Tumour necrosis factor-{alpha} polymorphism and the HLA-Cw*0602 allele in psoriatic arthritis

A. M. Al-Heresh, J. Proctor1, S. M. Jones, J. Dixey, B. Cox, K. Welsh1 and N. McHugh

Royal National Hospital for Rheumatic Diseases and Department of Medical Sciences, University of Bath, Bath and
1 Transplantation Immunology, Nuffield Department of Surgery, Oxford Transplant Centre, Churchill Hospital, Oxford, UK


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives. To investigate polymorphisms in the genes for tumour necrosis factor {alpha} (TNFA), interleukin 10 (IL10) and tumour necrosis factor receptor II (TNFRII) in patients with psoriatic arthritis (PsA) and their relationship to the HLA-Cw*0602 allele and to the ages at onset of psoriasis and arthritis and the pattern of joint involvement.

Methods. One hundred and twenty-four well-characterized patients with PsA were studied. Controls were 101 cadaveric organ donors. All were genotyped for single-nucleotide polymorphisms in TNFA (positions -308, -238, +488), IL10 (-1082, -819, -592) and in the 3'-untranslated region of TNFRII (+1663, +1668, +1690). The HLA-Cw*0602 allele was detected by polymerase chain reaction-based techniques. The frequencies of the respective variants were compared between patients and controls and in relation to the ages at onset of psoriasis and arthritis, to clinical subsets of the disease and to the presence of erosions.

Results. HLA-Cw*0602 was significantly increased in frequency in PsA (40 vs 26%; P<0.05) and was associated with younger age of onset of psoriasis (P<0.05). There was no significant increase in any of the polymorphisms studied within TNFA, IL10 or TNFRII in the total PsA group. Although the frequency of TNFA allele -238A was not increased in the total PsA group or in patients with a younger age of onset of psoriasis, TNFA allele -238A was absent in the spondyloarthritis group and increased in frequency in patients with peripheral polyarthritis. However, these latter findings could be explained by linkage disequilibrium as all TNFA -238A alleles (23/23) in patients with PsA were HLA-Cw*0602-positive (P<0.0001).

Conclusions. An association between young age of onset of psoriasis and HLA-Cw*0602 is confirmed in patients with PsA. The uncommon TNFA -238A allele is strongly linked to HLA-Cw*0602 and as such is associated with the development of peripheral polyarthritis rather than spondylitis. Further investigation of possible HLA-Cw*0602 linked genes in PsA is warranted.

KEY WORDS: Psoriatic arthritis, HLA, Cytokine gene, Tumour necrosis factor.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Psoriatic arthritis (PsA) is an inflammatory disorder of unknown aetiology that may affect the synovium and enthesis of peripheral and axial joints, and occurs in 7–42% of patients with psoriasis. The prevalence of PsA among first-degree relatives of patients with PsA is 5.5% compared with an estimated 0.1% in the normal population [1]. Significant gene linkage with psoriasis has been found on chromosomes 6p 17q, 4q and 1q [2, 3]. The main MHC class I allele that has been associated with susceptibility to psoriasis is HLA-Cw*0602 [4, 5]; there are other, weaker associations with HLA-B alleles, reflecting linkage disequilibrium. However, MHC class I alleles are involved in the regulation of NK cells, which have no proven role in psoriasis. There are weaker associations between PsA and MHC class II genes, such as HLA-DR7 [6, 7]. A possible explanation is that there may be several non-HLA genes in the MHC region, including the gene for psoriasis and/or PsA.

Tumour necrosis factor {alpha} (TNF-{alpha}) is a potent proinflammatory immunomodulatory cytokine that is produced by monocytes/macrophages. It plays a central role in the initiation and regulation of the immune response. The biological action of TNF-{alpha} is regulated through two receptors, TNF-RI and TNF-RII [8] and down-regulated through anti-inflammatory cytokines such as interleukin 10 (IL-10) [9]. The TNF-{alpha} gene (TNFA) lies within the class III region of the MHC, centromeric of HLA-B loci of class 1 and telomeric of HLA-D loci of class II on the short arm of chromosome 6. HLA-linked polymorphic variations within the promoter region(s) of the TNFA may influence the level of TNF-{alpha} secretion, i.e. HLA-DR3 and DR4 haplotypes are associated with high levels of TNF-{alpha} production [10], while HLA-DR2 haplotypes are associated with low production [11]. Persistent expression of TNF-{alpha} alone may be sufficient to induce arthritis in a transgenic mouse model in which mice that overexpress a human TNFA transgene develop chronic arthritis resembling rheumatoid arthritis [12]. In view of the TNFA gene location and the biological effect of TNF-{alpha}, it has been speculated that polymorphisms within this locus may contribute to MHC associations with autoimmune diseases, including PsA [13].

Several biallelic polymorphisms within promoter regions of TNFA have been described. Three commonly described variants consist of the substitution of adenosine (A) for guanine (G) at positions -308 [14], -238 [15] and +488 [16]. The less common TNF2 (-308A) allele has been associated with higher constitutive and inducible levels of TNF-{alpha} [17]. TNF2 (-308A) is in linkage disequilibrium with HLA-DR3 while TNFA (-238A) is in linkage disequilibrium with HLA-DR3 and HLA-DR7 [13]. Recently, it has been shown that TNFA -238A is associated with a higher risk of developing type I psoriasis [18]. IL-10 is an anti-inflammatory cytokine that has a major impact on immunoregulation by suppressing the production of proinflammatory cytokines, such as TNF-{alpha} [9]. It has been found that there is a deficiency in cutaneous IL-10 RNA expression in patients with psoriasis compared with patients with other inflammatory dermatoses [19].

The objective of this study was to determine whether known polymorphisms within the TNFA, IL10 and TNFRII gene loci influence susceptibility to PsA or are associated with particular disease subtypes. The relationship between TNFA polymorphisms and the HLA-Cw*0602 allele was also analysed.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients and controls
One hundred and twenty-four unselected Caucasian patients with PsA were studied. All had been referred to a PsA clinic at the Royal National Hospital for Rheumatic Diseases. All patients were negative for rheumatoid factor and fulfilled the Moll and Wright criteria for diagnosis of PsA [20]. One hundred and one cadaveric organ donors from the Oxford Transplant Centre, Churchill Hospital, Oxford, were used as controls for the TNFA, IL10, TNFRII and HLA-Cw*0602 polymorphisms. With these numbers, there is 80% power to detect an increase from 15 to 30% in the frequency of any given genotype at the 5% level of significance.

Clinical data were collected prospectively on patients with PsA at each clinic visit according to a standard protocol. Information included the age at onset of skin psoriasis and arthritis, the presence, site and number of inflamed joints and the presence or absence of radiologically determined joint erosions. For the purpose of this study, patients were divided into three main subgroups: oligoarthritis (four or fewer peripheral joints involved), polyarthritis (five or more peripheral joints involved) and spondylitis. Spondylitis was defined as a history of inflammatory back pain and radiological evidence of sacroiliitis.

DNA preparation
Genomic DNA was prepared from whole peripheral blood collected into EDTA (ethylenediamine tetraacetate) tubes using a standard salting out method. The extracted genomic DNA was used to type individuals for HLA-Cw6 alleles and single-nucleotide polymorphisms at the TNFA (-308, -238, +488), IL10 (-1082, -819, -592) and TNRII (+1663, +1668, +1690) loci.

HLA-Cw*0602 typing
HLA-Cw*0602 typing was performed by polymerase chain reaction (PCR) with sequence-specific primers (SSP) [21].

TNFA, IL10 and TNFRII typing
Biallelic polymorphisms in the promoter region of TNFA at positions -308 (G or A) and -238 (G or A) and in intron 1 at position +488 (G or A) were identified using a PCR haplotyping method as described previously [22, 23]. The method uses 3' mismatches in the forward and reverse primers that unequivocally establish the cis/trans status between the biallelic sites.

For the IL10 gene, three single-nucleotide promoter polymorphisms at positions -1082, -819 and -592 were genotyped by PCR–SSP [24].

Biallelic polymorphisms in exon 10 [in the 3' untranslated region (UTR)] of the TNFRII gene at positions 1663 (A or G), 1668 (T or G) and 1690 (C or T) were identified by PCR using primers incorporating mismatches at the 3' end, as described previously [25].

Statistical analysis
All data were recorded in a Microsoft Excel spreadsheet. Comparisons between patients with PsA and controls were made using 2x2 contingency tables with {chi}2 analysis and the three-way Mantel–Haenszel test where appropriate. The Mann–Whitney U-test was used for non-parametric data.

Ethical approval for the study was given by the Bath Local Research Ethics Committee and informed consent was obtained from the patients taking part in the study.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The 124 patients with PsA studied comprised 60 males and 64 females (mean age 54 yr, range 21–85 yr). The mean disease duration of arthritis was 18 yr (range 5–58 yr). Accurate information about ages at onset of psoriasis and arthritis was available for 87 patients. Thirty-one of 87 patients had an onset of psoriasis before the age of 21 yr and 11 of 87 patients had onset of PsA before the age of 21 yr. Erosions of peripheral joints were present in 58 patients.

TNFA polymorphisms
Although there was a slight increase in the less common TNFA -308A and TNFA -238A alleles in PsA, there were no significant differences in the nucleotide polymorphisms at positions -308, -238 or +488 between patients with PsA and controls (Table 1Go).


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TABLE 1.  TNFA polymorphisms in PsA patients and controls

 

IL10 polymorphisms
Only three different haplotypes were observed at positions -1082, -819 and -592 in the promoter region of IL10 in patients with PsA and controls because of the strong linkage disequilibrium between the nucleotides at these sites (Table 2Go). There was no difference in the distribution of these haplotypes between patients with PsA and controls. However, there was an increase in the number of patients homozygous for the IL10 -1882A, -819C, -592C haplotype in PsA patients compared with controls (P<0.05); this was not significant when corrected for multiple comparisons.


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TABLE 2.  IL10 polymorphisms in PsA patients and controls

 

TNFRII polymorphisms
There were no significant differences in the polymorphic variants at positions +1663, +1668 or +1690 in the 3'-UTR of TNFRII between patients with PsA and controls (Table 3Go).


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TABLE 3.  TNFRII polymorphisms in PsA patients and controls

 

HLA-Cw*0602
HLA-Cw*0602 was increased in frequency in PsA patients compared with controls (P<0.05) (Table 4Go). HLA-Cw*0602 was associated with a younger age of onset of psoriasis (Table 5Go). Sixteen of 31 patients (52%) with psoriasis onset before the age of 21 yr were HLA-Cw*0602-positive compared with sixteen of 56 patients (29%) with later age of onset of psoriasis (P<0.05). However, there was no association between HLA-Cw*0602 and age at onset of PsA (Table 5Go).


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TABLE 4.  TNFA and HLA-Cw*0602 phonotypes in disease subgroups compared with controls (percentages in parentheses)

 

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TABLE 5.  HLA-Cw*0602, and age at disease onset

 

Genetic associations with disease subsets
There were some differences in TNFA polymorphisms between the three clinical subgroups, although these differences were mostly small (Table 4Go). The most notable finding was an increase in frequency of the TNFA -238A allele in the group with polyarthritis (odds ratio 2.12 compared with controls) and a complete absence of TNFA -238A in the group with spondylitis, although the difference in frequency did not reach significance. In addition, these findings may be explained by linkage to HLA-Cw*0602, which was also increased in frequency in the polyarthritis group compared with the controls (odds ratio 2.48, P<0.02). There were no associations between the polymorphisms tested and the presence of peripheral joint erosions. There were no significant associations between IL10 or TNFRII polymorphisms and clinical subsets of PsA (data not shown).

HLA-Cw*0602, TNFA -238A and IL10 ACC homozygosity
The association between TNFA -238A alleles and HLA-Cw*0602 is shown in Table 6Go. In the normal controls there was an increase in frequency of the TNFA -238A allele in individuals who were HLA-Cw*0602-positive compared with HLA-Cw*0602-negative individuals (P<0.001). In the PsA group the association of TNFA -238A alleles with HLA-Cw*0602 was also notable in that all patients with TNFA -238A alleles were HLA-Cw*0602-positive (P<0.001). Therefore any conclusion about association of TNFA -238A alleles with PsA needs to take into account the strong linkage disequilibrium between this allele and HLA-Cw*0602.


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TABLE 6.  HLA-Cw*0602 and TNFA -238 phenotype

 
Homozygosity for IL10 ACC was not associated with HLA-Cw*0602. Also, nine of the 10 patients homozygous for IL10 ACC were negative for TNFA -238A. Therefore, we considered the possibility that peripheral joint arthritis in patients with PsA may be more strongly associated with the combination of the TNFA -238A allele with homozygosity for IL10 ACC than with either of these alone. Thirty-two of 111 patients with peripheral arthritis had this combination compared with 14 of 101 controls (P<0.01) and none of 13 patients with spondylitis (P<0.05). As these results were not corrected for multiple comparisons, they need confirmation in another data set.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Family studies have suggested a genetic contribution to the development of PsA [1]. Other chronic inflammatory forms of arthritis, such as ankylosing spondylitis and rheumatoid arthritis, are thought to have a complex genetic basis. However, the genetic component of PsA has been difficult to assess for several reasons. There is strong evidence for a genetic predisposition to psoriasis alone that may mask the genetic factors that are important for the development of PsA. Although most would accept PsA as a distinct disease entity, at times there is a phenotypic overlap with rheumatoid arthritis and ankylosing spondylitis. Also, PsA itself is not a homogeneous condition and various subgroups have been proposed. Although not all these confounding factors were overcome in the present study, we concentrated on investigating candidate genes in three broad categories of patients with PsA that cover the disease spectrum.

Polymorphisms in the promoter region of the TNFA region are of considerable interest as they may influence levels of TNF-{alpha} secretion [10, 11]. Increased amounts of TNF-{alpha} have been reported in both psoriatic skin [26] and synovial fluid [27]. Recent trials have shown a positive benefit of anti-TNF treatment in both PsA [28] and ankylosing spondylitis [29].

Furthermore, the locus for TNF-{alpha} resides within the class III region of the MHC and thus may provide tighter associations with PsA than those provided by flanking class I and class II regions. There were relatively weak associations with the TNFA alleles in our total PsA group. The uncommon TNFA -238A allele was increased in frequency in the group with peripheral polyarthritis and absent in those patients with spondylitis, although this finding may be explained by linkage disequilibrium with HLA-Cw*0602. Whether there are functional consequences associated with polymorphisms at the TNFA -238 allele is unclear [30]. Nonetheless, it is possible that the pattern of arthritis that develops in patients with psoriasis may be linked directly or indirectly to this particular allele.

Hohler et al. [18] found an increase in the frequency of the TNFA -238A allele in patients with PsA as well as in juvenile onset psoriasis. The association of TNFA -238A with both juvenile onset psoriasis and PsA was stronger than that with HLA-Cw6. Similarly, in our study, there were strong associations between juvenile onset psoriasis and both HLA-Cw*0602 and TNFA -238A, although neither allele had any relationship to the age of onset of arthritis. In our study, all patients with PsA who had at least one TNFA -238A allele were HLA-Cw6-positive, emphasizing the close linkage between these alleles in PsA. However, in contrast to the study by Hohler et al., and explainable by close linkage to HLA-Cw*0602, the TNFA -238A allele was only increased in patients with peripheral arthritis. It is also of interest that, in a separate study of ankylosing spondylitis, Hohler et al. found the uncommon TNFA -308A and -238A alleles to have a protective effect on the development of spondylitis, which is consistent with our findings [31].

Our study also addressed the possibility that certain polymorphisms within the IL10 gene could influence the development of PsA. IL10 is an attractive candidate gene due to its suppressive effects upon TNF-{alpha} production by monocytes. Subcutaneous administration of IL-10 has been used with some beneficial effect in a few patients with psoriasis [19]. Although we found no significant associations with any of the three IL10 polymorphisms studied, there was an increase in the frequency of homozygosity for an IL10 haplotype (-1082A/-819C/-592C) independently of any association with either HLA-Cw*0602 or TNFA -238A. It remains to be seen whether TNFA -238A and/or IL10 ACC are associated with cytokine expression at a functional level that predisposes to PsA. In addition, a homologue of IL-10, interleukin 20 (IL-20) has recently been discovered that forms part of an IL-10 family cluster on human chromosome 1q32 [32]. The IL-20 receptor heterodimer is strongly up-regulated in psoriatic skin [32]. Given the probable importance of IL-20 in epidermal function, IL20 is an important candidate gene in psoriasis.

The TNF receptors (TNF-RI and TNF-RII) are expressed on most nucleated cells and are cleaved into soluble forms. The TNF-RII receptor binds TNF-{alpha} and greatly enhances TNF-{alpha} and LTa ligation to TNF-RI by ligand passing [33]. Polymorphisms in the 3'-UTR of TNFRII have been described [25] and may control mRNA stability. In the present study we found no difference between PsA and controls in the frequency of the three single-nucleotide promoter polymorphisms in TNFRII that were studied. However, it is worth noting that our study was powered to detect only relatively large genetic differences, so minor effects cannot be dismissed.

There are several other candidate genes within the MHC class III region that may be more closely linked with the development of arthritis in patients with psoriasis. The MHC S gene (corneodesmosin) is located 160 kb telomeric of HLA-C and is involved in regulating the integrity of epithelial sheets and desquamation [34]. Recent work has linked polymorphisms within the S gene to the development of psoriasis [35]. MICA (MHC class I chain-related gene A) is 47 kb centromeric of HLA-B, and associations between the MICA-A9 allele and PsA have been reported [36]. Whether these genes will prove to have closer causative links with the development of PsA than the TNFA locus is an area of great interest.


    Acknowledgments
 
The authors are grateful to Remedi UK and to the Bath Area Medical Research Trust for help in funding the work.


    Notes
 
Correspondence to: N. J. McHugh, Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath BA1 1RL, UK. Back


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 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 27 February 2001; Accepted 9 November 2001





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