Meta-analysis of HLA-DRB1 polymorphism in Latin American patients with rheumatoid arthritis
Introduction
Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease characterized by symmetric polyarthritis with progressive damage of diarthrodial joints leading to disability, increased comorbidity and premature mortality [1]. RA is a complex and heterogeneous genetic disease in which multiple genetic and non-genetic factors interact over the time [1]. Latin America (i.e. the geographical area defined by Mexico, Central America, South America, and the islands of the Caribbean) is a growing and foremost region with a population of about 515 million people. The RA prevalence reported in Latin America is considered to be less than 0.5% [2], [3], [4].
Evidence of familial clustering was the first indication of a genetic susceptibility to RA. Using variance modelling, twin studies have determined that the RA heritability is about 60% based on the higher monozygotic twins concordance rates (12–15%) compared to dizygotic twins (2–4%) [5]. Familial aggregation for RA, measured by the sibling recurrent risk ratio, vary from 2 to 17 depending upon the disease prevalence in the population used as reference [6]. Segregation analysis showed that the RA pattern of inheritance likely follows a mixed model, with a major gene (probably at the MHC) operating against a polygenic background [7]. The above findings indicate an important genetic component in RA.
Several whole-genome scans for RA have been performed with multi-locus nonparametric linkage analysis to identify susceptibility loci (Fig. 1) [8], [9], [10], [11], [12], [13], [14], [15], [16]. The HLA region have been the only one with significant evidence of linkage (LOD score > 3.6 or P < 3 × 10− 5) across all the genome scans except the Japanese study [8]. In addition, consistent evidence gathered from association studies indicates that HLA-DRB1 is the strongest susceptibility locus for RA, accounting for about 30% of the total genetic component [6]. Hence, other non-HLA loci also contribute to disease susceptibility even though most of the non-HLA loci identified in individual studies have not been replicated [17]. This can be explained by insufficient sample size, low statistical power, and genetic or clinical heterogeneity. Genome-wide meta-analysis for RA have confirmed the HLA loci as the greatest susceptibility factor and provided greater statistical power to identify non-HLA loci at 1p, 2q, 5p, 6, 8p, 12, 16 y 18q [18], [19], [20]. A 2-locus linkage analysis detected improved evidence of linkage for loci on 6q16.3 and 16p12.3 after conditioning for HLA, and suggested an epistatic interaction between these loci and HLA-DRB1[21].
Thirty years have elapsed since Peter Stastny found RA to be associated with the mixed leukocyte culture type Dw4 (HLA-DRB1⁎0401) [22]. Further investigations have established more RA-associated alleles, mainly HLA-DRB1⁎0401, ⁎0404 and ⁎0408 in Caucasians; HLA-DRB1⁎0405 in Spaniards, Japanese and Jews, HLA-DRB1⁎0101/2 in Israelis, HLA-DRB1⁎1402 in some Native Americans such as Pima and Yakima Indians, and HLA-DRB1⁎1001 in Greeks [Reviewed in [23], [24]. By comparing amino acid sequences encoded by the disease-associated HLA-DRB1 alleles listed above, Gregresen et al. demonstrated a conserved motif (L-L-E-[Q/R]-[R/K]-R-A-A) comprising residues 67–74 in the third hypervariable region of the DRβ1 chain and named it the shared epitope[25]. These residues constitute an α-helical domain forming one side of the antigen binding site, a site likely to affect antigen presentation. Thus, the SE might selectively bind an arthritogenic peptide which could favour an autoimmune response. Negatively charged anchor residues best fit into this positive binding pocket 4, as in the case of the Collagen II peptide (261–263), an epitope in human-transgenic mouse models of RA [17]. HLA alleles with a negatively charged amino acid at any one of these positions are not associated with the disease. These alleles usually contain an aspartic acid (D) at residue 70 or the common motif D70-E-R-A-A74 (HLA-DRB1⁎0103, ⁎0402, ⁎1102, ⁎1103, ⁎1301, ⁎1302, and ⁎1304), and may protect against RA or favours a less erosive disease [26].
Current evidence indicates that the SE association with RA is highly complex and varying among populations [17], [27]. Moreover, the genotype penetrance is small because each susceptibility SE-allele is present in 5–15% of the normal population and the absolute risk for developing RA in SE-encoding allele carrying individuals is relatively low [24]. These observations indicate that SE is neither necessary nor sufficient for disease to occur, and successive investigations have suggested that the primary role of the SE could be related to severity of disease rather than to susceptibility [28].
HLA studies in Latin American patients with RA are scarce and results diverse. Such inconsistencies might be attributable to variations in genetic background and to insufficient sample size. Review and meta-analysis are both tools to synthesize and combining data across studies, the latter being a more objective statistical method to estimate the common effect across several studies improving statistical power. Thus, to estimate the genetic contribution of SE positive HLA-DRB1 alleles to disease susceptibility across different Latin American populations, we undertook a systematic review along with a meta-analysis of all case-control studies on HLA-DRB1 polymorphisms associated with RA conducted to date.
Section snippets
Search strategy and selection criteria
Electronic databases (MEDLINE, PUBMED, SCIELO, LILACS), were searched up to October 2006 for all genetic association studies evaluating the HLA-DRB1 polymorphism and RA in humans in all languages. The search strategy contained both MeSH terms and text words as follows: “Arthritis, Rheumatoid”[MeSH] AND “HLA-DR Antigens/genetics”[MAJR] in combination with all Latin America countries. No other limits were employed. Studies were included if they met the following requirements: the diagnosis of RA
Studies included
Eight association studies relating to HLA-DRB1 polymorphism and susceptibility to RA accomplished the inclusion requirements for the meta-analysis (Table 1) of which 2 were conducted in Mexicans [23], [32], 2 in Peruvians [33], [34], 1 in Colombians [35], 1 in Argentineans [36], 1 in Brazilians [37] and 1 in Chileans [38]. The SE genotype frequency could not be extracted from one study [36], hence it was only included in the meta-analysis for DR4 alleles associated to disease. In total, our
Discussion
The current meta-analysis indicates that HLA-DRB1 alleles expressing the SE are associated with RA in Latin American populations. The SE hypothesis suits not only association but also linkage data, and the localization to the peptide binding groove of the DRβ1 molecule support its functional significance. Disease susceptibility is mostly modified by changes in amino acid residues at positions 67, 70, 71 and 74 [24]. Most of HLA-DRB1 susceptibility alleles identified in all Latin American
Take-home messages
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In Latin Americans, RA is associated with shared epitope and DR4 positive HLA-DRB1 alleles, mainly HLA-DRB1⁎0404.
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The risk to develop RA conferred by shared epitope alleles is high (OR = 3.5).
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Admixture and population stratification must be considered in future genetics studies involving Latin Americans.
References (40)
- et al.
Rheumatoid arthritis in African Colombians from Quibdo
Semin Arthritis Rheum
(2001) - et al.
A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases
Am J Hum Genet
(2001) - et al.
Whole-genome scan, in a complex disease, using 11,245 single-nucleotide polymorphisms: comparison with microsatellites
Am J Hum Genet
(2004) - et al.
Relevant residues of DRbeta1 third hypervariable region contributing to the expression and to severity of rheumatoid arthritis (RA) in Mexicans
Hum Immunol
(1998) Teasing apart the complex genetics of human autoimmunity: lessons from rheumatoid arthritis
Clin Immunol
(2003)- et al.
The shared epitope and severity of rheumatoid arthritis
Rheum Dis Clin North Am
(2002) - et al.
HLA-DRB1 alleles encoding the “shared epitope” are associated with susceptibility to developing rheumatoid arthritis whereas HLA-DRB1 alleles encoding an aspartic acid at position 70 of the beta-chain are protective in Mexican Mestizos
Hum Immunol
(2004) - et al.
Artritis Reumatoide
Bases moleculares, clínicas y terapéuticas
(2006) - et al.
Community based study to estimate prevalence, burden of illness and help seeking behavior in rheumatic diseases in Mexico City. A COPCORD study
Clin Exp Rheumatol
(2002) - et al.
Prevalence of rheumatic diseases in Brazil: a study using the COPCORD approach
J Rheumatol
(2004)
Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins
Arthritis Rheum
The contribution of HLA to rheumatoid arthritis
Clin Genet
Familial clustering of rheumatoid arthritis with other autoimmune diseases
Hum Genet
Identification of the gene loci that predispose to rheumatoid arthritis
Int Immunol
New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study
Proc Natl Acad Sci U S A
Whole-genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom
Arthritis Rheum
Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families
Arthritis Rheum
Dense genome-wide linkage analysis of rheumatoid arthritis, including covariates
Arthritis Rheum
Whole genome association study of rheumatoid arthritis using 27 039 microsatellites
Hum Mol Genet
High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33
Genes Immun
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