This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.
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 FcÎ³RIIIb 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-Î³ 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-Î±) 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, IFNÎ±(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-Î³(12q) play a key role in development of autoimmune processes, More than 32 years ago, Hooks et al. found immune interferon (IFN-Î³ ) in the sera of patients with SLE and showed a good correlation between immune IFN-Î³ titers and disease activity. It is likely that excessive induction of IFN-Î³ 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-Î± 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 IFNÎ± 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 IFNÎ± 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 Ã- 10âˆ’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
 Tsao BP, Grossman JM. Genetics and systemic lupus erythematosus. Curr Rheumatol 2001; 3: 183-90.
 Arnett Jr FC. The genetic basis of systemic lupus erythématosous. In: Wallace DJ, Hahn BH, editors. Dubois's lupus erythematosus. 5th ed. Baltimore: Williams and Wilkins; 1997. p. 77-117.
 Sullivan KE. Genetics of systemic lupus erythematosus. Clinical implications. Rheum Dis Clin North Am 2000; 26: 229 -56.
 Tsao BP, Wu H. The genetics of human lupus. In: Wallace DJ, Hahn BH, editors. Dubois' lupus erythematosus. 7th. 6. Philadelphia: Lippincott Williams & Wilkins; 2007. pp. 54-81.
 Harley JB, Alarcón-Riquelme ME, Criswell LA, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in itgam, pxk, kiaa1542 and other loci. Nature Genetics 2008;40(2):204-210.
 Fernando MM, Stevens CR, Sabeti PC, et al. Identification of two independent risk factors for lupus within the MHC in United Kingdom families. Plos Genetics. 2007; 3(11): e192.
 Hom G, Graham RR, Modrek B, et al. Association of systemic lupus erythematosus with c8orf13-blk and itgam-itgax. New England Journal of Medicine. 2008;358(9):900-909.
 Chung SA, Taylor KE, Graham RR, et al. Differential genetic associations for systemic lupus erythematosus based on anti-dsdna autoantibody production. Plos Genetics. 2011;7(3) Article ID e1001323.
 Yang W, Shen N, Ye DQ, et al. Genome-wide association study in Asian populations identifies variants in ets1 and wdfy4 associated with systemic lupus erythematosus. Plos Genetics 2010;6(2) Article ID e1000841.
 Slingsby JH, Norsworthy P, Pearce G, et al. Homozygous hereditary C1q deficiency and systemic lupus erythematosus. A new family and the molecular basis of C1q deficiency in three families. Arthritis Rheum 1996;39(4):663-670.
 Barilla-LaBarca ML, Atkinson JP. Rheumatic syndromes associated with complement deficiency. Curr opin Rheumatol 2003;15:55-60.
 Y.L. Wu, et al. Phenotypes, genotypes and disease susceptibility associated with gene copy number variations: complement C4 CNVs in European American healthy subjects and those with systemic lupus erythematosus. Cytogenet Genome Res 2009; 123(1-4): 131-141.
 Salmon JE, Pricop L. Human receptors for immunoglobulin G: key elements in the pathogenesis of rheumatic disease. Arthritis Rheum 2001; 44: 739-750.
 S.Y.Fan. FcYRlla polymorphism in systemic Lupus erythematosus. Kidney Blood Pressure.2000:23:138-142.
 Salmon JE, Millard S, Schachter LA, et al. Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 1996;97:1348-1354.
 Salmon, J.E., Pricop, L. Human receptors for immunoglobulin G: key elements in the pathogenesis of rheumatic disease. Arthritis Rheum 2001; 44, 739 - 750
 Duits AJ, Bootsma H, Derksen RH, et al. Skewed distribution of IgG Fc receptor IIa(CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients. Arthritis Rheum 1995; 38: 1832-1836.
 Song YW, Han CW, Kang SW, et al. Abnormal distribution of Fc gamma receptor type IIa polymorphisms in Korean patients with systemic lupus erythematosus. Arthritis Rheum 1998; 41: 421-426.
 Karassa, F.B. et al. Role of the FcÎ³receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: a meta-analysis. Arthritis Rheum 2002; 46, 1563 - 1571
 Botto M, Theodoridis E, Thompson EM, et al. Fc gamma Râ…¡a polymorphism in systemic lupus erythematosus(SLE):No association with disease.cli Exp Immunol 1996;104:264-268.
 Smyth LJ, Snowden N, Carthy D, et al. Fc gamma Râ…¡a polymorphism in systemic lupus erythematosus. Ann Rheum Dis 1997; 56: 744-746.
 Mannger K, Repp R, Spriewald BM, Rascu A, Geiger A, Wassmuth R, Westerdaal NA, Wentz B, Manger B, Kalden JR, van de Winkel JG: Fc gamma Râ…¡a polymorphism in Caucasian patients with systemic lupus erythematosus: Association with clinical symptoms. Arthritis Rheum 1998;41:1181-1189.
 Yap SN, Phipps ME, Manivasagar M, et al. Human Fc gamma receptorâ…¡A(FcYRllA) genotyping and association with systemic lupus erythematosus (SLE)in Chinese and Malays in Malaysia. Lupus 1999; 8: 305-310.
 Li X, Wu J, Carter RH, et al. A novel polymorphism in the Fcgamma receptorâ…¡B(CD32B) transmembrane region alters receptor signaling. Arthritis Rheum 2003;48: 3242-3252.
 Chu ZT, Tsuchiya N, Kyogoku C, et al. Association of Fcgamma receptorâ…¡b polymorphism with susceptibility to systemic lupus erythematosus in Chinese: a common susceptibility gene in the Asian population. Tissue Antigens 2004;63: 21-27.
 Kyogoku C, Dijstelbloem HM, Tsuchiya N, et al. Fcgamma receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: contribution of FCGR2B to gene susceptibility. Arthritis Rheum 2002, 46: 1242-1254.
 Siriboonrit U, Tsuchiya N, Sirikong M, et al. Association of Fcgamma receptor â…¡b and â…¢b polymorphisms with susceptibility to systemic lupus erythematosus in Thais. Tissue Antigens 2003, 61: 374-383.
 Magnusson V, Zunec R, Odeberg J, et al. polymorphisms of the Fc gamma receptor typeâ…¡b gene are not associated with systemic lupus erythematosus in the Swedish population. Arthritis Rheum 2004, 50: 1348-1350.
 Su K, Wu J, Edberg JC, et al. A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcgammaRIIb alters receptor expression and associates with autoimmunity. I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus. J Immunol 2004; 172: 7186-7191.
 Su K, Li X, Edberg JC, et al. A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcgammaRIIb alters receptor expression and associates with autoimmunity. II. Differential binding of GATA4 and Yin-Yang1 transcription factors and correlated receptor expression and function. J Immunol 2004; 172:7192-7199.
 Karassa, F.B. et al. The Fcg RIIIA-F158 allele is a risk factor for the development of lupus nephritis: a meta-analysis. Kidney Int 2003; 63:1475 - 1482.
 Salmon JE, Edberg JC, Kimberly RP. Fc gamma receptor III on human neutrophils. Allelic variants have functionally distinct capacities. J Clin Invest 1990; 85: 1287-1295.
 Ravetch JV, Perussia B. Alternative membrane forms of Fc gamma RIII(CD16) on human natural killer cells and neutrophils. Cell type-specific expression of two genes that differ in single nucleotide substitutions. JExpMed1989;170: 481-497.
 Peng SL, Moslehi J, Craft J. Roles of interferon-Î³ and interleukin-4 in murine lupus. J Clin Invest 1997; 99:1936-46.
 Theofilopoulos AN, Dixon FJ. Murine models of systemic lupus erythematosus. Adv Immunol 1985; 37:269-390.
 Hooks JJ, Moutsopoulos HM, Geis SA, et al. Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med 1979; 301:5-8.
 Takahashi S, Fossati L, Iwamoto R, et al. Imbalance towards Th1 predominance is associated with acceleration of lupus-like autoimmune syndrome in MRL mice. J Clin Invest 1996; 97:1597Â±604.
 Löfgren SE, Yin H, Delgado-Vega AM, et al. Promoter insertion/deletion in the irf5 gene is highly associated with susceptibility to systemic lupus erythematosus in distinct populations, but exerts a modest effect on gene expression in peripheral blood mononuclear cells. Journal of Rheumatology 2010; 37(3): 574-578.
 Graham RR, Kozyrev SV, Baechler EC, 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. Nature Genetics 2006; 38(5): 550-555.
 Graham RR, Kyogoku C, Sigurdsson S, et al. Three functional variants of ifn regulatory factor 5 (irf5) define risk and protective haplotypes for human lupus. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104(16): 6758-6763.
 Demirci FYK, Manzi S, Ramsey-Goldman R, et al. Association of a common interferon regulatory factor 5 (IRF5) variant with increased risk of systemic lupus erythematosus (SLE) Annals of Human Genetics. 2007;71(3):308-311.
 Shin HD, Sung YK, Choi CB, Lee SO, Lee HW, Bae SC. Replication of the genetic effects of ifn regulatory factor 5 (irf5) on systemic lupus erythematosus in a korean population. Arthritis Research and Therapy. 2007;9, article no. R32
 Kawasaki A, Kyogoku C, Ohashi J, et al. Association of irf5 polymorphisms with systemic lupus erythematosus in a japanese population: support for a crucial role of intron 1 polymorphisms. Arthritis and Rheumatism. 2008;58(3):826-834.
 Siu HO, Yang W, Lau CS, et al. Association of a haplotype of irf5 gene with systemic lupus erythematosus in chinese. Journal of Rheumatology. 2008; 35(2): 360-362.
 Niewold TB, Kelly JA, Kariuki SN, et al. IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Annals of the Rheumatic Diseases. 2012;71(3):463-468.
 Kelly JA, Kelley JM, Kaufman KM, et al. Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in african americans. Genes and Immunity 2008; 9(3): 187-194.
 Niewold TB, Kelly JA, Flesch MH, Espinoza LR, Harley JB, Crow MK. Association of the irf5 risk haplotype with high serum interferon-Î± activity in systemic lupus erythematosus patients. Arthritis and Rheumatism. 2008;58(8):2481-2487.
 Hikami K, Kawasaki A, Ito I, et al. Association of a functional polymorphism in the 3'-untranslated region of spi1 with systemic lupus erythematosus. Arthritis and Rheumatism 2011; 63(3): 755-763.
 Yee AA, Yin P, Siderovski DP, et al. Cooperative interaction between the dna-binding domains of pu.1 and irf4. Journal of Molecular Biology. 1998; 279(5): 1075-1083.
 Huang W, Horvath E, Eklund EA. Pu.1, interferon regulatory factor (irf) 2, and the interferon consensus sequence-binding protein (icsbp/irf8) cooperate to activate nf1 transcription in differentiating myeloid cells. Journal of Biological Chemistry. 2007; 282(9): 6629-6643.
 Taylor KE, Remmers EF, Lee AT, et al. Specificity of the STAT4 Genetic Association for Severe Disease Manifestations of Systemic Lupus Erythematosus. PLoS Genet 2008. 4(5): e1000084.
 Kariuki SN, Kirou KA, MacDermott EJ, et al. Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-Î± in lupus patients in vivo. J Immunol 2009; 182(1): 34-38.
 Dunham I, Sargent CA, Trowsdale J, et al. Molecular mapping of the human major histocompatibility complex by pulsed-field gel electrophoresis. Proc Natl Acad Sci USA 1987; 84: 7237 -7241.
 Vassalli P. The pathophysiology of tumor necrosis factors. Annu Rev Immunol 1992; 10: 411- 452.
 Allen RD. Polymorphism of the human TNF- alpha promoter- random variation or functional diversity. Mol Immunol 1999; 36: 1017 - 1027.
 Bouma G, Crusius JB, Oudkerk Pool M, et al. Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease. Scand J Immunol 1996; 43: 456- 463.
 Kaluza W, Reuss E, Grossmann S, Hug R, Schopf RE, Galle PR, Maerker-Hermann E, Hoehler T. Different transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism. J Invest Dermatol 2000;114:1180 - 1183.
 Pociot F, D'Alfonso S, Compasso S, Scorza R, Richiardi PM. Functional analysis of a new polymorphism in the human TNF alpha gene promoter. Scand J Immunol 1995;42:501 - 504.
 Lee YH, Harley JB, Nath SK. Meta-analysis of TNF-alpha promoter 2308 A/G polymorphism and SLE susceptibility. Eur J Hum Genet 2006; 14: 364 - 371.
 López P, Gutiérrez C, Suáre A. IL-10 and TNFÎ± Genotypes in SLE. Journal of Biomedicine and Biotechnology 2010; Article ID 838390.
 Yap DYH, Lai KN. Cytokines and their roles in the pathogenesis of systemic lupus erythematosus: from basics to recent advances. Journal of Biomedicine and Biotechnology 2010 Article ID 365083.
 Graham DSC, Graham RR, Manku H, et al. Polymorphism at the tnf superfamily gene tnfsf4 confers susceptibility to systemic lupus erythematosus. Nature Genetics 2008; 40(1): 83-89.
 Bates JS, Lessard CJ, Leon JM, et al. Meta-analysis and imputation identifies a 109kb risk haplotype spanning tnfaip3 associated with lupus nephritis and hematologic manifestations. Genes and Immunity 2009; 10(5): 470-477.
 Musone SL, Taylor KE, Lu TT, et al. Multiple polymorphisms in the tnfaip3 region are independently associated with systemic lupus erythematosus. Nature Genetics 2008; 40(9): 1062-1064.
 Han JW, Zheng HF, Cui Y, et al. Genome-wide association study in a chinese han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nature Genetics 2009; 41(11): 1234-1237.
 Kawasaki A, Ito S, Furukawa H, et al. Association of tnfaip3 interacting protein 1, tnip1 with systemic lupus erythematosus in a japanese population: a case-control association study. Arthritis Research & Therapy. 2010;12(5):p. R174.
 Horwitz, D. A., W. Stohl, and J. D. Gray. 1997. T lymphocytes, natural killer cells, cytokines, and immune regulation. In Dubois' Lupus Erythematosus, Ed. D. J. Wallace and B. H. Hahn, eds. Williams & Wilkins, Baltimore, p. 155.
 Linker-Israeli, M., A. C. Bakke, R. C. Kitridou, S. Gendler, S. Gillis, and D. A. Horwitz. Defective production of interleukin 1 and 2 in patients with systemic lupus erythematosus (SLE). J. Immunol 1983; 130: 2651.
 Tsokos, G. C. 1999. Overview of cellular immune function in systemic lupus erythematosus. In Systemic Lupus Erythematosus , 3rd Ed. R. G. Lahita, ed. Ac-ademic Press, New York, p. 17.
 Via, C. S., G. C. Tsokos, B. Bermas, M. Clerici, and G. M. Shearer. 1993. T cell-antigen-presenting cell interactions in human systemic lupus erythematosus: evidence for heterogeneous expression of multiple defects. J. Immunol. 151:
 Snapper CM, Mond JJ. Towards a comprehensive view of immunoglobulin class switching. Immunol Today 1991; 12:223-7.
 Peng SL, Moslehi J, Craft J. Roles of interferon-Î³and interleukin-4 in murine lupus. J Clin Invest 1997; 99: 1936-46.
 Horwitz DA, Wang H, Gray JD. Cytokine gene profile in circulating blood mononuclear cells from patients with systemic lupus erythematosus: increased interleukin-2 but not interleukin-4 mRNA. Lupus 1994; 3:423-8.
 Akira, S., Taga, T., and Kishimoto, T., IL-6 in biology and medicine. Adv. Immunol 1993; 54: 1-78.
 Linker-Israeli, M., Deans, R. J., Wallace, D. J, et al. Elevated levels of endogenous IL-6 in systemic lupus erythematosus: A putative role in pathogenesis. J. Immunol 1991; 147: 117-123.
 Alcocer-Varela, J., Aleman-Hoey, D., and Alarcon-Segovia, D., IL-1 and IL-6 activities are increased in the CSF of patients with CNS lupus erythematosus and correlate with late T cell activa-tion markers. Lupus 1, 111-117, 1992.
 Stuart, R. A., Littlewood, A. J., Hall, N. D., and Maddison, P. J., Elevated serum interleukin-6 levels associated with active dis-ease in systemic connective tissue disorders. Clin. Exp. Rheum.13, 17-22, 1995.
 Gateva V, Sandling JK, Hom G, et al. A large-scale replication study identifies tnip1, prdm1, jazf1, uhrf1bp1 and il10 as risk loci for systemic lupus erythematosus. Nature Genetics 2009; 41(11): 1228-1233.
 Y. Tokano, S. Morimoto, H. Kaneko et al., "Levels of IL-12 in the sera of patients with systemic lupus erythematosus (SLE)- relation to Th1- and Th2-derived cytokines," Clinical and Experimental Immunology 1999; 116(1): 169-173.
 M. Tucci, L. Lombardi, H. B. Richards, F. Dammacco, and F. Silvestris, "Overexpression of interleukin-12 and T helper 1 predominance in lupus nephritis," Clinical and Experimental Immunology , vol. 154, no. 2, pp. 247-254, 2008.
 Calvani N., Richards H.B., Tucci M., et al. "Up-regulation of IL-18 and predominance of a Th1 immune response is a hallmark of lupus nephritis," Clinical and Experimental Immunology 2004; 138(1): 171-178.
 F. Favilli, C. Anzilotti, L. Martinelli et al., "IL-18 activity in systemic lupus erythematosus," Annals of the New York Academy of Sciences , vol. 1173, pp. 301-309, 2009.
 Nishimura H, Honjo T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol 2001.22:265-268.
 Prokunina, L.et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat. Genet 2002; 32: 666 - 669
 Prokunina L, Castillejo-Lopez C, Oberg F, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 2002; 32: 666-669.
 Sanghera DK, Manzi S, Bontempo F, et al. Role of an intronic polymorphism in the PDCD1 gene with the risk of sporadic systemic lupus erythematosus and the occurrence of antiphospholipid antibodies. Hum Genet 2004; 115: 393-398.
 Nielsen C, Hansen D, Husby S, et al. Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes. Tissue Antigens 2003; 62: 492-497.
 Kroner A, Mehling M, Hemmer B, et al. A PD-1 polymorphism is associated with disease progression in multiple sclerosis. Ann Neurol 2005; 58: 50-57.
 Gregersen PK (2005) Gaining insight into PTPN22 and autoim-munity. Nat Genet 37:1300-1302.
 Mori M, Yamada R, Kobayashi K, et al. Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. J Hum Genet 2005; 50:264-266.
 Gregersen PK, Lee HS, Batliwalla F, et al. PTPN22: setting thresholds for autoimmunity. Semin Immunol 2006; 18:214-223
 Pradhan V, Borse V, Ghosh K. PTPN22 gene polymorphisms in autoimmune diseases with special reference to systemic lupus erythematosus disease susceptibility. J Postgrad Med 2010; 56:239-242
 Aksoy R, Duman T, Keskin O, et al. No association of PTPN22 R620W gene polymorphism with rheumatic heart disease and systemic lupus erythematosus. Mol Biol Rep 2011; 38(8):5393-6.
 Orru V, Tsai SJ, Rueda B, et al. A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus. Hum Mol Genet 2009; 18(3): 569-579.
 Carroll, M. The complement system in regulation of adaptive immunity. Nat. Immunol 2004; 5: 981 - 986.
 Du Clos, T. (2003) C-reactive protein as a regulator of autoimmunity and inflammation. Arthritis Rheum. , 48, 1475 - 1477.
 Marnell, L., Mold, C. and Du Clos, T. C-reactive protein: ligands, receptors and role in inflammation. Clin. Immunol 2005; 117: 104 - 111.
 Pepys, M., Lanham, J. and De Beer, F. (1982) C-reactive protein in SLE. Clin. Rheum . Dis., 8, 91 - 103.
 Crawford, D., Sanders, C., Qin, X., et al. Genetic variation is associated with C-reactive protein levels in the Third National Health and Nutrition Examination Survey. Circulation 2006; 114: 2458 - 2465.
 Carlson, C., Aldred, S., Lee, P., et al. Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels. Am. J. Hum. Genet 2005; 77: 64 - 77.
 Lange, L., Carlson, C., Hindorff, L., Lange, E., Walston, J., Durda, J., Cushman, M., Bis, J., Zeng, D., Lin, D.et al.(2006) Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JAMA , 296, 2703 - 2711.
 Miller, D., Zee, R., Suk Danik, J., Kozlowski, P., Chasman, D., Lazarus, R., Cook, N., Ridker, P. and Kwiatkowski, D. (2005) Association of common CRP gene variants with CRP levels and cardiovascular events. Ann. Hum. Genet., 69, 623 - 638.
 Pankow, J., Folsom, A., Cushman, M., Borecki, I., Hopkins, P., Eckfeldt, J. and Tracy, R. (2001) Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study.Atherosclerosis,154, 681 - 689.
 Szalai, A., Wu, J., Lange, E., McCrory, M., Langefeld, C., Williams, A.,Zakharkin, S., George, V., Allison, D., Cooper, G. et al.(2005) Single-nucleotide polymorphisms in the C-reactive protein (CRP) gene promoter that affect transcription factor binding, alter transcriptional activity, and associate with differences in baseline serum CRP level. J. Mol. Med., 83, 440 - 447.
 Hage, F. and Szalai, A. (2007) C-reactive protein gene polymorphisms, C-reactive protein blood levels, and cardiovascular disease risk.J. Am.Coll. Cardiol., 50, 1115 - 1122.
 Parsa A, Peden E, Lum RF, Seligman VA, et al. Association of angiotensin-converting enzyme polymorphisms with systemic lupus erythematosus and nephritis: analysis of 644 SLE families. Genes and Immunity 2002; 3: 42-46.
 Guan T, Lui Z, Chen Z. Angiotensin-converting enzyme gene polymorphism and the clinical pathological features and progression in lupus nephritis. Zhonghua Nei Ke Za Zhi 1997; 36:461-464.
[13*åŠ ] Uhm WS , Lee HS, Chung YH. Angiotensin-converting enzyme gene polymorphism and vascular manifestations in Korean patients with SLE. Lupus 2002;11:227-233.
 Tsao, B.P. Lupus susceptibility genes on human chromosome 1.Int. Rev. Immunol2000; 19: 319 - 334
 Oei, S.L. and Shi, Y. Poly(ADP-ribosyl) ation of transcription factor Yin Yang 1 under conditions of DNA damage. Biochem. Biophys. Res. Commun2001; 285: 27 - 31
 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057-1061.
 Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4ï¼‹CD25ï¼‹regulatory T cells. Nat Immunol 2003; 4: 330-336.
 Bassuny WM, Ihara K, Sasaki Y, et al. A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes. Immuno genetics 2003; 55: 149-156.
 Sanchez E, Rueda B, Orozco G, et al. Analysis of a GT microsatellite in the promoter of the foxp3/scurfin gene in autoimmune diseases. Hum Immunol 2005; 66: 869-873.
 Lin YC, Lee JH, Wu SH, et al. Association of single-nucleotide polymorphisms in FOXP 3 gene with systemic lupus erythematosus susceptibility: a case-control study. Lupus 2011; 20:137-143.