship with the disease in our region, although the frequency of these alleles was higher in patients with RA. This may have resulted from the limited number of the patients in our study.

In a meta-analysis on the Asian population, the DRB1*1001 allele was shown to be more frequent in patients with RA compared to controls (17). In the Spanish (13) and Greek populations (14), the DRB1*1001 allele was found to be related with the predisposition to RA. In line with our study, RA patients in Greece were also observed to have the DRB1*10 alleles (14). However, no significant relationship between the DRB1*10 alleles and RA was observed in studies conducted in Morocco (18), Kuwait (19) and Pakistan (13). In our study, the DRB1*10 and DRB1*1001 were found to be statistically significantly associated with the predisposition to RA.

In other studies conducted in Turkey, the DRB1*01 and DRB1*0101 alleles were found to be related with the predisposition to RA (11,12). Similarly, among Ashkenazi Jews (13) and various populations from the Caucasus (5), the DRB1*01 allele has been shown to play a role in the pathogenesis of RA. In our study, the frequency of the DRB1*01 and DRB1*0101 alleles in RA patients were higher than in controls, although the difference was statistically insignificant. In line with our study, another study conducted in Northern Hungary found that the DRB1*01 and its subtypes had no significance in the predisposition to RA (16).

In the present study, the frequency of the DRB1*07, DRB1*11 types and the DRB1 *0402, DRB1*0403, DRB1*0701 subtypes in RA patients were observed to be significantly lower. In a meta-analysis on the Asian population, the DRB1*0403, DRB1*0701, DRB1*1101 and DRB1*1405 subtypes were found as the protective alleles in patients with RA (17). In addition, in another study on RA patients in Korea, DRB1*0701 has been described as the protective subtype (7). In another study conducted by Yelamos et al. in Spain, the DRB1*0402 and DRB1*07 were determined as the negative risk factors for RA (13). These results are also in compliance with those of our study. In a study from Turkey, the DRB1*0402 and DRB1*13 alleles were evaluated as the protective alleles (12). Besides, the DRB1*13 was found as the protective allele against RA in Asians (7,17, 20), Germans (21), and in people from Finland (6) and the Caucasus (22). Also, the DRB1*13 allele was observed more frequently in the control group compared to the patients with RA in our study, the difference was not statistically significant. In contrast with these studies, certain studies conducted in Kuwait and Italy failed to associate any of the subtypes with protectiveness (4,19).

In our study, no significant relationship was observed between seropositivity and the HLA-DRB1 alleles. In a study by Kinikli et al., (11) no association was observed between the HLA-DRB1 alleles and parameters, such as seropositivity, functional status, and radiological erosion indicating the severity of the disease. Similarly, another study conducted in Kuwait failed to point out any relationship between seropositivity and HLA-DRB1. Moreover, the DRB1*04 and the erosive and non-erosive forms of the disease were also found to be unrelated with each other (19). Contrarily, in a study in Morocco, the frequency of RF was observed to be higher in patients carrying the DRB1*04 and it was concluded that the HLA alleles may play an important role in patients with early seropositive RA (18).

In conclusion, the DRB1 *0401, DRB1*0408, DRB1*10 and DRB1*1001 alleles were identified to be related with RA. In contrast, the DRB1*0402 and DRB1*0403, DRB1*07, DRB1*0701 DRB1*11 alleles were observed to be the protective alleles in our region. The results obtained from this study reveal the HLA-DRB1 distribution among RA patients in the Southeastern Anatolia region of Turkey and its relationship with seropositivity. Although the protective alleles we detected in our region differ from the results of the studies conducted in other regions of Turkey (11,12), they still comply with various other studies (13,17).

Further studies conducted on larger patient populations are needed in order to define the relationship between the distribution of the HLA-DRB1 and RA.

DOI: 10.4274/tftr.83446

Conflict of Interest

Authors reported no conflicts of interest.

References

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(2.) Kochi Y, Suzuki A, Yamada R, Yamamoto K. Genetics of rheumatoid arthritis: underlying evidence of ethnic differences. J Autoimmun 2009;32:158-62.

(3.) Newton JL, Harney SM, Wordsworth BP, Brown MA. A review of the MHC genetics of rheumatoid arthritis. Genes Immun 2004;5:151-7.

(4.) Salvarani C, Macchioni PL, Mantovani W, Bragliani M, Collina E, Cremonesi T, et al. HLA-DRB1 alleles associated with rheumatoid arthritis in Northern Italy: correlation withdisease severity. Br J Rheumatol 1998;37:165-9.

(5.) Bridges SL Jr, Kelley JM, Hughes LB.The HLA-DRB1 shared epitope in Caucasians with rheumatoid arthritis: a lesson learned from tic-tac-toe. Arthritis Rheum 2008;58:1211-5.

(6.) Tuokko J, Nejentsev S, Luukkainen R, Toivanen A, Ilonen J. HLA haplotype analysis in Finnish patients with rheumatoid arthritis. Arthritis Rheum 2001;44:315-22.

(7.) Lee HS, Lee KW, Song GG, Kim HA, Kim SY, Bae SC. Increased susceptibility to rheumatoid arthritis in Koreans heterozygous for HLA-DRB1*0405 and *0901. Arthritis Rheum 2004;50:3468-75.

(8.) Delgado-Vega AM, Anaya JM. Meta-analysis of HLA DRB1 polymorphism in Latin American patients with rheumatoid arthritis. Autoimmun Rev 2007;6:402-8.

(9.) Seidl C, Koch U, Buhleier T, Frank R, Moller B, Markert E, et al. HLA-DRB1*04 subtypes are associated with increased inflammatory activity in earlyrheumatoid arthritis. Br J Rheumatol 1997;36:941-4.

(10.) Van der Woude D, Lie BA, Lundstrom E, Balsa A, Feitsma AL, Houwing-Duistermaat JJ, et al. Protection against anti-citrullinated protein antibody-positive rheumatoid arthritis ispredominantly 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;62:1236-45.

(11.) Kinikli G, Ates A, Turgay M, Akay G, Kinikli S, Tokgoz G. HLA-DRB1 genes and disease severity in rheumatoid arthritis in Turkey. Scand J Rheumatol 2003;32:277-80.

(12.) Ucar F, Karkucak M, Alemdaroglu E, Capkin E, Yucel B, Sonmez M, et al. HLADRB1 allele distribution andits relation to rheumatoid arthritis in eastern Black Sea Turkish population. Rheumatol Int 2012;32:1003-7.

(13.) Yelamos J, Garcia-Lozano JR, Moreno I, Aguilera I, Gonzalez MF, Garcia A, et al. Association of HLA-DR4- Dw15 (DRB1*0405) and DR10 with rheumatoid arthritis in a Spanish population. Arthritis Rheum 1993;36:811-4.

(14.) Boki KA, Panayi GS, Vaughan RW, Drosos AA, Moutsopoulos HM, Lanchbury JS. HLA class II sequence polymorphisms and susceptibility to rheumatoid arthritis in Greeks. Arthritis Rheum 1992;35:749-55.

(15.) Chun-Lai T, Padyukov L, Dhaliwal JS, Lundstrom E, Yahya A, Muhamad NA, et al. Shared epitope alleles remain a risk factor for anti-citrullinated proteins antibody (ACPA) positive rheumatoid arthritis in three asian ethnic groups. PLoS One 2011;6: e21069.

(16.) Kapitany A, Zilahi E, Szanto S, Szucs G, Szabo Z, Vegvari A, et al. Association of rheumatoid arthritis with HLA- DR1 and HLA-DR4 in Hungary. Ann N Y Acad Sci 2005;1051:263-70.

(17.) Jun KR, Choi SE, Cha CH, Oh HB, Heo YS, Ahn HY, et al. Meta-analysis of the association between HLA-DRB1 allele and rheumatoid arthritis susceptibility in asian populations. J Korean Med Sci 2007;22:973-80.

(18.) Atouf O, Benbouazza K, Brick C, Bzami F, Bennani N, Amine B, et al. HLA polymorphism and early rheumatoid arthritis in the Moroccan population. Joint Bone Spine 2008;75:554-8.

(19.) Alsaeid K, Alawadhi A, Al-Saeed O, Haider MZ. Human leukocyte antigen DRB1*04 is associated with rheumatoid arthritis in Kuwaiti patients. Joint Bone Spine 2006;73:62-5.

(20.) Xue Y, Zhang J, Chen YM, Guan M, Zheng SG, Zou HJ. The HLA-DRB1 shared epitope is not associated with antibodies gainst cyclic citrullinated peptide in Chinese patients with rheumatoid arthritis. Scand J Rheumatol 2008;37:183-7.

(21.) De Vries N, Tijssen H, van Riel PL, van de Putte LB. Reshaping the shared epitope hypothesis: HLA-associated risk for rheumatoid arthritis is encoded by amino acid substitutions at positions 67-74 of the HLA-DRB1 molecule. Arthritis Rheum 2002;46:921-8.

(22.) Morgan AW, Haroon-Rashid L, Martin SG, Gooi HC, Worthington J, Thomson W, et al. The shared epitope hypothesis in rheumatoid arthritis: evaluation of alternative classification criteria in a large UK Caucasian cohort. Arthritis Rheum 2008;58:1275-83.

Ibrahim BATMAZ, Mustafa Akif SARIYILDIZ, Banu DILEK, Ismail YILDIZ *, kemal NAS, Orhan AYYILDIZ **, Remzi CEVIK

Dicle University, Department of Physical Medicine and Rehabilitation, Diiyarbakir, Turkey

* Dicle University, Department of Biostatistics, Diyarbakir, Turkey

** Dicle University, Department of Haematology, Diyarbakir, Turkey

Address for Correspondence:/Yazisma Adresi: Mustafa Akif Sariyildiz MD, Dicle University, Department of Physical Medicine and Rehabilitation, Diiyarbakir, Turkey

Phone: +90 212 534 69 00-1306 E-mail: sariyildiz@doctor.com

Received/Gelis Tarihi: December/Aralik 2011 Accepted/Kabul Tarihi: April/Nisan 2012
Table 1. Demographic and clinical characteristics in RA patients.

Characteristics                               n=96

Age (years)                                   46.97 [+ or -] 13.44
Sex (Female%)                                 81.2%
Accompanying systemic disease (%)             32.3%
Morning stiffness [+ or -] SD (minutes)       83.71 [+ or -] 53.70
Median disease duration [+ or -] SD (years)    7.52 [+ or -] 6.86
ESR mean [+ or -] SD (mm/h)                   28.55 [+ or -] 21.38
CRP mean [+ or -] SD (mg/dl)                   3.20 [+ or -] 6.17
RF mean [+ or -] SD (IU/mL)                  123.10 [+ or -] 18.44

ESR: Erythrocyte Sedimentation Rate; CRP: C-Reactive Protein;
RF: Rheumatoid Factor; SD: Standart Deviation

Table 2. The distribution of HLA DRB1 alleles in RA and control
groups.

HLA-DRB1  RA patients   Control     OR      95% CI      p

           n%   AF      n%   AF

DRB1*01    13   6.8%    4    2.4%    2.98   0.95-9.32   0.08
DRB1*03    17   8.9%    17   10.1%   0.86   0.43-1.75   0.72
DRB1*04    53   27.6%   33   19.6%   1.56   0.95-2.56   0.08
DRB1*07    8    4.2%    25   14.9%   0.25   0.11-0.57   0.001
DRB1*08    6    3.1%    1    0.6%    5.39   0.64-45.21  0.12
DRB1*10    17   8.9%    2    1.2%    8.06   1.83-35.44  0.006
DRB1*11    28   14.6%   41   24.4%   0.53   0.31-0.90   0.02
DRB1*13    14   7.3%    16   9.5%    0.75   0.35-1.58   0.45
DRB1*14    6    3.1%    5    3%      1.05   0.32-3.51   0.93
DRB1*15    26   13.5%   19   11.3%   1.23   0.65-2.31   0.63
DRB1*16    4    2.1%    5    3%      0.69   0.18-2.63   0.59
Total      192  100%    168  100%

RA: Rheumatoid Arthritis, AF: Allele Frequency

Table 3. The distribution of HLA DRB1 subtypes in RA and control
groups.

HLADRB1     RA patients  Control      OR      95% CI        p

            n%   AF      n%   AF%

DRB1*0101   13   13.4%   4    6.2%    2.43    0.76-7.86     0.13
DRB1*0401   7    7.2%    0    0%      10.69   0.6-190.55    0.04
DRB1*0402   6    6.2%    13   20.3%   0.26    0.09-0.75     0.01
DRB1*0403   8    8.2%    14   21.9%   0.32    0.13-0.86     0.02
DRB1*0404   6    6.2%    1    1.6%    4.15    0.49-35.35    0.25
DRB1*0405   17   17.5%   5    7.8%    2.51    0.88-7.18     0.10
DRB1*0408   9    9.3%    0    0%      14.50   0.79-242.26   0.01
DRB1*0701   8    8.2%    24   37.5%   0.15    0.06-0.36     <0.001
DRB1*0801   6    6.2%    0    0%      9.16    0.51-165.57   0.08
DRB1*0804   0    0%      1    1.6%    0.22    0.01-5.41     0.4
DRB1*1001   13   13.4%   2    3.1%    6.59    1.47-29.59    0.05
Total       93   100%    64   100%

RA: Rheumatoid Arthritis, AF: Allele Frequency
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Title Annotation:Original Article/Orijinal Makale
Author:Batmaz, Ibrahim; Sariyildiz, Mustafa Akif; Dilek, Banu; Yildiz, Ismail; Nas, Kemal; Ayyildiz, Orhan;
Publication:Turkish Journal of Physical Medicine and Rehabilitation
Article Type:Report
Geographic Code:7TURK
Date:Jun 1, 2013
Words:3145
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