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Genetic factors play a major role in the development of lupus. The estimated prevalence of lupus is 1/2000, and about 5-12% of cases are familial . In first-degree relatives of SLE patients, the risk of SLE is about 20 times higher than in the general population . the disease concordance rate is 2 - 5% for dizygotic twins and 24 - 58% for monozygotic twins. This 10-fold difference in the disease concordance rate between identical twins (who shared almost all of their genes) and fraternal twins (who shared half of their genes) suggests that multiple genes shared between each pair of twins greatly influence the susceptibility to SLE.
During the past three decades, linkage studies and candidate gene studies have assessed many genes for potential roles in predisposing to SLE. Until now the number of confirmed genes predisposing to SLE has catapulted to approximately 30. And many candidate genes have been identified based on their location or possible pathogenic roles. Specific characteristics of the HLA region, as well as complement factor deficiencies, may facilitate nuclear antigen presentation, thereby triggering autoantibody production. The genetic polymorphism of cytokines may conduce to deregulate lymphocyte activity. Furthermore, The polymorphism of the Fc receptors of immunoglobulins may affect immune complex clearance, thereby promoting tissue damage.
previous genetic studies have implicated
The extended MHC is a gene dense, transcriptionally active, 7.6 Mb interval on chromosome 6p21.3, It comprises the classical human leukocyte antigen (HLA) class I(HLA-A, -B and -C)and class II regions(HLA-DR, -DQ and -DP)that encode the genes involved in antigen presentation. This region is highly polymorphic and, not surprisingly, has been associated with most autoimmune, inflammatory and infectious diseases . In addition, it comprises the class III region that contains many immune genes, such as cytokines and early complement components.
HLA Class II
Many studies, of which the earliest were done more than 20 years ago, have shown that SLE is associated with HLA class II haplotypes involving the HLA-DRB1 and HLA-DQB1 loci, in particular, haplotypes bearing the DRB1*1501/DQB1*0602 (DR2) and DRB1*0301/DQB1*0201 (DR3) alleles have been associated with SLE in Caucasian populations. and studies suggest that these alleles confer an overall 2-to-3-fold increased risk for SLE , Class II HLA specificities seem associated mainly with specific autoantibody profiles. In general, Compared to Caucasians, the HLA association in non-Caucasian populations is less well established.
HLA Class III and the Complement System
In the Class III gene, mutS homolog 5 (MSH5) gene, has been associated with SLE and was in fact the strongest association in the GWAS by Harley et al. . Super viralicidic activity 2-like (SKIV2L), is another Class III gene previously identified as an SLE candidate, and a study of 314 trios from the United Kingdom  implicated this locus independent of class II variants. The integrin alpha M gene (ITGAM) has also been associated with SLE by a number of studies [36, 37, 34, 38].
The strongest single genetic risk factors of SLE are complement defects. for instance, 90% of Homozygous C1q deficiency individuals develop SLE. C1q participates in clearance of apoptotic cells, and thus has a role in the maintenance of immune tolerance. a hierarchy of susceptibility among the absence of classical complement component (C1q ï¼žC4ï¼žC2, in decreasing order of risk for SLE susceptibility) has been suggested. The C4 fraction of complement is encoded by two Class II genes, C4A and C4B. Complete C4 deficiency is associated with a 70% risk of SLE development. In addition, lower copy number of C4 is a risk factor for and higher gene copy number of C4 is a protective factor against SLE disease susceptibility.
IgG Fc receptorï¼ˆ(FCGR)
Fc gamma receptors (FcYR) are members of the immunoglobulin superfamily, which recognize and bind the constant (Fc) portion of specific monomeric IgG and IgG-containing immune complexes , In human, the FcYR genes are clustered on the long arm of chromosome 1q21.1-24, and the classical FcYR family is divided into three receptor families (FcYRI (CD64), FcYRII (CD32) and FcYRIII (CD16)) based on structural homology.
FcYR-lls play an important role in the clearance of immune complexes. that Fc receptor function in SLE may be impaired ,evidence that [43,44]non-synonymous G-to-A variant in the FCGR2A gene (rs1801274) results in a single amino-acid difference at position 131 (R131 and H131) in the second extracellular Ig-like domain of the FcYRIIa protein. This allelic difference alters recognition of ligand. The Fcg RIIA-H131 (histidine residue at position 131) allele is able to bind IgG2 effectively, whereas the R131 (arginine residue at position 131) binds less efficiently to IgG2 and might delay clearance of IgG2 containing ICs . More than 20 studies in several ethnic groups, which including Dutch Caucasians, European-Americans, African-Americans and Koreans[46,44,47], have accessed the relationship between R/H 131 and the susceptibility to SLE and also the development of lupus nephritis. However, results of these studies are inconsistent. A meta-analysis of 17 studies consisting thousands of SLE patients without lupus nephritis, lupus nephritis patients and non-SLE controls has concluded that the low-binding R131 allele confers a 1.3-fold increased risk for developing SLE but confers no significant risk for developing renal disease among SLE patients .which including several Caucasian[49,50,51], Afro-caribbean, Chinese[49,52], and malay ethnic groups.
A single SNP corresponding to isoleucine(I) to threonine (T) at the residue 232(also known as I/T 187 excluding the signal peptide) in the transmembrane domain that may alter the B-cell receptor(BCR) signaling has been associated with SLE in chinese, Japanese and Thais[54-56], but not in blacks, whites in the united states, and Swedish whites[53,57].Therefore, The FcYRIIb I/T 232(also known as I/T 187) may be a risk factor for SLE in Asians but not in other studied populations. Moreover, In 2004, Su et al.  identified a promoter haplotype that alters FcYRIIb promoter activity. The less frequent promoter haplotype (-386C-120A) showed increased promoter activity and drove higher receptor expression in both transfected cell lines and on cells ex vivo from genotyped donors than the more frequent haplotype(-386G-120T)[58,59].The less frequent and more active promoter haplotype was associated with SLE in a Caucasian population with an odds ratio of 1.6.
FcYRIIIa (CD16) is expressed on cell surfaces of natural killer (NK) cells, monocytes and macrophages, and it binds to both IgG1 and IgG3 subclasses. A T-G polymorphism results in phenylalanine (F) - valine (V) at amino acid 176 (counting in the leader sequence or at amino acid 158 of the mature sequence) . Individuals homozygous for F - F bind IgG1 and IgG3 less efficiently than those with V- V genotypes, suggesting less efficient clearance of IgG1 or IgG3 containing ICs  . At least 13 publications address the association between the FcYRIIIa-V- F158 polymorphism and susceptibility to SLE and/or to lupus nephritis. A recent meta-analysis of more than one thousand subjects in each of the three categories (lupus nephritis, SLE without renal involvement and non-SLE controls) has concluded that the F158 allele confers a 1.2-fold increased risk for developing lupus nephritis in patients of European, African and Asian descent but not for SLE susceptibility per se in the absence of nephritis.
Three different allotypic variants of FcYRIIIb, NA1, NA2 and SH, have been identified through serological studies. The six SNP differences underlying these three serologic allotypes include five non-synonymous SNPs and one synonymous SNP. The five amino-acid changes are all in the first extracellular domain of FcYRIIIb. with the amino-acid 65 change resulting in a loss of a glycosylation site in the NA2 allele[61,62]. The enhanced functional capacity of the NA1 allele is firmly established. Some studies have suggested differing binding affinities for IgG1 and IgG3 between the FcYRIIIB-NA1 and FcYRIIIb-NA2 alleles, with the NA1 allele showing higher binding. Alternatively, the NA1 and NA2 alleles may interact differently with other cell surface receptors, such as the b2-integrin, CD11b/CD18. Interactions with other cell surface receptors may be critical or essential to FcYRIIIb function. The NA2/NA2 variant has been shown to confer reduced phagocytic capacity of neutrophils as compared with the NA1/NA1 genotype and is possibly associated with SLE and thrombocytopenia in SLE. More recently, a copy number variation in FcγRIIIb has also been associated with SLE. Aitman and colleagues first suggested that reduced FCGR3B copy number is a risk factor for glomerulonephritis in SLE patients. Further investigation, It is well established that increased CN was protective and decreased CN was a risk factor.
Th1 and Th2 cytokines
Recent studies in animal models of SLE suggested that in SLE there is an alteration in Th1 and/or Th2 lymphocyte function resulting in an enhanced production of cytokines that up-regulate autoantibody production by B cells. Accordingly, in murine models of SLE an altered production of both Th1 (such as IFN-γ and IL-2 and TNF-a) and Th2 (such as IL-4 and IL-6 and IL-10) cytokines have been reported [63,64].[65,96,97,101,104,105,107]
Interferon alpha (IFN-α) is a pleiotropic type I interferon with the potential to break immunologic self-tolerance by activating antigen-presenting cells after uptake of self material. Moreover, IFNα(9q) promotes long term antibody production, class switching and immunological memory Several set of compelling date suggest an important pathogenic roles for IFNa in SLE. Papers published as early as 1979 described increase serum levels of IFN in patient with SLE, particularly Those with active disease. IFN-γ(12q) play a key role in development of autoimmune processes, More than 32 years ago, Hooks et al. found immune interferon (IFN-γ ) in the sera of patients with SLE and showed a good correlation between immune IFN-γ titers and disease activity. It is likely that excessive induction of IFN-γ gene expression up-regulates IgG production by mononuclear cells in patients with SLE ,which may enhance disease development.
It is noteworthy that many interferon regulatory factors are also strongly associated risk factors for SLE because it can induce transcription of IFN-α mRNA. Löfgren et al.  showed that the rs10954213 is the main SNP responsible for altered IRF5 expression in PBMC peripheral blood mononuclear cells (PBMC). Graham et al.  identified an association between the rs2004640 SNP of IRF5 and SLE, and this locus has subsequently been replicated by GWAS in individuals of European, African and Asian ancestry [69,70,71,72,73,74,75,76]. Harley et al.  identified a significant association between SLE risk and locus between IRF7 and the PHRF1 (PHD and ring finger domains 1) gene in a European population. Hikami et al.  found that a functional polymorphism in the 3'-untranslated region of SPI1, known to regulate expression of IRF2, IRF4, and IRF8 [78,79] is associated with increased risk of SLE. In addition, it was recently shown that the risk allele of STAT4 was associated with increased sensitivity to IFNα signaling in lupus patients. SLE patients that carry the STAT4 risk variant have increased expression of downstream IFN-I-regulated genes in vivo compared with patients who do not carry the allele . providing biologic relevance for STAT4 in the IFNα pathway. Recent results show that rs7574865, a variant allele of STAT4, is strongly associated with SLE characterized by double-stranded DNA autoantibodies.
TNF-a gene is located on chromosome 6 (6p21.31)ï¼Œwithin the class III region of major histocompatibility complex (MHC) . TNF- a is a ubiquitous cytokine plays an important role in various physiologic as well as pathologic processes such as inflammation, immunoregulation, proliferation, and apoptosis . It has two differing actions in SLE. On the one hand, TNF- a could be an immunosuppressive mediator of auto-antibody synthesis. On the other hand, TNF-a might be a proinflammatory factor acutely released in the local tissues. Several single-nucleotide polymorphisms have been identified in the TNF-a promoter . Among these, Two common functional polymorphisms in the promoter region of TNF-a have been identified. The first is characterized by a G to A substitution at position -238(TNF- a -238 Gï¼žA, rs361525) has been associated with systemic lupus erythematosus (SLE) [85,86,87]. especially in Caucasian population. The second is characterized by a G to A substitution at position -308 (TNF-a -308 Gï¼žA, rs1800629), The recent meta-analysis of TNF-a promoter-308A/G polymorphism has concluded that the A allele contributed to susceptibility to SLE in Caucasians but not in Asians.
Also of note is that TNF-a is a pleiotropic inflammatory cytokine whose effects are mediated through two distinct cell surface receptors, TNF-RI (TNFRSF1A) and TNF-RII (TNFRSF1B) . A recent meta-analysis of seven case-control studies revealed that a polymorphism at position 196(a methionine to arginine substitution; M196R) of TNF-RII was significantly associated with an increased risk of SLE . Moreover, Graham et al.  used family-based and case-control approaches to identify a risk allele upstream of TNFS4(TNF superfamily, member 4) that predisposes to SLE and is correlated with increased TNFSF4 expression. A number of polymorphisms in TNF alpha-induced protein 3 (TNFAIP3) have been associated with increased susceptibility to SLE [92, 93]. And TNFAIP3-interacting protein 1 (TNIP1) is a also closely related gene, also identified by GWAS as significantly associated with SLE [94, 69, 95] in both European and Chinese populations.
IL-2 is a growth factor for both T and B lymphocytes that is exclusively produced by T cells. high inducibility was independent of stage of disease. Accumulated evidence has suggested that SLE T cells produce decreased amounts of IL-2 following antigenic stimulation in vitro [96, 97, 98, 99]. and its decreased transcription in SLE T cells is probably multifactorial. IL-4 was originally described as a cytokine that delivers early activation and class-switch signals to lymphocyte . In the murine model of SLE, up-regulation of IL-4 expression has been demonstrated . However, in the SLE patients, many investigators, including Anna Csiszar and Horwitz et al, found a significant decrease in IL-4 mRNA expression in unstimulated PBMC of SLE patients. Moreover, IL-6 plays a important role in the regulation of immune responses, by supplying positive and negative signals to activated T and B cells . It is essential for growth of EBV-transformed B cells and, in late stages of B cell activation, it down-regulates proliferation, while promoting terminal differentiation and Ig secretion. High levels of IL-6 mRNA and protein were detected in freshly isolated monocytes and lymphocytes of SLE patients, high serum levels correlated with disease activity [104,105,106]. IL10 is also an attractive positional candidate gene since it maps in 1q32 because it is a potent stimulator of B cells and direct effect on B cell survival and on autoantibody production. B cells and monocytes of SLE or rheumatoid arthritis (RA) patients produce an increased amount of IL10 compared to non-affected individuals. And Many lines of evidence suggest that the IL10 production level to the SNP haplotypes. SNPs located more distally in the 5'flanking region, were tested for association with SLE. A GWA replication study by Gateva et al.  confirmed an association between a SNP (rs3024505) on IL10 and SLE in individuals of European ancestry(P = 3.95 - 10−8).
Herein, It would be also necessary to show that a number of other genes that encode interleukin proteins have also been associated with SLE. including IL-12 [ 108 , 109 ]andIL-18[110 , 111 ]. Those are involved in the onset and progression of the autoimmune disease in lupus.
Other susceptibility gene
programmed cell death 1(pdcd1)
The programmed cell death 1 gene(PDCD1) located within 2q37, encode an inhibitory immunoreceptor of the CD28/CTLA4/ICOS family that have a pivotal role in peripheral tolerance  PDCD1-/-mice have been shown to develop arthritis and lupus-like glomer-ulonephritis. A recent study of , 2500 individuals has shown association between an intronic SNP in PDCD1 and SLE susceptibility conferring a 2.6-fold increased risk to Europeans and a 3.5-fold increased risk to Mexicans . Indeed PDCD1 has in many studies been shown to be associated not only to SLE, but also rheumatoid arthritis, type I diabetes and multiple sclerosis.[114-117]
protein tyrosine phosphatase non-receptor type 22 (PTPN22)
PTPN22 gene located on chromosome 1p13 encodes the cytoplasmic lymphoid-specific phosphatase (Lyp), which is a negative regulator of T cell antigen receptor (TCR) signaling, by binding the regulatory Src tyrosine kinase, Csk to inhibit T cell activation. a functional PTPN22 1858Cï¼žT (R620 W) polymorphism (rs2476601) resides in a motif involved in Csk binding. When a tryptophan (W) residue replaces an arginine (R) at this site, it disrupts the interaction of Lyp with Csk, thereby disturbing the regulation of the TCR-signaling kinases, Lck, Fyn, and ZAP-70. Recently, Indeed genetic studies with different populations revealed a different frequency of the disease-associated 1858T allele in Europe[119-121], but not associated with SLE in Norwegian and Turkish population . contrast to the R620W SNP, a rare missense substitution (R263Q) in PTPN22 was shown to reduce phosphatase activity and was associated with protection from SLE .
C-reactive protein (CRP)
C-reactive protein (CRP), a pentraxin, is an important innate immune modulator that facilitates the clearance and handling of cellular debris and apoptotic bodies [125,126]. CRP is an important liver-derived acute-phase protein that can increase up to 1000-fold in serum as a response to diverse stimuli such as infection or injury. Interestingly, some studies have suggested that SLE is characterized by lower CRP levels than would be predicted [127,128]. The gene coding for CRP is located at 1q23, recent studie by Jeffrey C. Edberg et al and others have shown that CRP levels are influenced by genetic variation in the CRP promoter [129,130,131,132,133,134,135]. In multiple independent study populations, including both African-Americans and Caucasians, the variation in the CRP promoter at CRP-707 (rs3093061), strongly and reproducibly associates with the SLE phenotype.
Angiotensin-converting enzyme (ACE)
In humans, the ACE gene is located on chromosome 17q22-q24 (Mattei et al., 1989; Jeunemaitre et al., 1992) It is involved in the conversion of Angiotensinâ… to Angiotensinâ…¡by its metalloproteinase enzymatic activity and plays a major role in the renin-angiotensin and kallikrein- kininogen systems. It also has the ability to inactivate bradykinin. Recently Several groups have established an association with the insertion /deletion in the ACE gene with systemic lupus erythematosus. A large study of 644 SLE families using the TDT shows significant association between ACE polymorphisms and SLE (or lupus nephritis). a another study of LN among Chinese patients demonstrated association of an Alu I/D genotype with progressive renal disease. In contrast, uhm et al. showed the I/D polymorphisms of ACE gene did not affect susceptibility of SLE, lupus nephritis. In order to demonstrate the reliability of this discrepancy ,further studies in an extended cohort of multinational patients or meta-analysis will be required .
PARP(poly ADP-ribose polymerase) is a nuclear enzyme that mediates a post-translational modification (i.e. ADP-ribosylation) of proteins. Subnormal levels of PARP activity and of mRNA in SLE patients and intermediate levels in unaffected relatives of SLE patients have implicated a role of PARP in SLE , which makes PARP an excellent candidate gene located within the 1q41 - 42 region linked to SLE. A polymorphic CA dinucleotide repeat of the promoter region of PARP, might affect transcription , which has been associated with SLE. The role for PARP in the pathogenesis of SLE remains unclear. PARP is crucial to DNA repair and stability, and decreased PARP activity may promote apoptosis.
Foxp3, encoded by the human FOXP 3 gene(located in Xp11.23), is a transcription factor that regulates CD4ï¼‹ CD25ï¼‹Tregs development and function[140,141]. Treg deficiency might play a role in the initiation and perpetuation of immune dysregulation, and modulate autoantibody production and renal pathology in SLE. A recent study showed that the presence of the (GT)n microsatellite polymorphism in the FOXP 3 gene was associated with enhancer activity.[142,143] Lin et al. found evidence for an association of the FOXP3-6054 SNP with lower risk of lupus nephritis, and of the FOXP3-3279 SNP with lower anti-dsDNA levels in female SLE patients.
Table 1 Main candidate genes and their location within regions of interest candidate genes
Regions of interest
complement component 1, q subcomponent
Fc gamma receptors class IIA
Fc gamma receptors class IIB
Fc gamma receptors class III A
Fc gamma receptors class III B
TNF superfamily, member 4
Protein tyrosine phosphatase non-receptor type 22
poly ADP-ribose polymerase
1q41 - 42
TNFAIP3 interacting protein 1
Signal transducer and activator of transcription 4
programmed cell death 1
Class II HLA genes
Human leukocyte antigen Class II
Class III HLA genes
Human leukocyte antigen Class III
Complement component 2
Complement component 4
Tumor necrosis factor alpha
TNF- a-induced protein 3
Interferon regulatory factor 5
Forkhead box p3