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The complex immunogenetic basis of systemic lupus erythematosus
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Autoimmunity Reviews 7 (2008) 345 – 351 www.elsevier.com/locate/autrev
The complex immunogenetic basis of systemic lupus erythematosus Jesús Castro, Eva Balada, Josep Ordi-Ros ⁎, Miquel Vilardell-Tarrés Autoimmune Diseases Research Laboratory, Vall d'Hebron Research Institute, Barcelona, Spain Received 9 December 2007; accepted 8 January 2008 Available online 1 February 2008
Abstract Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology with a complex genetic basis that includes many susceptibility genes on multiple chromosomes. As complex human diseases like SLE involve multiple, interacting genetic and environmental determinants, identifying genes for complex traits is challenging and has had limited success so far. Several key approaches that are necessary to identify disease susceptibility genes in common diseases such as SLE are now available. Collectively, these approaches will allow the prioritization of candidate genes based on available knowledge of map position and biologic relevance. They will also allow us to obtain the genomic structure of these genes as well as to study sequence variants that will facilitate the identification of genes that are important in the development and expression (severity) of lupus and associated phenotypes. Although it is still a labor-intensive and expensive project to identify susceptibility genes in common diseases such as SLE, the new techniques that are now being used will undoubtedly improve gene mapping in such a kind of diseases. In this review we highlight the current findings in the genetics of human SLE after using these approaches. © 2008 Published by Elsevier B.V. Keywords: Genetics; Immunology; SLE; Candidate genes; SNP; Autoantibodies
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . Genetic approaches used to identify SLE disease genes 2.1. Candidate-gene studies . . . . . . . . . . . . . 2.1.1. HLA association . . . . . . . . . . . . 2.1.2. Complement components . . . . . . . 2.1.3. Fcγ receptors . . . . . . . . . . . . . 2.1.4. Mannose-binding lectin . . . . . . . . 2.1.5. Cytotoxic T lymphocyte antigen-4 . . . 2.1.6. Programmed cell death-1. . . . . . . . 2.1.7. Interferon regulatory factor 5 . . . . . 2.2. Genome-wide linkage analysis studies . . . . .
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⁎ Corresponding author. Autoimmune Diseases Research Laboratory, Vall d'Hebron Research Institute, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain. Tel.: +34 93 4894047; fax: +34 93 4894045. E-mail address: [email protected] (J. Ordi-Ros). 1568-9972/$ - see front matter © 2008 Published by Elsevier B.V. doi:10.1016/j.autrev.2008.01.001
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3. Conclusions and perspectives . Take-home messages . . . . . . . . Acknowledgement . . . . . . . . . References . . . . . . . . . . . . .
J. Castro et al. / Autoimmunity Reviews 7 (2008) 345–351
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1. Introduction Systemic lupus erythematosus (SLE) is a prototype systemic, autoimmune inflammatory disease that can affect virtually any organ system. The disease primarily affects women in their reproductive years (female:male ratio = 9:1) and the estimated prevalence varies between 12 and 64 cases per 100,000 inhabitants in Europeanderived populations, with a higher prevalence, in general, in non-European-derived populations [1]. The clinical manifestations vary greatly from one lupus patient to another, and the course of the disease is characterized by periods of relapse and remission. The pathogenesis behind the disease remains unclear. The main immunological feature is uncontrolled formation of autoantibodies, leading to excess formation of immune complexes which deposit in different tissues, causing inflammation and tissue damage. The disease may be triggered by environmental factors, such as viruses, certain drugs and sun exposure [2]. Based on epidemiological studies, there is clear clustering of SLE patients in families which suggests an underlying genetic susceptibility. The mode of inheritance of SLE is however unknown. The criteria for the classification of SLE promulgated by the American College of Rheumatology [3] support the likelihood of many phenocopies for this phenotype. They allow the classification as SLE by satisfying any four of eleven criteria, making this a potentially very heterogeneous collection of patients. Even this being the case, some chromosome regions and particular gene variants seem to be in fact shared by some SLE patients. Several candidate susceptibility loci for SLE have been identified in case-control association studies in humans. 2. Genetic approaches used to identify SLE disease genes disease genes The search for genes predisposing to complex traits, such as SLE, can be broadly divided into two strategies: the hypothesis-driven candidate-gene-association analysis and the genome-wide linkage studies. In candidategene analysis an allele or haplotype, or any DNA polymorphism, is directly assessed and a difference in frequency is usually demonstrated (hopefully repeatedly
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in independently ascertained samples) between affected patients and appropriate controls. Therefore, genetic association with a candidate gene suggests that the detected anomaly being measured may be related to the disease or may, in fact, be located very closely to the responsible gene. Linkage, however, is fundamentally a statistical process testing for the co-inheritance of genetic markers (such as DNA microsatellites) with the disease phenotype in families with multiple affected members. Consistent co-inheritance of the marker with the disease in many families indicates that it is in close proximity to the actual disease gene, and might be ‘linked’ to it. Linkage provides evidence of genetic effects, but it is a much poorer discriminator for gene identity than the assessment of individual alleles in candidate genes. 2.1. Candidate-gene studies Since the loss of immune tolerance to self-components is the basis of SLE etiology, many genes encoding proteins with regulatory or adaptive functions in the immune system have been considered as candidates. Several candidate genes have been studied and found to be associated with SLE (Fig. 1). Some of the important candidate genes are discussed below. 2.1.1. HLA association The genetic association of SLE with the major histocompatibility complex HLA has been known for more than 35 years and it is a consistent finding in Northern-European-derived populations. HLA-DR2 and HLA-DR3 have been consistently associated in SLE. The most definitive study of this region has been produced by Tim Behrens' group [4]. They evaluated the DNA polymorphisms in- (and around HLA) of European, Afro-American, and Hispanic lupus families and showed that the genetic association effect centered on HLA-DR2, effectively eliminating polymorphisms at the surrounding loci from consideration. SLE patients with HLA-DR3 had so little variation across a large extended haplotype, that polymorphisms at the surrounding genes could not be eliminated from consideration. Consequently, this group [4] concludes that HLADR2 (but not HLA-DR3) must be identified as a
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Fig. 1. Approximate location of positional candidate genes found to be associated with SLE. Gene symbols: PTPN22, FcγRIIA/FcγRIIIA, FasL, CTLA-4, PDCD-1, HLA-DR2/DR3, C4, IRF5, MBL, Fas, Dnase1.
susceptibility allele for SLE. Haplotypes containing the HLA-DR3 allele should be cautiously considered as we do not know whether this allele (or one on the surrounding loci) may pose a risk for the disease. 2.1.2. Complement components Deficiency of complement components C1q, C1r/s, C2 and C4 predispose to SLE [5,6]. Out of them, C1q carries the strongest disease risk, with over 90% of cases developing rheumatic disease, followed by C4 and C2 (at 75% and 10%, respectively). Deficiencies in C1r/s, C5 and C8 have also been associated with SLE or lupuslike syndromes. Of note, no single mutation has been found to be responsible for these deficiencies. 2.1.3. Fcγ receptors Our understanding of the role of human Fcγ receptors (FcγRs) in SLE pathogenesis has increased considerably over the past several years. These receptors vary in their affinity for IgG, their preferences for IgG subclasses, and cell type-specific expression patterns. FcγRs bind to Fc fragments of IgG and transmit effector signaling in many kinds of immune cells. Allelic variants of FcγR genes that reduce binding affinity to subclasses of IgG might influence phagocyte activity, providing a basis for inherited predisposition to SLE due to the inefficient removal of immunocomplexes [7]. The evidence of association with at least one of the low affinity FcγR polymorphisms has been demonstrated in various populations [8–14]. However, the results have been inconsistent among the studies.
Salmon et al. [14] noted that the FcγRIIA gene has 2 codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2. The 2 alleles differ by the amino acid, arginine or histidine, at position 131. H131 is the only FcγR that recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state. Since immune complex clearance is essential in SLE, they hypothesized that the FcγRIIA genes are important disease susceptibility factors for SLE, particularly lupus nephritis. Distinct classes of FcγR are recognized: FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, and FcγIIIB. The most widely studied and thought to be SLEassociated are FcγRIIA and FcγRIIIA, which are genes located on chromosome 1q23 and separated by only 35 kb, but which are not usually in linkage disequilibrium. Consequently, their associations with lupus might be independent of each other. It is possible that risk alleles exist at FcγRIIA and FcγRIIIA simultaneously, and both might be present to confer increased susceptibility, although this model is also still uncertain [15]. The other three members of this gene family (FcγRIIB, FcγRIIC and FcγRIIIB) also map on chromosome 1q23 and have been reported in various populations to be associated with SLE [9,16,17] but these studies have not yet been replicated. 2.1.4. Mannose-binding lectin MBL is a key element in innate immunity with functions and structure similar to that of complement C1q. Recently, it has been reported by several studies that MBL deficiency, or low serum MBL levels caused by polymorphisms in the
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structural portion or promoter region of the gene, might be associated with SLE [18–20]. Several polymorphisms have been reported for the MBL gene, and large inter-individual differences in serum MBL concentration among test subjects is caused by the possession of variant alleles. The codon 52, 54 and 57 polymorphisms are all on exon 1, and the presence of any of the minority alleles results in a significant reduction of the serum MBL concentration. Similarly, three additional SNPs at positions (H/L at −550, X/Yat −221 and P/Q at +4) in the 5′-flanking region of the MBL gene also influence serum MBL levels. When studying a cohort of 125 SLE patients and 138 geographically matched controls we found that patients carried the MBL codon 54 mutant allele more frequently than controls and the haplotype HY W52 W54 W57 was found to be significantly lower in cases compared with controls. We concluded that the MBL gene codon 54 mutant allele appears to be a risk factor for SLE, whilst haplotypes encoding for high levels of MBL are protective against the disease [21]. 2.1.5. Cytotoxic T lymphocyte antigen-4 CTLA-4 is a structural homologue of CD28 and is an important negative regulator of autoimmune diseases. Recent studies show that CTLA-4 gene polymorphisms are associated with several kinds of human autoimmunity, suggesting that CTLA-4 gene might be a more general susceptibility gene for autoimmune disease. Several polymorphisms have been variously associated to SLE, such as, a T→C change at position −1722, a C→T transition at position −319, and an A→G transition at position +49. The evidence supporting CTLA-4 as a gene important in SLE pathogenesis is strong [22–24]. 2.1.6. Programmed cell death-1 PDCD-1 is a CD28 family member that contains a cytoplasmic immunoreceptor tyrosine-based inhibitory motif and it is expressed on the surface of activated T and B cells. Of all the known and confirmed genetic associations with SLE, PDCD-1 has been the only one to be detected so far by using reverse genetics [25]. This gene was considered the strongest candidate for association with the disease. Prokunina et al. [25] analyzed 2510 individuals, including members of 5 independent sets of families as well as unrelated individuals affected with SLE, for SNPs that they had identified in PDCD-1. They showed that one intronic SNP (7146G→A regulatory polymorphism also called PD 1.3) was associated with the development of SLE in Europeans and Mexicans. The associated allele of this SNP alters a binding site for the RUNT-related transcription factor-1 (RUNX1) located in an intronic enhancer, suggesting a mechanism through
which it can contribute to the development of SLE in humans. The PDCD-1 association is presumed to explain the 2q37 linkage found in Scandinavian pedigrees. This association is found in European-derived people and it is not present in African–American families. The association at the PDCD-1 allele has been confirmed in a second large independent collection [26]. Interestingly, a confirmatory study has found association with PDCD-1 in Spanish cases of lupus, but with an inverted allele distribution [27]. 2.1.7. Interferon regulatory factor 5 Type I IFN system plays a pivotal role when selftolerance is broken and autoimmune reactions develop. A causative role of type I IFN in the initiation and maintenance of autoimmunity is suggested by the finding that up to 19% of IFN-treated patients with a malignant disease ultimately developed an autoimmune disorder [28]. Sigurdsson et al. [29] analyzed 44 SNPs in 13 genes from the type I IFN pathway of 679 Swedish, Finnish, and Icelandic patients with SLE, 798 unaffected family members, and 438 unrelated control individuals for joint linkage and association with SLE. In 2 of the genes, Tyk-2 and IRF5, they identified SNPs that displayed strong signals in joint analysis of linkage and association with SLE. Tyk2 binds to the type I IFN receptor complex, and IRF5 is a regulator of type I IFN gene expression. The results of Prof. Sigurdsson's group supported a disease mechanism in SLE that involves key components of the type I IFN signaling system. On the other hand, Graham et al. [30] replicated the association of the IRF5 T allele (rs2004640) with SLE in 4 independent case-control cohorts and by family-based transmission disequilibrium test analysis, thus confirming the findings of Sigurdsson et al. The T allele creates a 5-prime donor splice site in exon 1B of the IRF5 gene, allowing expression of several unique IRF5 isoforms. Graham et al. also studied an independent cis-acting variant (rs2280714) associated with elevated expression of IRF5 [31] and linked to the exon 1B splice site. Haplotypes carrying the cis-acting variant and lacking the exon 1B donor site did not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE. Other groups have also identified two functional polymorphisms in the IRF5 gene above-mentioned: a) a 3′-UTR SNP (rs10954213) where the A allele leads to a shorter polyadenylation signal providing the causative explanation for the high expression of IRF5 in SLE [32], and b) an insertion/deletion in the 6th exon of the gene that defines the isoforms of IRF5 that are translated into protein [32]. In this same work, a tag SNP (rs2070197) clearly broke-up the originally identified haplotype (comprised of SNPs
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rs2004640 and rs2280714) into an ancestral haplotype of lower frequency that contained the risk alleles of rs2004640, rs2070197, rs10954213 and the 6th exon insertion. The insertion is, by itself, not associated with the disease as it was found also in the protective haplotype suggesting that its impact on the disease process might also be small. The SNP with potentially the most important impact on function is rs10954213, by altering IRF5 levels; however, the allele A of this SNP by itself cannot explain the complete risk conferred by IRF5 to disease susceptibility. Such risk is only conferred by the complete risk haplotype. This risk haplotype has a frequency of 15.8% in SLE patients of European ancestry. It is feasible that a new functional variation is yet to be identified for IRF5. Investigation of genetic associations in populations other than the European may help in the identification of novel causative variants or provide clues about the role of the gene in SLE susceptibility in those populations. In a report from Dr. Gonzalez's group in Spain (with whom I collaborated) [33], fourteen European sample collections with a total of 1383 SLE patients and 1614 controls were obtained in order to better define the role of the different IRF5 gene variants. Eleven polymorphisms were studied, including nine tag SNPs and two extra functional polymorphisms. Two tag SNPs showed independent and opposed associations: susceptibility allele (rs10488631, p b 10− 17) and protection allele (rs729302, p b 10− 6). Haplotype analyses showed that the susceptibility haplotype, identified by the minor allele of rs10488631, can be due to epistasis effects between three IRF5 functional polymorphisms. These polymorphisms determine increased mRNA expression levels, a splice variant with a different exon 1 and a longer prolinerich region in exon 6. This result is striking as none of the three polymorphisms had an independent effect on their own. Protection was independent of these polymorphisms and seemed to reside in the 5′-side of the gene. In conclusion, these results help to understand the role of the IRF5 locus in SLE susceptibility by clearly separating protection from susceptibility as caused by independent polymorphisms. In addition, evidence for epistasis between known functional polymorphisms for the susceptibility effect was found.
been carried out by the four major scientific groups, in USA (California, Oklahoma, Minnesota) and one in Europe (Uppsala, Sweden) which have revealed many loci spread across the genome. To date, 13 major cytogenetic locations have shown significant evidence of linkage to SLE, and have been confirmed in an independent sample. These key regions, along with several suggested genes identified by at least two independent groups of pedigrees, are summarized in Table 1. It is well known that linkages to many loci are not usually replicated across different population groups and study sites [34,35]. Among the identified linkages, there are eight SLE susceptibility regions that have also been replicated independently using particular lupus subphenotypes. These are: 1q23, 1q41, 2q37, 4p16, 6p21, 11p13, 12q24 and 16q13. Each of these linkages is best detected
Table 1 Replicated linkages and candidate susceptibility genes studies in systemic lupus erythematosus Major linkage (cM)
Study center a
Study design
Associated Major ethnicity b gene(s)
1q23
OMRF
1q41
FcγRIIA, AA, EA FcγRIIIA Not known EA, HIS
2q34
UCLA USC OMRF
2q37
UU
4p16
OMRF
5p15
OMRF
6p11-21
MN
10q22
OMRF
11p13
OMRF
11q14
OMRF
12q24
OMRF
16q13 16q13
MN OMRF
17p12
OMRF
Extended pedigrees Extended pedigrees Extended pedigrees Extended pedigrees Extended pedigrees Extended pedigrees Sib-pairs, simplex Extended pedigrees Extended pedigrees Extended pedigrees Extended pedigrees Sib-pairs Extended pedigrees Extended pedigrees
2.2. Genome-wide linkage analysis studies There are several different study design approaches that have been used for genome-wide scanning to identify novel susceptibility loci for SLE. Some of the study designs involve: sibling pairs, which might or might not have parents available, and small and large pedigrees with several generations available. Several genome scans have
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a
Not known AA (Nephritis) PD-1
EU, MEX
Not known EA Not known EA, AA, HIS (Polyarthritis) HLA-DR EA Not known EA (Nephritis) Not known AA (Thrombocytopenia) Not known AA (Hemolytic Anemia) Not known HIS, EA Not known EA Not known AA, HIS Not known EA (Vitiligo)
MN: University of Minnesota; OMRF: Oklahoma Medical Research Foundation; UCLA: University of California at Los Angeles; USC: University of Southern California; UU: Uppsala University. b AA: African–American; EA: European–American; EU: European; HIS: Hispanic; MEX: Mexican. Additional stratification criteria are presented in parenthesis.
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in families from a single ethnicity or racial group. Interestingly, some of these linked regions were linked to other autoimmune diseases, suggesting that the same genes may be involved in related disorders. 3. Conclusions and perspectives We anticipate that family-based classical linkage analysis followed by the association-based positional cloning approach will continue to advance our understanding of the biology of SLE disease phenotypes. We should take into account that many different genes along with many modifying effects of the environment probably influence the disease phenotype. Therefore, gene–gene and gene–environment interactions that combine to cause the disease complicate the interpretation of the data generated from family-based linkage and association studies. In this line, epigenetics, i.e., alterations on the DNA structure not due to nucleotide changes, may have an important role on SLE pathogenesis as demonstrated by the fact that these patients have a low DNA methylation level in their CD4+ T cells [36]. Recently, as an alternative to the DNA approach, a RNA-based approach has also been used to evaluate the expression of important genes that are responsible for the development of complex phenotypes for SLE [37]. Therefore, together with DNA-based results, many other newer approaches promise to further advance our knowledge of the SLE ethiopathology, which hopefully would lead to the finding of new therapeutic targets. In the future, knowledge of an individual's genotype may help us tailor the most appropriate treatment for that SLE individual. Although it is still difficult to know the precise mechanism by which individual allelic variations confer susceptibility to autoimmune diseases such as SLE, we expect that novel candidate gene will be identified within the next decade through these powerful approaches, thus providing new insights into disease mechanisms and expanding the array of potential targets for the development of therapeutic strategies. Take-home messages • The patho-etiology of SLE probably depends on complex multifactorial interactions between various genetic and environmental factors as well as on epistatic effects. • Genetic linkage analysis provides localization of SLE susceptibility loci in different ethnic groups; some of these loci have been linked to specific lclinical manifestations.
• Multiple genes contribute to SLE disease susceptibility, such as HLA class I and II alleles as well as alterations in genes encoding complement and other components of the immune response. • Either case-control or family-based approaches have contributed to generate convincing evidence for the role of a growing number of genes which increase the risk for SLE. • Some SLE-associated genes have been associated with multiple autoimmune diseases, which suggest their pivotal role in immune regulation and autoimmunity in general. • The identification of susceptibility genes and the understanding of their contribution to the development of SLE will help to elucidate the complex immunogenetic basis of the disease and it will undoubtedly lead to innovative and targeted therapies.
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[23] Fernandez-Blanco L, Perez-Pampin E, Gomez-Reino JJ, Gonzalez A. A CTLA-4 polymorphism associated with susceptibility to systemic lupus erythematosus. Arthritis Rheum 2004;50:328–9. [24] Liu MF, Wang CR, Lin LC, Wu CR. CTLA-4 gene polymorphism in promoter and exon-1 regions in Chinese patients with systemic lupus erythematosus. Lupus 2001;10:647–9. [25] Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 2002;32:666–9. [26] Prokunina L, Gunnarsson I, Sturfelt G, Truedsson L, Seligman VA, Olson JL, et al. The systemic lupus erythematosusassociated PDCD1 polymorphism PD1.3A in lupus nephritis. Arthritis Rheum 2004;50:327–8. [27] Ferreiros-Vidal I, Gomez-Reino JJ, Barros F, Carracedo A, Carreira P, Gonzalez-Escribano F, et al. Association of PDCD1 with susceptibility to systemic lupus erythematosus: evidence of population-specific effects. Arthritis Rheum 2004;50:2590–7. [28] Ronnblom L, Eloranta ML, Alm GV. The type I interferon system in systemic lupus erythematosus. Arthritis Rheum 2006;54:408–20. [29] Sigurdsson S, Nordmark G, Goring HH, Lindroos K, Wiman AC, Sturfelt G, et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 2005;76:528–37. [30] Graham RR, Kozyrev SV, Baechler EC, Reddy MV, Plenge RM, Bauer JW, et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet 2006;38:550–5. [31] Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, Spielman RS, et al. Genetic analysis of genome-wide variation in human gene expression. Nature 2004;430:743–7. [32] Kozyrev SV, Lewen S, Reddy PM, Pons-Estel B, Witte T, Junker P, et al. Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus. Arthritis Rheum 2007;56:1234–41. [33] Ferreiro-Neira I, Calaza M, Alonso-Perez E, Marchini M, Scorza R, Sebastiani GD, et al. Opposed independent effects and epistasis in the complex association of IRF5 to SLE. Genes Immun 2007;8:429–38. [34] Kelly JA, Moser KL, Harley JB. The genetics of systemic lupus erythematosus: putting the pieces together. Genes Immun 2002;3 (Suppl 1):S71–85. [35] Tsao BP. The genetics of human systemic lupus erythematosus. Trends Immunol 2003;24:595–602. [36] Balada E, Ordi-Ros J, Vilardell-Tarres M. DNA methylation and systemic lupus erythematosus. Ann N Y Acad Sci 2007;1108:127–36. [37] Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A 2003;100:2610–5.
Autoimmunity Reviews 7 (2008) 345 – 351 www.elsevier.com/locate/autrev
The complex immunogenetic basis of systemic lupus erythematosus Jesús Castro, Eva Balada, Josep Ordi-Ros ⁎, Miquel Vilardell-Tarrés Autoimmune Diseases Research Laboratory, Vall d'Hebron Research Institute, Barcelona, Spain Received 9 December 2007; accepted 8 January 2008 Available online 1 February 2008
Abstract Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology with a complex genetic basis that includes many susceptibility genes on multiple chromosomes. As complex human diseases like SLE involve multiple, interacting genetic and environmental determinants, identifying genes for complex traits is challenging and has had limited success so far. Several key approaches that are necessary to identify disease susceptibility genes in common diseases such as SLE are now available. Collectively, these approaches will allow the prioritization of candidate genes based on available knowledge of map position and biologic relevance. They will also allow us to obtain the genomic structure of these genes as well as to study sequence variants that will facilitate the identification of genes that are important in the development and expression (severity) of lupus and associated phenotypes. Although it is still a labor-intensive and expensive project to identify susceptibility genes in common diseases such as SLE, the new techniques that are now being used will undoubtedly improve gene mapping in such a kind of diseases. In this review we highlight the current findings in the genetics of human SLE after using these approaches. © 2008 Published by Elsevier B.V. Keywords: Genetics; Immunology; SLE; Candidate genes; SNP; Autoantibodies
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . . Genetic approaches used to identify SLE disease genes 2.1. Candidate-gene studies . . . . . . . . . . . . . 2.1.1. HLA association . . . . . . . . . . . . 2.1.2. Complement components . . . . . . . 2.1.3. Fcγ receptors . . . . . . . . . . . . . 2.1.4. Mannose-binding lectin . . . . . . . . 2.1.5. Cytotoxic T lymphocyte antigen-4 . . . 2.1.6. Programmed cell death-1. . . . . . . . 2.1.7. Interferon regulatory factor 5 . . . . . 2.2. Genome-wide linkage analysis studies . . . . .
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⁎ Corresponding author. Autoimmune Diseases Research Laboratory, Vall d'Hebron Research Institute, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain. Tel.: +34 93 4894047; fax: +34 93 4894045. E-mail address: [email protected] (J. Ordi-Ros). 1568-9972/$ - see front matter © 2008 Published by Elsevier B.V. doi:10.1016/j.autrev.2008.01.001
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3. Conclusions and perspectives . Take-home messages . . . . . . . . Acknowledgement . . . . . . . . . References . . . . . . . . . . . . .
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1. Introduction Systemic lupus erythematosus (SLE) is a prototype systemic, autoimmune inflammatory disease that can affect virtually any organ system. The disease primarily affects women in their reproductive years (female:male ratio = 9:1) and the estimated prevalence varies between 12 and 64 cases per 100,000 inhabitants in Europeanderived populations, with a higher prevalence, in general, in non-European-derived populations [1]. The clinical manifestations vary greatly from one lupus patient to another, and the course of the disease is characterized by periods of relapse and remission. The pathogenesis behind the disease remains unclear. The main immunological feature is uncontrolled formation of autoantibodies, leading to excess formation of immune complexes which deposit in different tissues, causing inflammation and tissue damage. The disease may be triggered by environmental factors, such as viruses, certain drugs and sun exposure [2]. Based on epidemiological studies, there is clear clustering of SLE patients in families which suggests an underlying genetic susceptibility. The mode of inheritance of SLE is however unknown. The criteria for the classification of SLE promulgated by the American College of Rheumatology [3] support the likelihood of many phenocopies for this phenotype. They allow the classification as SLE by satisfying any four of eleven criteria, making this a potentially very heterogeneous collection of patients. Even this being the case, some chromosome regions and particular gene variants seem to be in fact shared by some SLE patients. Several candidate susceptibility loci for SLE have been identified in case-control association studies in humans. 2. Genetic approaches used to identify SLE disease genes disease genes The search for genes predisposing to complex traits, such as SLE, can be broadly divided into two strategies: the hypothesis-driven candidate-gene-association analysis and the genome-wide linkage studies. In candidategene analysis an allele or haplotype, or any DNA polymorphism, is directly assessed and a difference in frequency is usually demonstrated (hopefully repeatedly
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in independently ascertained samples) between affected patients and appropriate controls. Therefore, genetic association with a candidate gene suggests that the detected anomaly being measured may be related to the disease or may, in fact, be located very closely to the responsible gene. Linkage, however, is fundamentally a statistical process testing for the co-inheritance of genetic markers (such as DNA microsatellites) with the disease phenotype in families with multiple affected members. Consistent co-inheritance of the marker with the disease in many families indicates that it is in close proximity to the actual disease gene, and might be ‘linked’ to it. Linkage provides evidence of genetic effects, but it is a much poorer discriminator for gene identity than the assessment of individual alleles in candidate genes. 2.1. Candidate-gene studies Since the loss of immune tolerance to self-components is the basis of SLE etiology, many genes encoding proteins with regulatory or adaptive functions in the immune system have been considered as candidates. Several candidate genes have been studied and found to be associated with SLE (Fig. 1). Some of the important candidate genes are discussed below. 2.1.1. HLA association The genetic association of SLE with the major histocompatibility complex HLA has been known for more than 35 years and it is a consistent finding in Northern-European-derived populations. HLA-DR2 and HLA-DR3 have been consistently associated in SLE. The most definitive study of this region has been produced by Tim Behrens' group [4]. They evaluated the DNA polymorphisms in- (and around HLA) of European, Afro-American, and Hispanic lupus families and showed that the genetic association effect centered on HLA-DR2, effectively eliminating polymorphisms at the surrounding loci from consideration. SLE patients with HLA-DR3 had so little variation across a large extended haplotype, that polymorphisms at the surrounding genes could not be eliminated from consideration. Consequently, this group [4] concludes that HLADR2 (but not HLA-DR3) must be identified as a
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Fig. 1. Approximate location of positional candidate genes found to be associated with SLE. Gene symbols: PTPN22, FcγRIIA/FcγRIIIA, FasL, CTLA-4, PDCD-1, HLA-DR2/DR3, C4, IRF5, MBL, Fas, Dnase1.
susceptibility allele for SLE. Haplotypes containing the HLA-DR3 allele should be cautiously considered as we do not know whether this allele (or one on the surrounding loci) may pose a risk for the disease. 2.1.2. Complement components Deficiency of complement components C1q, C1r/s, C2 and C4 predispose to SLE [5,6]. Out of them, C1q carries the strongest disease risk, with over 90% of cases developing rheumatic disease, followed by C4 and C2 (at 75% and 10%, respectively). Deficiencies in C1r/s, C5 and C8 have also been associated with SLE or lupuslike syndromes. Of note, no single mutation has been found to be responsible for these deficiencies. 2.1.3. Fcγ receptors Our understanding of the role of human Fcγ receptors (FcγRs) in SLE pathogenesis has increased considerably over the past several years. These receptors vary in their affinity for IgG, their preferences for IgG subclasses, and cell type-specific expression patterns. FcγRs bind to Fc fragments of IgG and transmit effector signaling in many kinds of immune cells. Allelic variants of FcγR genes that reduce binding affinity to subclasses of IgG might influence phagocyte activity, providing a basis for inherited predisposition to SLE due to the inefficient removal of immunocomplexes [7]. The evidence of association with at least one of the low affinity FcγR polymorphisms has been demonstrated in various populations [8–14]. However, the results have been inconsistent among the studies.
Salmon et al. [14] noted that the FcγRIIA gene has 2 codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2. The 2 alleles differ by the amino acid, arginine or histidine, at position 131. H131 is the only FcγR that recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state. Since immune complex clearance is essential in SLE, they hypothesized that the FcγRIIA genes are important disease susceptibility factors for SLE, particularly lupus nephritis. Distinct classes of FcγR are recognized: FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, and FcγIIIB. The most widely studied and thought to be SLEassociated are FcγRIIA and FcγRIIIA, which are genes located on chromosome 1q23 and separated by only 35 kb, but which are not usually in linkage disequilibrium. Consequently, their associations with lupus might be independent of each other. It is possible that risk alleles exist at FcγRIIA and FcγRIIIA simultaneously, and both might be present to confer increased susceptibility, although this model is also still uncertain [15]. The other three members of this gene family (FcγRIIB, FcγRIIC and FcγRIIIB) also map on chromosome 1q23 and have been reported in various populations to be associated with SLE [9,16,17] but these studies have not yet been replicated. 2.1.4. Mannose-binding lectin MBL is a key element in innate immunity with functions and structure similar to that of complement C1q. Recently, it has been reported by several studies that MBL deficiency, or low serum MBL levels caused by polymorphisms in the
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structural portion or promoter region of the gene, might be associated with SLE [18–20]. Several polymorphisms have been reported for the MBL gene, and large inter-individual differences in serum MBL concentration among test subjects is caused by the possession of variant alleles. The codon 52, 54 and 57 polymorphisms are all on exon 1, and the presence of any of the minority alleles results in a significant reduction of the serum MBL concentration. Similarly, three additional SNPs at positions (H/L at −550, X/Yat −221 and P/Q at +4) in the 5′-flanking region of the MBL gene also influence serum MBL levels. When studying a cohort of 125 SLE patients and 138 geographically matched controls we found that patients carried the MBL codon 54 mutant allele more frequently than controls and the haplotype HY W52 W54 W57 was found to be significantly lower in cases compared with controls. We concluded that the MBL gene codon 54 mutant allele appears to be a risk factor for SLE, whilst haplotypes encoding for high levels of MBL are protective against the disease [21]. 2.1.5. Cytotoxic T lymphocyte antigen-4 CTLA-4 is a structural homologue of CD28 and is an important negative regulator of autoimmune diseases. Recent studies show that CTLA-4 gene polymorphisms are associated with several kinds of human autoimmunity, suggesting that CTLA-4 gene might be a more general susceptibility gene for autoimmune disease. Several polymorphisms have been variously associated to SLE, such as, a T→C change at position −1722, a C→T transition at position −319, and an A→G transition at position +49. The evidence supporting CTLA-4 as a gene important in SLE pathogenesis is strong [22–24]. 2.1.6. Programmed cell death-1 PDCD-1 is a CD28 family member that contains a cytoplasmic immunoreceptor tyrosine-based inhibitory motif and it is expressed on the surface of activated T and B cells. Of all the known and confirmed genetic associations with SLE, PDCD-1 has been the only one to be detected so far by using reverse genetics [25]. This gene was considered the strongest candidate for association with the disease. Prokunina et al. [25] analyzed 2510 individuals, including members of 5 independent sets of families as well as unrelated individuals affected with SLE, for SNPs that they had identified in PDCD-1. They showed that one intronic SNP (7146G→A regulatory polymorphism also called PD 1.3) was associated with the development of SLE in Europeans and Mexicans. The associated allele of this SNP alters a binding site for the RUNT-related transcription factor-1 (RUNX1) located in an intronic enhancer, suggesting a mechanism through
which it can contribute to the development of SLE in humans. The PDCD-1 association is presumed to explain the 2q37 linkage found in Scandinavian pedigrees. This association is found in European-derived people and it is not present in African–American families. The association at the PDCD-1 allele has been confirmed in a second large independent collection [26]. Interestingly, a confirmatory study has found association with PDCD-1 in Spanish cases of lupus, but with an inverted allele distribution [27]. 2.1.7. Interferon regulatory factor 5 Type I IFN system plays a pivotal role when selftolerance is broken and autoimmune reactions develop. A causative role of type I IFN in the initiation and maintenance of autoimmunity is suggested by the finding that up to 19% of IFN-treated patients with a malignant disease ultimately developed an autoimmune disorder [28]. Sigurdsson et al. [29] analyzed 44 SNPs in 13 genes from the type I IFN pathway of 679 Swedish, Finnish, and Icelandic patients with SLE, 798 unaffected family members, and 438 unrelated control individuals for joint linkage and association with SLE. In 2 of the genes, Tyk-2 and IRF5, they identified SNPs that displayed strong signals in joint analysis of linkage and association with SLE. Tyk2 binds to the type I IFN receptor complex, and IRF5 is a regulator of type I IFN gene expression. The results of Prof. Sigurdsson's group supported a disease mechanism in SLE that involves key components of the type I IFN signaling system. On the other hand, Graham et al. [30] replicated the association of the IRF5 T allele (rs2004640) with SLE in 4 independent case-control cohorts and by family-based transmission disequilibrium test analysis, thus confirming the findings of Sigurdsson et al. The T allele creates a 5-prime donor splice site in exon 1B of the IRF5 gene, allowing expression of several unique IRF5 isoforms. Graham et al. also studied an independent cis-acting variant (rs2280714) associated with elevated expression of IRF5 [31] and linked to the exon 1B splice site. Haplotypes carrying the cis-acting variant and lacking the exon 1B donor site did not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE. Other groups have also identified two functional polymorphisms in the IRF5 gene above-mentioned: a) a 3′-UTR SNP (rs10954213) where the A allele leads to a shorter polyadenylation signal providing the causative explanation for the high expression of IRF5 in SLE [32], and b) an insertion/deletion in the 6th exon of the gene that defines the isoforms of IRF5 that are translated into protein [32]. In this same work, a tag SNP (rs2070197) clearly broke-up the originally identified haplotype (comprised of SNPs
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rs2004640 and rs2280714) into an ancestral haplotype of lower frequency that contained the risk alleles of rs2004640, rs2070197, rs10954213 and the 6th exon insertion. The insertion is, by itself, not associated with the disease as it was found also in the protective haplotype suggesting that its impact on the disease process might also be small. The SNP with potentially the most important impact on function is rs10954213, by altering IRF5 levels; however, the allele A of this SNP by itself cannot explain the complete risk conferred by IRF5 to disease susceptibility. Such risk is only conferred by the complete risk haplotype. This risk haplotype has a frequency of 15.8% in SLE patients of European ancestry. It is feasible that a new functional variation is yet to be identified for IRF5. Investigation of genetic associations in populations other than the European may help in the identification of novel causative variants or provide clues about the role of the gene in SLE susceptibility in those populations. In a report from Dr. Gonzalez's group in Spain (with whom I collaborated) [33], fourteen European sample collections with a total of 1383 SLE patients and 1614 controls were obtained in order to better define the role of the different IRF5 gene variants. Eleven polymorphisms were studied, including nine tag SNPs and two extra functional polymorphisms. Two tag SNPs showed independent and opposed associations: susceptibility allele (rs10488631, p b 10− 17) and protection allele (rs729302, p b 10− 6). Haplotype analyses showed that the susceptibility haplotype, identified by the minor allele of rs10488631, can be due to epistasis effects between three IRF5 functional polymorphisms. These polymorphisms determine increased mRNA expression levels, a splice variant with a different exon 1 and a longer prolinerich region in exon 6. This result is striking as none of the three polymorphisms had an independent effect on their own. Protection was independent of these polymorphisms and seemed to reside in the 5′-side of the gene. In conclusion, these results help to understand the role of the IRF5 locus in SLE susceptibility by clearly separating protection from susceptibility as caused by independent polymorphisms. In addition, evidence for epistasis between known functional polymorphisms for the susceptibility effect was found.
been carried out by the four major scientific groups, in USA (California, Oklahoma, Minnesota) and one in Europe (Uppsala, Sweden) which have revealed many loci spread across the genome. To date, 13 major cytogenetic locations have shown significant evidence of linkage to SLE, and have been confirmed in an independent sample. These key regions, along with several suggested genes identified by at least two independent groups of pedigrees, are summarized in Table 1. It is well known that linkages to many loci are not usually replicated across different population groups and study sites [34,35]. Among the identified linkages, there are eight SLE susceptibility regions that have also been replicated independently using particular lupus subphenotypes. These are: 1q23, 1q41, 2q37, 4p16, 6p21, 11p13, 12q24 and 16q13. Each of these linkages is best detected
Table 1 Replicated linkages and candidate susceptibility genes studies in systemic lupus erythematosus Major linkage (cM)
Study center a
Study design
Associated Major ethnicity b gene(s)
1q23
OMRF
1q41
FcγRIIA, AA, EA FcγRIIIA Not known EA, HIS
2q34
UCLA USC OMRF
2q37
UU
4p16
OMRF
5p15
OMRF
6p11-21
MN
10q22
OMRF
11p13
OMRF
11q14
OMRF
12q24
OMRF
16q13 16q13
MN OMRF
17p12
OMRF
Extended pedigrees Extended pedigrees Extended pedigrees Extended pedigrees Extended pedigrees Extended pedigrees Sib-pairs, simplex Extended pedigrees Extended pedigrees Extended pedigrees Extended pedigrees Sib-pairs Extended pedigrees Extended pedigrees
2.2. Genome-wide linkage analysis studies There are several different study design approaches that have been used for genome-wide scanning to identify novel susceptibility loci for SLE. Some of the study designs involve: sibling pairs, which might or might not have parents available, and small and large pedigrees with several generations available. Several genome scans have
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a
Not known AA (Nephritis) PD-1
EU, MEX
Not known EA Not known EA, AA, HIS (Polyarthritis) HLA-DR EA Not known EA (Nephritis) Not known AA (Thrombocytopenia) Not known AA (Hemolytic Anemia) Not known HIS, EA Not known EA Not known AA, HIS Not known EA (Vitiligo)
MN: University of Minnesota; OMRF: Oklahoma Medical Research Foundation; UCLA: University of California at Los Angeles; USC: University of Southern California; UU: Uppsala University. b AA: African–American; EA: European–American; EU: European; HIS: Hispanic; MEX: Mexican. Additional stratification criteria are presented in parenthesis.
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in families from a single ethnicity or racial group. Interestingly, some of these linked regions were linked to other autoimmune diseases, suggesting that the same genes may be involved in related disorders. 3. Conclusions and perspectives We anticipate that family-based classical linkage analysis followed by the association-based positional cloning approach will continue to advance our understanding of the biology of SLE disease phenotypes. We should take into account that many different genes along with many modifying effects of the environment probably influence the disease phenotype. Therefore, gene–gene and gene–environment interactions that combine to cause the disease complicate the interpretation of the data generated from family-based linkage and association studies. In this line, epigenetics, i.e., alterations on the DNA structure not due to nucleotide changes, may have an important role on SLE pathogenesis as demonstrated by the fact that these patients have a low DNA methylation level in their CD4+ T cells [36]. Recently, as an alternative to the DNA approach, a RNA-based approach has also been used to evaluate the expression of important genes that are responsible for the development of complex phenotypes for SLE [37]. Therefore, together with DNA-based results, many other newer approaches promise to further advance our knowledge of the SLE ethiopathology, which hopefully would lead to the finding of new therapeutic targets. In the future, knowledge of an individual's genotype may help us tailor the most appropriate treatment for that SLE individual. Although it is still difficult to know the precise mechanism by which individual allelic variations confer susceptibility to autoimmune diseases such as SLE, we expect that novel candidate gene will be identified within the next decade through these powerful approaches, thus providing new insights into disease mechanisms and expanding the array of potential targets for the development of therapeutic strategies. Take-home messages • The patho-etiology of SLE probably depends on complex multifactorial interactions between various genetic and environmental factors as well as on epistatic effects. • Genetic linkage analysis provides localization of SLE susceptibility loci in different ethnic groups; some of these loci have been linked to specific lclinical manifestations.
• Multiple genes contribute to SLE disease susceptibility, such as HLA class I and II alleles as well as alterations in genes encoding complement and other components of the immune response. • Either case-control or family-based approaches have contributed to generate convincing evidence for the role of a growing number of genes which increase the risk for SLE. • Some SLE-associated genes have been associated with multiple autoimmune diseases, which suggest their pivotal role in immune regulation and autoimmunity in general. • The identification of susceptibility genes and the understanding of their contribution to the development of SLE will help to elucidate the complex immunogenetic basis of the disease and it will undoubtedly lead to innovative and targeted therapies.
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