the complex immunogenetic basis of systemic lupus erythematosus

Available online at www.sciencedirect.com

(2008) 345–351www.elsevier.com/locate/autrev

Autoimmunity Reviews 7

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 2008Available online 1 February 2008

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology with a complex genetic basisthat 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 limitedsuccess so far. Several key approaches that are necessary to identify disease susceptibility genes in common diseases such asSLE are now available. Collectively, these approaches will allow the prioritization of candidate genes based on availableknowledge of map position and biologic relevance. They will also allow us to obtain the genomic structure of these genes aswell as to study sequence variants that will facilitate the identification of genes that are important in the development andexpression (severity) of lupus and associated phenotypes. Although it is still a labor-intensive and expensive project to identifysusceptibility genes in common diseases such as SLE, the new techniques that are now being used will undoubtedly improvegene mapping in such a kind of diseases. In this review we highlight the current findings in the genetics of human SLE afterusing these approaches.© 2008 Published by Elsevier B.V.

Keywords: Genetics; Immunology; SLE; Candidate genes; SNP; Autoantibodies

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3462. Genetic approaches used to identify SLE disease genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346

2.1. Candidate-gene studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3462.1.1. HLA association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3462.1.2. Complement components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3472.1.3. Fcγ receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3472.1.4. Mannose-binding lectin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3472.1.5. Cytotoxic T lymphocyte antigen-4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3482.1.6. Programmed cell death-1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3482.1.7. Interferon regulatory factor 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348

2.2. Genome-wide linkage analysis studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349

⁎ Corresponding author. Autoimmune Diseases Research Laboratory, Vall d'Hebron Research Institute, Passeig Vall d'Hebron 119-129, 08035Barcelona, 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

mailto:[email protected]

http://dx.doi.org/10.1016/j.autrev.2008.01.001

346 J. Castro et al. / Autoimmunity Reviews 7 (2008) 345–351

3. Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350

1. Introduction

Systemic lupus erythematosus (SLE) is a prototypesystemic, autoimmune inflammatory disease that canaffect virtually any organ system. The disease primarilyaffects women in their reproductive years (female:maleratio=9:1) and the estimated prevalence varies between12 and 64 cases per 100,000 inhabitants in European-derived populations, with a higher prevalence, ingeneral, in non-European-derived populations [1]. Theclinical manifestations vary greatly from one lupuspatient to another, and the course of the disease ischaracterized by periods of relapse and remission. Thepathogenesis behind the disease remains unclear. Themain immunological feature is uncontrolled formationof autoantibodies, leading to excess formation ofimmune complexes which deposit in different tissues,causing inflammation and tissue damage. The diseasemay be triggered by environmental factors, such asviruses, certain drugs and sun exposure [2]. Based onepidemiological studies, there is clear clustering of SLEpatients in families which suggests an underlyinggenetic susceptibility. The mode of inheritance of SLEis however unknown. The criteria for the classificationof SLE promulgated by the American College ofRheumatology [3] support the likelihood of manyphenocopies for this phenotype. They allow theclassification as SLE by satisfying any four of elevencriteria, making this a potentially very heterogeneouscollection of patients. Even this being the case, somechromosome regions and particular gene variants seemto be in fact shared by some SLE patients. Severalcandidate susceptibility loci for SLE have beenidentified in case-control association studies in humans.

2. Genetic approaches used to identify SLE diseasegenes

The search for genes predisposing to complex traits,such as SLE, can be broadly divided into two strategies:the hypothesis-driven candidate-gene-association ana-lysis and the genome-wide linkage studies. In candidate-gene analysis an allele or haplotype, or any DNApolymorphism, is directly assessed and a difference infrequency is usually demonstrated (hopefully repeatedly

2. Genetic approaches used to identify SLEdisease genes

in independently ascertained samples) between affectedpatients and appropriate controls. Therefore, geneticassociation with a candidate gene suggests that thedetected anomaly being measured may be related to thedisease or may, in fact, be located very closely to theresponsible gene. Linkage, however, is fundamentally astatistical process testing for the co-inheritance ofgenetic markers (such as DNA microsatellites) withthe disease phenotype in families with multiple affectedmembers. Consistent co-inheritance of the marker withthe disease in many families indicates that it is in closeproximity to the actual disease gene, and might be‘linked’ to it. Linkage provides evidence of geneticeffects, but it is a much poorer discriminator for geneidentity than the assessment of individual alleles incandidate genes.

2.1. Candidate-gene studies

Since the loss of immune tolerance to self-compo-nents is the basis of SLE etiology, many genes encodingproteins with regulatory or adaptive functions in theimmune system have been considered as candidates.Several candidate genes have been studied and found tobe associated with SLE (Fig. 1). Some of the importantcandidate genes are discussed below.

2.1.1. HLA associationThe genetic association of SLE with the major

histocompatibility complex HLA has been known formore than 35 years and it is a consistent finding inNorthern-European-derived populations. HLA-DR2and HLA-DR3 have been consistently associated inSLE. The most definitive study of this region has beenproduced by Tim Behrens' group [4]. They evaluatedthe DNA polymorphisms in- (and around HLA) ofEuropean, Afro-American, and Hispanic lupus familiesand showed that the genetic association effect centeredon HLA-DR2, effectively eliminating polymorphisms atthe surrounding loci from consideration. SLE patientswith HLA-DR3 had so little variation across a largeextended haplotype, that polymorphisms at the sur-rounding genes could not be eliminated from considera-tion. Consequently, this group [4] concludes that HLA-DR2 (but not HLA-DR3) must be identified as a

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.

347J. Castro et al. / Autoimmunity Reviews 7 (2008) 345–351

susceptibility allele for SLE. Haplotypes containing theHLA-DR3 allele should be cautiously considered as wedo not know whether this allele (or one on thesurrounding loci) may pose a risk for the disease.

2.1.2. Complement componentsDeficiency of complement components C1q, C1r/s,

C2 and C4 predispose to SLE [5,6]. Out of them, C1qcarries the strongest disease risk, with over 90% of casesdeveloping 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 lupus-like syndromes. Of note, no single mutation has beenfound to be responsible for these deficiencies.

2.1.3. Fcγ receptorsOur understanding of the role of human Fcγ receptors

(FcγRs) in SLE pathogenesis has increased considerablyover the past several years. These receptors vary in theiraffinity for IgG, their preferences for IgG subclasses, andcell type-specific expression patterns. FcγRs bind to Fcfragments of IgG and transmit effector signaling in manykinds of immune cells. Allelic variants of FcγR genes thatreduce binding affinity to subclasses of IgGmight influencephagocyte activity, providing a basis for inherited predis-position to SLE due to the inefficient removal ofimmunocomplexes [7]. The evidence of association withat least one of the low affinity FcγR polymorphisms hasbeen demonstrated in various populations [8–14]. How-ever, the results have been inconsistent among the studies.

Salmon et al. [14] noted that the FcγRIIA gene has 2codominantly expressed alleles, R131 and H131, whichdiffer 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 recognizesIgG2 efficiently and optimal IgG2 handling occurs only inthe homozygous state. Since immune complex clearance isessential in SLE, they hypothesized that the FcγRIIA genesare important disease susceptibility factors for SLE,particularly lupus nephritis. Distinct classes of FcγR arerecognized: FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, andFcγIIIB. The most widely studied and thought to be SLE-associated are FcγRIIA and FcγRIIIA, which are geneslocated on chromosome 1q23 and separated by only 35 kb,but which are not usually in linkage disequilibrium.Consequently, their associations with lupus might beindependent of each other. It is possible that risk allelesexist at FcγRIIA and FcγRIIIA simultaneously, and bothmight be present to confer increased susceptibility,although this model is also still uncertain [15]. The otherthree members of this gene family (FcγRIIB, FcγRIIC andFcγRIIIB) also map on chromosome 1q23 and have beenreported in various populations to be associated with SLE[9,16,17] but these studies have not yet been replicated.

2.1.4. Mannose-binding lectinMBL is a key element in innate immunitywith functions

and structure similar to that of complement C1q. Recently,it has been reported by several studies thatMBLdeficiency,or low serumMBL levels caused by polymorphisms in the


structural portion or promoter region of the gene, might beassociatedwith SLE [18–20]. Several polymorphisms havebeen reported for the MBL gene, and large inter-individualdifferences in serum MBL concentration among testsubjects 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 asignificant 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 theMBL gene also influence serum MBL levels. Whenstudying a cohort of 125 SLE patients and 138geographically matched controls we found that patientscarried the MBL codon 54 mutant allele more frequentlythan controls and the haplotype HY W52 W54 W57 wasfound to be significantly lower in cases compared withcontrols. We concluded that the MBL gene codon 54mutant allele appears to be a risk factor for SLE, whilsthaplotypes encoding for high levels of MBL are protectiveagainst the disease [21].

2.1.5. Cytotoxic T lymphocyte antigen-4CTLA-4 is a structural homologue of CD28 and is an

important negative regulator of autoimmune diseases.Recent studies show that CTLA-4 gene polymorphismsare associated with several kinds of human autoimmunity,suggesting that CTLA-4 gene might be a more generalsusceptibility gene for autoimmune disease. Severalpolymorphisms have been variously associated to SLE,such as, a T→C change at position −1722, a C→Ttransition at position −319, and an A→G transition atposition +49. The evidence supporting CTLA-4 as a geneimportant in SLE pathogenesis is strong [22–24].

2.1.6. Programmed cell death-1PDCD-1 is a CD28 family member that contains a

cytoplasmic immunoreceptor tyrosine-based inhibitorymotif and it is expressed on the surface of activated Tand B cells. Of all the known and confirmed geneticassociations with SLE, PDCD-1 has been the only one tobe detected so far by using reverse genetics [25]. This genewas considered the strongest candidate for associationwiththe disease. Prokunina et al. [25] analyzed 2510individuals, including members of 5 independent sets offamilies aswell as unrelated individuals affectedwith SLE,for SNPs that they had identified in PDCD-1. Theyshowed that one intronic SNP (7146G→A regulatorypolymorphism also called PD 1.3) was associated with thedevelopment of SLE in Europeans and Mexicans. Theassociated allele of this SNP alters a binding site for theRUNT-related transcription factor-1 (RUNX1) located inan intronic enhancer, suggesting a mechanism through

which it can contribute to the development of SLE inhumans. The PDCD-1 association is presumed to explainthe 2q37 linkage found in Scandinavian pedigrees. Thisassociation is found in European-derived people and it isnot present in African–American families. The associationat the PDCD-1 allele has been confirmed in a second largeindependent collection [26]. Interestingly, a confirmatorystudy has found associationwith PDCD-1 in Spanish casesof lupus, but with an inverted allele distribution [27].

2.1.7. Interferon regulatory factor 5Type I IFN system plays a pivotal role when self-

tolerance is broken and autoimmune reactions develop. Acausative role of type I IFN in the initiation and main-tenance of autoimmunity is suggested by the finding thatup to 19% of IFN-treated patients with amalignant diseaseultimately developed an autoimmune disorder [28].Sigurdsson et al. [29] analyzed 44 SNPs in 13 genesfrom the type I IFN pathway of 679 Swedish, Finnish, andIcelandic patients with SLE, 798 unaffected familymembers, and 438 unrelated control individuals for jointlinkage and associationwith SLE. In 2 of the genes, Tyk-2and IRF5, they identified SNPs that displayed strongsignals in joint analysis of linkage and association withSLE. Tyk2 binds to the type I IFN receptor complex, andIRF5 is a regulator of type I IFN gene expression. Theresults of Prof. Sigurdsson's group supported a diseasemechanism in SLE that involves key components of thetype I IFN signaling system. On the other hand, Graham etal. [30] replicated the association of the IRF5 T allele(rs2004640) with SLE in 4 independent case-controlcohorts and by family-based transmission disequilibriumtest analysis, thus confirming the findings of Sigurdsson etal. The T allele creates a 5-prime donor splice site in exon1B of the IRF5 gene, allowing expression of severalunique IRF5 isoforms. Graham et al. also studied anindependent cis-acting variant (rs2280714) associatedwith elevated expression of IRF5 [31] and linked to theexon 1B splice site. Haplotypes carrying the cis-actingvariant and lacking the exon 1B donor site did not conferrisk of SLE. Thus, a common IRF5 haplotype drivingelevated expression ofmultiple unique isoforms of IRF5 isan important genetic risk factor for SLE. Other groupshave also identified two functional polymorphisms inthe IRF5 gene above-mentioned: a) a 3′-UTR SNP(rs10954213) where the A allele leads to a shorter poly-adenylation signal providing the causative explanation forthe high expression of IRF5 in SLE [32], and b) aninsertion/deletion in the 6th exon of the gene that definesthe isoforms of IRF5 that are translated into protein [32].In this samework, a tag SNP (rs2070197) clearly broke-upthe originally identified haplotype (comprised of SNPs

Table 1Replicated linkages and candidate susceptibility genes studies insystemic lupus erythematosus

Majorlinkage(cM)

Studycenter a

Studydesign

Associatedgene(s)

Major ethnicity b

1q23 OMRF Extendedpedigrees

FcγRIIA,FcγRIIIA

AA, EA

1q41 UCLAUSC

Extendedpedigrees

Not known EA, HIS


Not known AA (Nephritis)

2q37 UU Extendedpedigrees

PD-1 EU, MEX

4p16 OMRF Extendedpedigrees

Not known EA


Not known EA, AA, HIS(Polyarthritis)

6p11-21 MN Sib-pairs,simplex

HLA-DR EA


Not known EA (Nephritis)


Not known AA(Thrombocytopenia)


Not known AA(Hemolytic Anemia)


Not known HIS, EA

16q13 MN Sib-pairs Not known EA16q13 OMRF Extended

pedigreesNot known AA, HIS


Not known EA (Vitiligo)

a MN: University of Minnesota; OMRF: Oklahoma MedicalResearch 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 arepresented in parenthesis.


rs2004640 and rs2280714) into an ancestral haplotype oflower frequency that contained the risk alleles ofrs2004640, rs2070197, rs10954213 and the 6th exoninsertion. The insertion is, by itself, not associatedwith thedisease as it was found also in the protective haplotypesuggesting that its impact on the disease process mightalso be small. The SNP with potentially the mostimportant impact on function is rs10954213, by alteringIRF5 levels; however, the allele A of this SNP by itselfcannot explain the complete risk conferred by IRF5 todisease susceptibility. Such risk is only conferred by thecomplete risk haplotype. This risk haplotype has afrequency of 15.8% in SLE patients of European ancestry.It is feasible that a new functional variation is yet to beidentified for IRF5. Investigation of genetic associationsin populations other than the European may help in theidentification of novel causative variants or provide cluesabout the role of the gene in SLE susceptibility in thosepopulations. In a report from Dr. Gonzalez's group inSpain (with whom I collaborated) [33], fourteen Europeansample collections with a total of 1383 SLE patients and1614 controls were obtained in order to better define therole of the different IRF5 gene variants. Eleven poly-morphismswere studied, including nine tag SNPs and twoextra functional polymorphisms. Two tag SNPs showedindependent and opposed associations: susceptibilityallele (rs10488631, pb10−17) and protection allele(rs729302, pb10−6). Haplotype analyses showed thatthe susceptibility haplotype, identified by the minor alleleof rs10488631, can be due to epistasis effects betweenthree IRF5 functional polymorphisms. These polymorph-isms determine increased mRNA expression levels, asplice variant with a different exon 1 and a longer proline-rich region in exon 6. This result is striking as none of thethree polymorphisms had an independent effect on theirown. Protection was independent of these polymorphismsand seemed to reside in the 5′-side of the gene. Inconclusion, these results help to understand the role of theIRF5 locus in SLE susceptibility by clearly separatingprotection from susceptibility as caused by independentpolymorphisms. In addition, evidence for epistasisbetween known functional polymorphisms for thesusceptibility effect was found.

2.2. Genome-wide linkage analysis studies

There are several different study design approachesthat have been used for genome-wide scanning to identifynovel susceptibility loci for SLE. Some of the studydesigns involve: sibling pairs, which might or might nothave parents available, and small and large pedigrees withseveral generations available. Several genome scans have

been carried out by the four major scientific groups, inUSA (California, Oklahoma, Minnesota) and one inEurope (Uppsala, Sweden) which have revealed manyloci spread across the genome. To date, 13 majorcytogenetic locations have shown significant evidenceof linkage to SLE, and have been confirmed in anindependent sample. These key regions, along withseveral suggested genes identified by at least twoindependent groups of pedigrees, are summarized inTable 1. It is well known that linkages tomany loci are notusually replicated across different population groups andstudy sites [34,35]. Among the identified linkages, thereare eight SLE susceptibility regions that have also beenreplicated independently using particular lupus subphe-notypes. These are: 1q23, 1q41, 2q37, 4p16, 6p21, 11p13,12q24 and 16q13. Each of these linkages is best detected


in families from a single ethnicity or racial group.Interestingly, some of these linked regions were linkedto other autoimmune diseases, suggesting that the samegenes may be involved in related disorders.

3. Conclusions and perspectives

We anticipate that family-based classical linkageanalysis followed by the association-based positionalcloning approach will continue to advance our under-standing of the biology of SLE disease phenotypes. Weshould take into account that many different genes alongwith many modifying effects of the environmentprobably influence the disease phenotype. Therefore,gene–gene and gene–environment interactions thatcombine to cause the disease complicate the interpreta-tion of the data generated from family-based linkage andassociation studies. In this line, epigenetics, i.e.,alterations on the DNA structure not due to nucleotidechanges, may have an important role on SLE pathogen-esis as demonstrated by the fact that these patients havea low DNAmethylation level in their CD4+ T cells [36].Recently, as an alternative to the DNA approach, aRNA-based approach has also been used to evaluate theexpression of important genes that are responsible forthe development of complex phenotypes for SLE [37].Therefore, together with DNA-based results, many othernewer approaches promise to further advance ourknowledge of the SLE ethiopathology, which hopefullywould lead to the finding of new therapeutic targets. Inthe future, knowledge of an individual's genotype mayhelp us tailor the most appropriate treatment for thatSLE individual. Although it is still difficult to know theprecise mechanism by which individual allelic varia-tions confer susceptibility to autoimmune diseases suchas SLE, we expect that novel candidate gene will beidentified within the next decade through these powerfulapproaches, thus providing new insights into diseasemechanisms and expanding the array of potential targetsfor the development of therapeutic strategies.

Take-home messages

• The patho-etiology of SLE probably depends oncomplex multifactorial interactions between variousgenetic and environmental factors as well as onepistatic effects.

• Genetic linkage analysis provides localization of SLEsusceptibility loci in different ethnic groups; some ofthese loci have been linked to specific lclinicalmanifestations.

• Multiple genes contribute to SLE disease suscept-ibility, such as HLA class I and II alleles as well asalterations in genes encoding complement and othercomponents of the immune response.

• Either case-control or family-based approaches havecontributed to generate convincing evidence for therole of a growing number of genes which increase therisk for SLE.

• Some SLE-associated genes have been associatedwithmultiple autoimmune diseases, which suggest theirpivotal role in immune regulation and autoimmunity ingeneral.

• The identification of susceptibility genes and theunderstanding of their contribution to the developmentof SLE will help to elucidate the complex immuno-genetic basis of the disease and itwill undoubtedly leadto innovative and targeted therapies.

Acknowledgement

This work was supported by funds provided fromMOTEMA, S.A.

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the complex immunogenetic basis of systemic lupus erythematosus

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