Q J Med 2001; 94: 237-246
© 2001 Association of Physicians
Review |
Tumour necrosis factor polymorphisms in rheumatic diseases
From the Centre For Rheumatic Diseases, University Department of Medicine, Glasgow Royal Infirmary, Glasgow, UK
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Introduction |
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 Top Introduction Polymorphisms in the TNF...Function of the polymorphisms...ConclusionsReferences |
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Tumour necrosis factor
(TNF)
is a pro-inflammatory cytokine that plays a key role in the pathogenesis
of many infections and inflammatory diseases.
1 It was identified through its ability to lyse tumour cells,2 but in retrospect this ability
was first noted nearly 100 years ago, when Coley's toxins were shown
to destroy sarcoma cells. TNF is now recognized to be involved
in stimulation of cytokine production, enhancing expression of adhesion molecules
and neutrophil activation, and it is also a co-stimulator for T-cell
activation and antibody production by B cells.
1 As such, it contributes to the regulation of normal homeostasis,
as well as playing an important role in inflammation.
TNF belongs to a family of proteins that includes lymphotoxin
(LT, previously known as TNFß)
and lymphotoxin ß (LTß). Although T
cells can produce TNF, activated monocytes (macrophages)
are the major source of TNF, which is synthesized as a 20 kDa
pro-protein and cleaved by TNF converting enzyme (TACE)
to a 17 kDa monomer. Under physiological conditions, TNF circulates as a stable cone-shaped homotrimer3 that mediates its effects by binding to
two receptor molecules TNF RI (p55) and TNF RII (p75).1 Genes for these receptors also
contain polymorphic variants, but these are beyond the scope of this review.
By the mid 1980s, the TNF protein had been purified, and
its gene cloned, sequenced and mapped to the MHC Class III region on the short
arm of chromosome six.4
The TNF gene is tandemly arranged with that for LT and LTß, within the ‘TNF locus’, a 7 kb
region 250 kb centromeric to the HLA B locus, 400 kb telomeric
to the C2/BF locus and 
1000 kb from the MHC Class II DR genes (Figure 1
). This genetic region is important
to rheumatic diseases, as HLA Class I B27 antigen is associated with ankylosing
spondylitis (AS), and MHC Class II genes are associated with rheumatoid
arthritis (HLA DR1 and DR4) and systemic lupus erythematosus (DR2
and DR3).
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Moreover, TNF
is now recognized to contribute to the pathogenesis
of joint disease. The successful therapeutic use of monoclonal antibodies
against TNF in RA clinical trials confirms this observation,
and implies that the genes within the TNF locus that could regulate its production
may well be important in RA pathogenesis.
5 Similarly, messenger RNA for TNF is found
in the inflamed sacroiliac joint in patients with ankylosing spondylitis,6 and in macrophages in the inflamed
arterial wall in giant-cell arteritis,
7 implying a role for TNF in the vasculitides.
The first suggestion that there could be inter-individual variations
in TNF production came from studies in normal individuals
and patients with SLE.8
The presence of HLA-DR2 was associated with lower TNF
production following stimulation of PBMCs by LPS. This implies that the MHC
exerts some genetic control over TNF production, and as DR2
is found in SLE patients, particularly those of Afro-Caribbean ethnicity,
that an inability to produce TNF is important in the development
of SLE. Treatment of New Zealand BlackxWhite F1 mice, a murine model
of SLE,9 with TNF
partially improved renal function, and prolonged life, suggesting
that even minor stable differences in TNF production may have
a role to play in the resulting auto-immune disease. Genetic analysis
of the MHC Class III region in these mice showed a polymorphism in the TNF
gene. The NZW parent strain also had this polymorphism, and an
impaired ability to produce TNF, implying a genetic predisposition
to low TNF production.
These studies instigated an enquiry into the genetics surrounding the TNF
gene in humans, to see whether there are markers that predict
variations in TNF production and thereby development of rheumatic
diseases. The development of the polymerase chain reaction (PCR)
allowed expansion of unique portions of DNA in vitro so as to provide
large amounts of DNA of identical sequence sufficient for further study.
The ‘TNF locus’ has yielded a variety of polymorphic sites,
both within the TNF gene and in close proximity to it (Figure 1
). Two forms of polymorphism are described.
Firstly, the single-nucleotide polymorphisms (SNPs) are single-base
changes that can be found at any site in the DNA, either in the 5' regulatory
sequences (promoter) or after the coding region (3' untranslated
region), or within the DNA which codes for the gene product. One example
of an SNP is the position –308 in the regulatory sequence of the TNF
promoter (Figure 2).
Here the base change from the common guanine (80% in Caucasians)
to a rarer adenine (20% in Caucasians) alters the DNA sequence
such that the DNA restriction enzyme Nco1 can bind and cut the DNA
at that position. Analysis by gel electrophoresis identifies the difference
between the intact DNA in comparison to that which is cut.10 There are a variety of SNPs in each
gene of the ‘TNF locus’. Some are designated by the enzyme used
to cut the DNA e.g. LT Nco-1.11 By convention, the common allele is
designated B*1 and the rarer allele B*2. Other polymorphic sites,
usually those where a variety of polymorphic sites have been identified, are
defined by the position in the genome from the beginning of the DNA sequence
for the gene, e.g. TNF –308. Polymorphisms before the
start site of the coding sequence for the protein conventionally have a negative
designation and those after it a positive one. Some of the frequently quoted
SNP sites are shown in Figure 1
below the line. These include that described at position +386 in the
LT gene,11
position –238 in the TNF promoter12 and +489
13 in the TNF gene itself.
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The second polymorphic variant is the DNA microsatellite. These are distributed on all chromosomes throughout the genome. These are repeat sequences (usually the bases C and T) of DNA found in the non-coding introns which are not transcribed into mRNA. They can be of variable length in each individual, a difference that can be detected by gel electrophoresis (Figure 3
). Although they are not transcribed
to make up any part of the messenger RNA, the insertion of microsatellites
may alter DNA folding, and have implications for DNA-binding proteins
and enzymes that might effect the rates of transcription. Examination of the
genes within the ‘TNF locus’ reveals five microsatellites (labelled
TNFa, TNFb, ..., TNFe), and their positions
in relation to the TNF gene are shown in Figure 1 (above the line). These have
variable lengths and are designated according to the number of repeat sequences;14 for example, the TNFc microsatellite
has only two variants consisting of 9 or 10 repeats (TNFc1 and TNFc2,
respectively), that are represented in 80% and 20% of Caucasian
populations, respectively (Figure 3).
The TNFa microsatellite is the most polymorphic within the TNF locus, having
thirteen possible different sizes (TNFa1–13).
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Polymorphisms in the TNF genes in rheumatic diseases |
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TopIntroductionPolymorphisms in the TNF...Function of the polymorphisms...ConclusionsReferences |
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Two methods have been used to establish whether certain regions of the chromosomes are implicated in specific diseases. Firstly, there are comparative studies where DNA from twins, one or both of whom are affected by disease, is compared for areas of interest on particular chromosomes, such as has been found for AS.15 These studies scan the genome using microsatellite markers, looking for variations in the pattern that are more commonly represented in the patients. Similar studies have examined multi-case families and compared common regions of DNA in affected and unaffected individuals with AS,16 RA 17 and SLE,18,19 but have not found the MHC Class III region or the ‘TNF locus’ to be specific areas of interest in any of these diseases.
In the second approach, individual genes have been targeted, and because
of the interest in TNF in the rheumatic diseases, this region
of DNA has been well studied. However, its proximity to the MHC raises the
possibility that any variations within the TNF locus are present simply because
of linkage disequilibrium with the MHC. Studies on cell lines have shown that
haplotypes crossing MHC Class I and II, such as HLA A3-B7-DR2-DQ1
and HLA A1-B8-DR3-DQ2, are probably inherited as a group.20 The latter is frequently
seen in autoimmune rheumatic diseases (particularly SLE) in the
Caucasian population,22
and has been linked with high TNF production.9 It is therefore likely that any variations
in the Class III region, including the ‘TNF locus’, will also
be inherited with this haplotype. Studies to address this issue have confirmed
that the microsatellites TNFb3–TNFa2 and the rare polymorphism at TNF–308 (B*2—A
allele) are all linked with this extended haplotype.22,
23 These close associations with the MHC necessitate careful
study to tease out any direct links with the various TNF polymorphisms in
the absence of associations with the extended haplotypes.
Rheumatoid arthritis
The association with the MHC DRß1 alleles that share the
amino-acid sequence at position 70–74 in the binding grove of
the MHC has been well recognized in Caucasian patients with RA.24,
25 The alleles commonly involved in this association have
been HLA-DR1 (DRß1*0101 and 0102), DR4 (DR
ß1*0401, 0404 and 0405) contributing approximately 30%
to the genetic susceptibility to RA. However, the ‘TNF locus’
could be implicated in predisposition to RA or in disease severity.
The data concerning the role of TNF polymorphisms in RA remain controversial.
Two analyses of multi-case families have suggested a link with a susceptibility
gene for RA in or near the ‘TNF locus’.
17,26
However, our comparisons failed to demonstrate any link with the LT
Nco1 polymorphism site.27
More extensive studies comparing RA patients and MHC-matched controls
suggested that the TNFa2 and TNFe3 microsatellites are more commonly found
in the RA patients.28
This was confirmed in the more closely matched studies where three haplotypes
were observed in RA. In the first, the TNFa2 microsatellite is seen in linkage
with HLA B62, which is recognized to be in linkage disequilibrium with HLA
DRß1*04, which is more common in patients with extra-articular
disease.29 In the
second haplotype, TNFa6-TNFb5-TNFc1-TNFd4 microsatellites
are associated with HLA DRß1*0401, which is in linkage disequilibrium
with HLA B44 in the RA population,
23 and in studies from the Republic of Ireland is also linked
with the TNFe3 microsatellite.26
Hence the variations seen in all these studies
26,28,29 may simply be present because
of the MHC association. The third haplotype found in the RA population is
the common combination of HLA A1-B8-DR3 that contains the TNFa2-TNFb3-TNFc1-TNFd1-TNFe3
microsatellites. It is therefore probable that the ‘TNF locus’
is inherited as part of individual haplotypes with the MHC Class I and II
genes and, therefore, may not be directly implicated in development of RA.
A recent comparative study has upheld this view, confirming that while there
is an association between RA and the MHC Class II alleles, the influence of
the TNF polymorphisms is not significant.
30
Other studies have addressed the relationship of TNF polymorphisms to clinical
heterogeneity of RA. The diagnostic radiological feature in RA is development
of erosions and the presence of narrowing of the joint space, which has been
quantified by Sharp.31
Patients with the most severe joint disease develop early damage that progresses
rapidly. Studies of the polymorphism site at position –238 within the
TNF promoter, show either a guanine (G) or an adenine (A)
at this site. Of the three possible genotypes on the two chromosomes, the
GG and GA are the most common. When scoring radiological damage in a prospective
study over 3 years, patients with the GG genotype deteriorated at a faster
rate on the Sharp score, whereas those with the GA genotype deteriorated more
slowly.32 This effect
is apparently independent of the MHC Class II alleles; in fact, when taken
into account with the –238 GG genotype, the presence of HLA DR4, the
OR for the presence of erosions in patients with both risk factors compared
to patients who lack these factors was 11.1. Similar studies on this patient
cohort have shown a similar association with the site at +489 (33),
with the GG genotype being having the more severe erosive disease. Although
comparable studies using the microsatellites are small in number, the presence
of TNFa6 influences the effect of the shared epitope on the MHC. The erosion
score and frequency of joint replacements were higher when TNFa6 was present
in the presence of the shared epitope.
34 Although a link has been suggested,33 it remains to be established whether
the G variant at the +489 is linked with the TNFa6 microsatellite. If
it is, this suggests that TNF gene polymorphisms are implicated
in RA disease severity. Interestingly, the Manchester studies also implied
that when two microsatellites TNFa6 and TNFa11 were present in one patient
the erosion score was worse, suggesting a possible input to disease severity
of the TNF polymorphism from the second chromosome.
33
Systemic lupus erythematosus
The situation in SLE is more complex. Not only is the disease rarer, but
the diagnosis requires any four of eleven different ARA criteria,35 so the clinical variation
in disease is far greater. In addition, SLE has a wide ethnic spectrum, with
common manifestations differing by each ethnic subgroup. The genetic makeup
at the MHC in each ethnic group is also different, and is further complicated
by mixed ethnicity. Nevertheless, the MHC Class III region has been implicated
in pathogenesis because of the frequency of the HLA A1 B8 DR3 extended haplotype
in Caucasians36,37 which can incorporate either
DQw1 or DQw2.38 In
those of Afro-Caribbean extraction, the common haplotype contains B44
DR2 DQ6.39,40 The MHC Class III region
is important because of the presence of the C4aQ0 null allele that has been
identified in both ethnic groups.37, 41,42 The genome screening approach
in Caucasian multiple-case families with SLE has also identified the
MHC as an area of specific interest.
18,43
Initial examination of the ‘TNF locus’ showed an association
with the LTB*1 allele, which is found in linkage disequilibrium
with the extended haplotype HLA A1 B8 DR3 DQ2.
44 Further studies showed that there is an increase in the
frequency of the TNF –308A in Caucasians45,
46 which is also part of this haplotype in non-Caucasians.
This haplotype contains the microsatellite combination of TNFa2 TNFb3 TNFd2,
and these are also more common in Caucasians with SLE,47,
48 suggesting no specific link between these alleles and
SLE over and above that associated with the extended haplotype. However, two
studies have implied that there may be more to the associations with the TNF
–308A allele in SLE. Firstly, the frequency of TNF
–308A was higher in African American SLE patients,49 and there is no association
with DR3 in African Americans. Furthermore, this link is supported by the
demonstration in a Dutch population of a higher odds ratios for TNF –308A with SLE over and above that for DR3,50 suggesting that this allele may be an
independent risk factor in Caucasians too.
Various studies have suggested an association between certain alleles in
the ‘TNF locus’ and clinical features of SLE. The malar rash and
anaemia are connected to the presence of the TNF –308A
in African Americans.49
In Greek patients, TNFa11 is more common in SLE patients with nephritis;48 similarly, photosensitivity
and Raynaud's phenomenon were more common in TNFa2-TNFb3-TNFd2-positive
UK patients.47 It
remains to be seen whether it is the TNF –308A or the
HLA antigens coded for by the genes within the extended haplotype that is
associated with antibodies against La/SS-B51 as originally suggested.45 Many of these studies are not sufficiently
large to reach significance if corrected for multiple comparisons, and more
extensive studies will be necessary to confirm these observations.
Ankylosing spondylitis
The genome-wide screening approach in AS families has confirmed
that the MHC is important in AS development, much as would be expected from
the known associations with HLA B27.
52 However, a recent study of monozygotic and dizygotic
twins has claimed the disease risk attributable to B27 to be 16%,15 implying that the genetic
association may extend beyond Class I.
16 Initial analyses of the MHC Class III region studied
the SNP at position –308 in the promoter region of the TNF gene and the Nco1 locus in the LT gene, and
failed to show an association at either locus.
53,54
However, larger analysis of patients and controls, together with a comparison
of HLA B27 positive ‘normal donors’ confirmed no association between
the Nco1 locus and AS, but showed a link with the TNF –308.B*1 (G allele) in the AS patients, independent
of HLA B27.55 One
local study has confirmed this association,
56 but one based on patients from a larger geographical
distribution has not.57
In studies examining the extra-spinal features of AS, the polymorphism
at position –238 in the TNF gene failed to demonstrate
an association with anterior uveitis.
58 Although McGarry's study suggested a negative association
between uveitis and the TNFa4 allele,
55 this study was insufficiently large to make significant
links with different features of AS. Nevertheless, it will be of interest
to assess the influence of this gene, particularly on uveitis, peripheral
joint disease, and different disease severity markers, which it appears to
influence in RA. This will require collaborative studies so as to gain appropriate
numbers of patients.
Vasculitides
Several studies have examined the influence of MHC genes on the vasculitides,
but because of the rarity of these diseases, all have examined small groups
of patients. The first set studied Behcet's syndrome, where in Japanese
and other patients, HLA B51 is more frequent in patients than in controls.59 Analysis of 102 Middle-Eastern
Behcet's patients and 115 matched controls showed that the LT Nco-1B*2 polymorphism containing the A base in the ‘TNF
locus’ is linked with HLA-B51 in the normal population.60 However, the combination
of HLA-B51 and LTNco-1B*2 was more commonly
found in patients with complete blindness, implying that genes within the
TNF locus may be implicated in disease severity in Behcet's syndrome.
By comparison, examination of the –308 polymorphism in the TNF
promoter in patients with Wegener's granulomatosis has failed
to demonstrate any associations with this disease in patients from a variety
of areas.61–63 Similarly, there were no
associations observed with Kawasaki's disease,
64 and this despite the fact that the patients with significant
coronary artery disease demonstrated increased production of TNF after in vitro stimulation with a variety of antigens.
One study has examined patients with confirmed giant-cell arteritis (GCA) and those with polymyalgia rheumatica (PMR).65 The TNFa2 microsatellite was more common in GCA, over and above the links between HLA DRß1*0401 and HLA DRß1*0101 that are more common in GCA. In PMR patients, the TNFb3 microsatellite was present in excess in this population in the absence of an MHC association. These studies argue not for a causal role for the TNF locus in individual diseases, but rather for significance in different clinical features of disease in the PMR/GCA spectrum.
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Function of the polymorphisms in the TNF genes |
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TopIntroductionPolymorphisms in the TNF...Function of the polymorphisms...ConclusionsReferences |
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The association studies between disease manifestations and TNF
polymorphisms shed no light on whether these variations have any specific
function that might be important in disease pathogenesis. Stimulation of PBMCs
from patients expressing HLA-DR3 and DR4 produced more TNF than those from DR2-positive cases, showing that there is undoubtedly
some genetic regulation of TNF production related to the MHC.8 However it is tantalizingly
difficult to obtain a consensus as to the relevance of each of the polymorphisms
in the TNF gene.
Data from in vitro culture experiments using PBMCs will depend
on the stimulus applied. Both monocytes and T cells have the capability to
produce TNF, and it is likely that LPS will stimulate the
monocytes more that T cells, and that PHA and PMA will activate the T cells
more efficiently. Although the promoter region for TNF is
identical in each cell, it is possible that these regulatory sequences may
respond differently, depending on which second messengers are activated by
the external stimulus. Therefore, for example, the G/A polymorphism at
position –308 in the TNF promoter may be relevant to
macrophage response but not following T-cell activation. In addition,
because each cell contains two chromosomes, the influence of the DNA sequence
of the second chromosome on the one of interest will always be difficult to
quantify unless studies are performed in individuals shown to be homozygous
at all the loci of interest.
Despite these inherent problems, various in vitro studies have
been undertaken to establish whether individual polymorphisms can exert influence
over TNF production. Identical twins show consistent TNF
production from stimulated cultured PBMCs,66 implying a genetic regulation. Initial
studies of the ‘TNF locus’ examined the Nco1 polymorphism
site at position +368 in the coding region of the LT
gene.11 At this locus,
the change from the common C base (64% in Caucasians) to
the rarer A base leads to an increase in TNF production from monocytes after
in vitro monocyte stimulation with LPS.
67 However, stimulation of T cells using PMA failed to show
any variation in TNF production dependent upon differences
at this allele.11
Later studies by the same group confirmed the link between high TNF
production8
and DR3 and DR4, compared to lower than average TNF production
from monocytes with DR2 and DR5.68 However, in these studies the TNFa2 and the TNFc2 microsatellites
were also linked with higher TNF production. All these studies
included small numbers of individuals, and usually failed to take into account
the other variable sites in the vicinity. However, the presence of the TNFa2
microsatellite within the HLA A1 B8 DR3 haplotype,
22 recognized to be associated with high TNF production, could possibly explain this link.
Few studies have compared TNF production with the allele
variation at position –308 in the TNF promoter. The position within
the gene promoter makes this an attractive candidate to exert regulatory control.
Recent studies have shown that in vitro the common G allele (TNF-308*1)
is linked with reduced TNF production by stimulated PBMCs
from patients with chronic reactive arthritis, most of whom are HLA-B27-positive.69 These studies are in keeping
with the observation that patients with the A allele (TNF-308*2)
make more TNF under those circumstances. The fact that TNF-308*2
is also part of the A1 B8 DR3 haplotype suggests that this site could also
be important in the high TNF production associated with this
haplotype.
To overcome the problems with in vitro culture, an alternative
approach has investigated the effect of the individual polymorphism on mRNA
transcription. In these experiments, DNA is constructed containing the relevant
polymorphism, together with a reporter gene which is used as the read-out
system. It was first reported that the TNF promoter containing
the –308A allele produced up to six times more mRNA than the construct
containing the gene containing the –308G allele.70 These data support the in vitro culture data from the AS patients.
69 Similarly, studies using transfected DNA containing the –308A
allele in Jurkat (T cell) and U937 (macrophage) cell lines
produced double the mRNA over cells containing the TNF gene
with the –308G allele.71
Again, this argues in favour of the presence of the –308A variant in
the extended haplotype regulating TNF production.
However, other studies using transfected DNA containing the different bases
at position –308 found no difference to production of a reporter gene
in a variety of cell lines.72
These studies were carried out in the presence or absence of the 3'
untranslated region of the TNF gene to exclude an effect of
this region on TNF transcription. Substitutions at –308
in three different mutants spanning across this site similarly exerted no
effect on the ability to produce TNF mRNA.72 The same laboratory has also shown no
effect on TNF mRNA production using stimulated monocytes or
T cells of either variant at –308.
73 Similar analyses following substitutions at positions –238
and +489 within the TNF gene failed to show any variation
in mRNA production,33
despite the suggestion that the +489 polymorphism is linked with disease
severity.32 It seems
likely that there will be genetic control of TNF production,
and unlikely that this will be independent of variations with the TNF
gene itself. Unfortunately the differences between in vitro production data after cell culture and the analysis by genetic methods
cannot be explained, and do little to clarify the role of the different polymorphisms
in regulating TNF production.
However, murine studies continue to confirm a role for regulation of TNF
production, with the NZB/NZW F1 mice having impaired ability
to produce TNF. In these mice, a promoter polymorphism within
the TNF gene may be important in TNF regulation.
However, reporter gene assays in macrophage cell lines failed to demonstrate
any change in mRNA production between the possible variants at this site.74 It was only when these gene
constructs were transfected with a second mutation to the 3'UTR region
that the polymorphisms in the promoter region had any influence, and then
only on protein synthesis and not mRNA production. This implies that a ‘double
hit’ may be necessary where variations at both ends of the TNF gene are necessary to alter protein synthesis. Unfortunately the studies
in human cells lines investigating this hypothesis failed to show any difference
in mRNA production after removal of the 3'UTR of the TNF gene.72 It
remains to be established whether these changes in human DNA structure have
functional implications relating to control over TNF protein
production.
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Conclusions |
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TopIntroductionPolymorphisms in the TNF...Function of the polymorphisms...ConclusionsReferences |
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The MHC Class III region is clearly relevant in autoimmune diseases. However, the conflicting results from published studies of association between any specific human autoimmune disease and genetic differences in the genes in the TNF
locus fail to show that the links are of major importance
in pathogenesis. They simply show the importance of the size of the study
population, and the strict collection of correct control populations in showing
any statistically demonstrable effect of any gene on disease predisposition.
Nevertheless, the individual polymorphisms within the TNF
gene may be important in disease severity. If so, then it would be predicted
that the high TNF production associated with the TNF polymorphisms
in the extended haplotype HLA A1 B8 DR3 should protect from glomerulonephritis
in SLE, but none of the studies are large enough to address this issue adequately.45,
47–50
The RA data showing that erosion rate is related to the +489 polymorphism
show that associations can be found,
32 and provide a rationale for continued study. However,
large patient numbers (>250) were necessary in this study, confirming
that links can be detected only if analyses are sufficiently powered.
One complication not yet addressed is that most studies are hospital-based,
and thus automatically select for the most severely affected in any population.
By failing to study mild disease, these may mask the effect of any one polymorphism
in disease severity. Analysis of community based RA patients has suggested
a role for the MHC Class II in development of erosions in those patients seronegative
for rheumatoid factor.75
However, it remains to be established whether the variations within the TNF
gene are more relevant in prognosis in this cohort. If they confirm
a role for TNF polymorphisms in RA severity, this can only
assist clinicians in planning appropriate protocols for treatment in the future.
The inconsistent data from the human in vitro studies further
exacerbates the dilemma of the relevance of the genetic polymorphisms in the
TNF locus. Nevertheless, murine studies clearly demonstrate the importance
of variable TNF production. Altering the TNF
allele from a low TNF producer in NZB/W F1 mice to a high secreting phenotype
delayed the onset of renal disease.
76 However, even in these murine studies, it remains unclear
how altering TNF production protects mice from glomerulonephritis, when the
genome scanning techniques clearly show this as having a polygenic aetiology.
In order to fulfil Koch's postulates for each gene, it will be necessary to develop models that target each gene to establish its relevance. Transfer of DNA segments identified as being of interest in the genome scans of murine models of SLE77 into mice with a non-SLE background has identified regions linked with T- and B-cell dysregulation. Crossbreeding experiments using these single gene mutants have generated normal background mice containing more than one of these genes. Characterization of the clinical features of these ‘polygenic’ mice confirms that some combinations are important in autoantibody production, and some with glomerulonephritis.78 These experiments already provide useful models for examining clinical features and targeting therapeutic options. None has been generated so far using genes of interest in models of RA. 79
To clarify any associations of genes with clinical features or disease severity in human patients, much larger studies will be necessary. This requires collaborations between centres using objectively characterized patients similar to those for the genome screening techniques. In the meantime, examination of these artificially-created murine disease models generated with relevant sections of DNA seems the best way to study and clarify their potential involvement.
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Acknowledgments |
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Ms C. Ryder provided invaluable secretarial support. I am grateful to Ms F. McGarry who undertook the PCR, gel electrophoresis and radiographs necessary for this review. Financial support was provided by the Arthritis Research Campaign (ICAC grant SO590).
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Notes |
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Address correspondence to Dr M. Field, Centre For Rheumatic Diseases, University Department of Medicine, Glasgow Royal Infirmary, Alexandra Parade, Glasgow G31 2ER. e-mail: m.field{at}clinmed.gla.ac.uk
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References |
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TopIntroductionPolymorphisms in the TNF...Function of the polymorphisms...ConclusionsReferences |
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