INFO - Genetic basis of rheumatoid arthritis

[Guest guest]

Arthritis Foundation

Genetic Basis of Rheumatoid Arthritis

Excerpt from the Primer on the Rheumatic Diseases, edition 12:

Family studies and studies in monozygotic and dizygotic twins support the

concept that genetic factors are important for the susceptibility of

rheumatoid arthritis (RA). However, RA does not frequently aggregate in

families and does not show a segregation pattern found in disorders of

single- and high-penetrance genes. Many different genes, each of which makes

only a small contribution to disease susceptibility, appear to be involved.

Interactive genetic effects are suspected to modulate the impact of

individual disease-risk genes and likely contribute to the low penetrance.

Genetic risk factors not only determine susceptibility for the disease but

also correlate with disease severity and phenotype, providing the unique

opportunity to use genetic markers as prognostic tools in the management of

RA. A measure used to estimate the genetic component to disease is the

coefficient of familial clustering, as, defined as the ratio of the

prevalence in affected siblings to the population prevalence. For RA, λs

ranges from two to 12, depending on the published data set used. Although

clearly supporting the influence of genetic factors, this λs is rather low

compared with other autoimmune diseases or common genetic diseases, leaving

considerable room for environmental or stochastic events in the pathogenesis

of the disease. In part, λs may be rather low because RA is a heterogeneous

syndrome that includes several genetically semi-homogeneous subsets.

The genetic system studied most thoroughly is the major histocompatibility

complex (MHC). In initial studies, RA was shown to be associated with human

leukocyte antigen (HLA)-DR4 (2). Studies of the HLA-D region’s genomic

organization and of the molecular characterization of allelic polymorphisms

are the basis for a model showing that the actual disease-conferring

sequence is confined to a short sequence that encompasses amino acids 67-74

of the HLA-DRB1 gene (3). Comparing sequences of the disease-associated

HLA-DRB1 alleles demonstrates sharing of a sequence motif in the third

hypervariable region. Association studies in different ethnic populations

support the concept that HLA-DRB1 alleles expressing this sequence motif are

over-represented among people with RA (1). The sequence polymorphism is

characterized by a glutamine or arginine at position 70, a lysine or alanine

at position 71, and an alanine at position 74. Alleles with a negatively

charged amino acid at any one of these positions are not associated with the

disease. The disease-associated alleles include HLA-DRB1*0401, 0404, and

0408. Additional disease-associated alleles include HLA-DRB1*0101/2 mainly

in the Caucasian population, HLA-DRB1*0405 in the Asian population,

HLA-DRB1*1402 in some Native American populations, and HLA-DRB1*10 in the

Greek population.

Clinical-association studies have provided important information to lace

these genes in the pathophysiology of the disease. In essence, evidence has

been provided that HLA-DRB1 alleles modify disease expression. Patents with

a disease-associated HLA-DRB1 allele different from HLA-DR4 often develop

mild and seronegative disease (4). Disease severity also appears to be

influenced by the Lys/Arg dimorphism at position 71 of the

disease-associated HLA-DRB1 sequence stretch. Patients with severe joint

disease and/or extra-articular manifestations have the strongest HLA-DRB1

association. These patients frequently express two disease-associated

HLA-DRB1*04 alleles (5). Family studies have emphasized the importance of

the second haplotype. Concordance rates in siblings who share both

disease-associated MHC haplotypes are higher than in siblings who share only

one haplotype. These data suggest that the disease-associated HLA-DRB1

alleles are important not only in disease initiation, but also in disease

progression. Sequence polymorphisms within these alleles and gene-dose

effects are important variables influencing the expression of RA. The data

further suggest that these alleles act in concert with other MHC genes as

well as background genes.

Crystallographic studies of HLA-DR peptide complexes have mapped the

conserved sequence stretch to an a helix that borders the antigen-binding

cleft of the HLA-DR molecule (6). Side chains of the MHC molecules form

pockets that interact with side chains of antigenic peptides, usually nine

amino acids in length, thereby determining the peptide specificity of MHC

binding. The polymorphic residues of the shared epitope form the pocket that

interacts with the side chains of the fourth amino acid in the bound

peptide. In particular, the positively charged amino acid at position 71 of

the shared epitope favors the binding of peptides with a negatively charged

amino acid. Amino acids of the shared epitope also can interact with the

T-cell receptor (TCR) that recognizes the HLA-peptide complex. Depending on

the peptide bound, the α-helical conformation is altered and the amino acid

at position 70 points to the T-cell receptor.

Based on this structural knowledge, three models for the function of

disease-associated polymorphisms have been proposed: 1) selective binding of

autoantigenic peptides; 2) selective binding of TCR molecules; and 3) the

HLA molecule functioning as a peptide donor. In the first model, antigenic

peptides with a negatively charged amino acid in the middle would be prone

to trigger a disease-inducing T-cell response. One possible scenario is that

peptides derived from pathogenetic microorganisms cross-react with

autoantigens. It is likely that different antigenic peptides would be

involved in different patients because the peptide-binding profiles of the

different disease-associated HLA-DRB1 alleles are quite different, except

for their preference for a negatively charged amino acid at position 4.

However, it is unclear what aspect could be unique for a particular set of

peptides. In the second model, the disease-associated sequence stretch would

be involved by directly interacting with contact residues of the TCR.

TCR--HLA-DR contact residues contribute to the affinity of the complex

formation. The shared epitope could be involved in the selection of a

particular set of T cells, either during T-cell repertoire formation in the

thymus or by influencing T-cell survival in the periphery (7). In the third

model, the disease-associated sequence would not function as a part of the

entire HLA-DR molecule but as a peptide. HLA-derived peptides are recognized

in the thymus and influence the selection of T cells. Positive selection of

such T cells could result in a repertoire that is biased toward the

recognition of cross-reactive microbial peptides (8). Molecular mimicry

between the disease-associated sequence and bacterial heat-shock proteins

has been described. The RA-associated HLA-DRB1 amino acid sequence, QKRAA,

also is present in the bacterial heat-shock protein dnaJ, which is able to

trigger proliferative responses of synovial-fluid T cells from RA patients.

Although elegant, all three models have limitations in explaining how MGC

genes influence the induction or progression of RA. Understanding the role

of the HLA-DRB1 polymorphisms remains one of the major challenges, but also

one of the best prospects, to define the etiology of RA.

MHC genes are not the only germline-encoded genes influencing susceptibility

to RA. Female sex clearly increases the risk, and female patients develop a

different phenotype of the disease than do male patients. However, no

sex-linked genes have been identified as disease-risk genes. Several

consortiums have started genome-wide searches, using affected sibling pairs

(9,10). In these studies, the role of the HLA region was evident and

accounted for as λs of 1.7 (compared with a λs of two to 12 for the entire

genetic load contributing to RA), suggesting that the λs of other

susceptibility genes would be very small. Susceptibility regions have been

proposed for chromosomes 1, 3, 8, and 18, which will require confirmation

and further refinement by other investigators. Eventually, the candidate

gene approach may be more sensitive for identifying risk genes, in

particular when considering the heterogeneity of disease severity and

phenotype. The recent definition of single nucleotide polymorphisms

throughout the human genome has increased significantly the feasibility of

this approach. Studies of TCR and immunoglobulin genes have not been

revealing; several cytokine polymorphisms, including tumor necrosis factor

(TNF-)-α and interferon (IFN)- γ were described to influence disease

severity, but studies are needed to confirm this hypothesis.

http://www.arthritis.org/conditions/diseasecenter/ra/ra_genetic.asp

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org