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1.  Identification of novel genetic susceptibility loci in African-American lupus patients using a candidate gene association study 
Arthritis and rheumatism  2011;63(11):3493-3501.
Candidate gene and genome-wide association studies have identified several disease susceptibility loci in lupus patients. These studies have been largely performed in European-derived and Asian lupus patients. In this study, we examine if some of these same susceptibility loci increase lupus risk in African-American individuals.
Single nucleotide polymorphisms tagging 15 independent lupus susceptibility loci were genotyped in a set of 1,724 lupus patients and 2,024 normal healthy controls of African-American descent. The loci examined included: PTPN22, FCGR2A, TNFSF4, STAT4, CTLA4, PDCD1, PXK, BANK1, MSH5 (HLA region), CFB (HLA region), C8orf13-BLK region, MBL2, KIAA1542, ITGAM, and MECP2/IRAK1.
We provide the first evidence for genetic association between lupus and five susceptibility loci in African-American patients (C8orf13-BLK, BANK1, TNFSF4, KIAA1542 andCTLA4; P values= 8.0 × 10−6, 1.9 × 10−5, 5.7 × 10−5, 0.00099, 0.0045, respectively). Further, we confirm the genetic association between lupus and five additional lupus susceptibility loci (ITGAM, MSH5, CFB, STAT4, and FCGR2A; P values= 7.5 × 10−11, 5.2 × 10−8, 8.7 × 10−7, 0.0058, and 0.0070, respectively), and provide evidence for a genome-wide significance for the association between ITGAM and MSH5 (HLA region) for the first time in African-American lupus patients.
These findings provide evidence for novel genetic susceptibility loci for lupus in African-Americans and demonstrate that the majority of lupus susceptibility loci examined confer lupus risk across multiple ethnicities.
PMCID: PMC3205224  PMID: 21792837
2.  Risk Alleles for Systemic Lupus Erythematosus in a Large Case-Control Collection and Associations with Clinical Subphenotypes 
PLoS Genetics  2011;7(2):e1001311.
Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p<5×10−8) in 1919 SLE cases from 9 independent Caucasian SLE case series and 4813 independent controls. The mean number of risk alleles in cases was 15.1 (SD 3.1) while the mean in controls was 13.1 (SD 2.8), with trend p = 4×10−128. We defined a genetic risk score (GRS) for SLE as the number of risk alleles with each weighted by the SLE risk odds ratio (OR). The OR for high-low GRS tertiles, adjusted for intra-European ancestry, sex, and parent study, was 4.4 (95% CI 3.8–5.1). We studied associations of individual SNPs and the GRS with clinical manifestations for the cases: age at diagnosis, the 11 American College of Rheumatology classification criteria, and double-stranded DNA antibody (anti-dsDNA) production. Six subphenotypes were significantly associated with the GRS, most notably anti-dsDNA (ORhigh-low = 2.36, p = 9e−9), the immunologic criterion (ORhigh-low = 2.23, p = 3e−7), and age at diagnosis (ORhigh-low = 1.45, p = 0.0060). Finally, we developed a subphenotype-specific GRS (sub-GRS) for each phenotype with more power to detect cumulative genetic associations. The sub-GRS was more strongly associated than any single SNP effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers), while single loci are more significantly associated with renal disease (HLA-DRB1, OR = 1.37, 95% CI 1.14–1.64) and arthritis (ITGAM, OR = 0.72, 95% CI 0.59–0.88). We did not observe significant associations for other subphenotypes, for individual loci or the sub-GRS. Thus our analysis categorizes SLE subphenotypes into three groups: those having cumulative, single, and no known genetic association with respect to the currently established SLE risk loci.
Author Summary
Systemic lupus erythematosus is a chronic disabling autoimmune disease, most commonly striking women in their thirties or forties. It can cause a wide variety of clinical manifestations, including kidney disease, arthritis, and skin disorders. Prognosis varies greatly depending on these clinical features, with kidney disease and related characteristics leading to greater morbidity and mortality. It is also complex genetically; while lupus runs in families, genes increase one's risk for lupus but do not fully determine the outcome. The interactions of multiple genes and/or interactions between genes and environmental factors may cause lupus, but the causes and disease pathways of this very heterogeneous disease are not well understood. By examining relationships between the presence of multiple lupus risk genes, lupus susceptibility, and clinical manifestations, we hope to better understand how lupus is triggered and by what biological pathways it progresses. We show in this work that certain clinical manifestations of lupus are highly associated with cumulative genetic variations, i.e. multiple risk alleles, while others are associated with a single variation or none at all.
PMCID: PMC3040652  PMID: 21379322
3.  Time to Renal Disease and End-Stage Renal Disease in PROFILE: A Multiethnic Lupus Cohort 
PLoS Medicine  2006;3(10):e396.
Renal involvement is a serious manifestation of systemic lupus erythematosus (SLE); it may portend a poor prognosis as it may lead to end-stage renal disease (ESRD). The purpose of this study was to determine the factors predicting the development of renal involvement and its progression to ESRD in a multi-ethnic SLE cohort (PROFILE).
Methods and Findings
PROFILE includes SLE patients from five different United States institutions. We examined at baseline the socioeconomic–demographic, clinical, and genetic variables associated with the development of renal involvement and its progression to ESRD by univariable and multivariable Cox proportional hazards regression analyses. Analyses of onset of renal involvement included only patients with renal involvement after SLE diagnosis (n = 229). Analyses of ESRD included all patients, regardless of whether renal involvement occurred before, at, or after SLE diagnosis (34 of 438 patients). In addition, we performed a multivariable logistic regression analysis of the variables associated with the development of renal involvement at any time during the course of SLE.
In the time-dependent multivariable analysis, patients developing renal involvement were more likely to have more American College of Rheumatology criteria for SLE, and to be younger, hypertensive, and of African-American or Hispanic (from Texas) ethnicity. Alternative regression models were consistent with these results. In addition to greater accrued disease damage (renal damage excluded), younger age, and Hispanic ethnicity (from Texas), homozygosity for the valine allele of FcγRIIIa (FCGR3A*GG) was a significant predictor of ESRD. Results from the multivariable logistic regression model that included all cases of renal involvement were consistent with those from the Cox model.
Fcγ receptor genotype is a risk factor for progression of renal disease to ESRD. Since the frequency distribution of FCGR3A alleles does not vary significantly among the ethnic groups studied, the additional factors underlying the ethnic disparities in renal disease progression remain to be elucidated.
Fcγ receptor genotype is a risk factor for progression of renal disease to ESRD but does not explain the ethnic disparities in renal disease progression.
Editors' Summary
Systemic lupus erythematosis (SLE, commonly known as “lupus”) is an illness of many manifestations that appear to result from the immune system attacking components of the body's own cells. One of the unfortunate effects of SLE is kidney damage, which can, in a minority of patients, progress to kidney failure (formally called “end-stage renal disease,” or ESRD). Compared to White Americans, other ethnic groups tend to develop renal complications of lupus more often and with worse outcomes.
Why Was This Study Done?
It is unclear why some people with lupus develop kidney problems. The purpose of this US-based study was to confirm the factors that increase the risk of kidney damage and kidney failure, particularly in racial and ethnic minority patients, and to determine which of these factors accelerate the pace of kidney disease. Knowing these risk factors could allow the development and targeting of interventions, such as screening tests and preventive treatments, to prevent long-term loss of kidney function in patients with lupus.
What Did the Researchers Do and Find?
The researchers measured a number of factors in a multi-ethnic group of 1,008 patients with lupus, almost half of whom had some degree of kidney involvement. They found that those who developed kidney damage after being diagnosed with lupus tended to be younger, to have had lupus for a longer time, and to have experienced more effects of lupus in general than those who did not have kidney involvement. Those who developed kidney problems were also more likely to have been unemployed, to have had fewer years of formal education, and to have had high blood pressure before developing kidney involvement. African-American and Texan Hispanic individuals with lupus were more likely to develop kidney involvement, and tended to develop it more rapidly, than White Americans or Puerto Rican Hispanic ethnicity. Actual kidney failure (ESRD requiring dialysis or kidney transplantation) was more likely to occur among Texan Hispanics with kidney involvement than in the other ethnic groups. Diabetes and high blood pressure were not found to predict ESRD, but people with a particular variant of a protein that helps antibodies bind to cells (know as Fc-gamma receptor IIIa, or FcγRIIIa) were found to be more likely to develop ESRD, and to develop it more quickly.
What Do These Findings Mean?
These results suggest that the emergence and progression of kidney disease in patients with lupus depends on medical, genetic, and socioeconomic factors. Because no single test or intervention can be expected to address all of these factors, those treating patients with lupus must remain aware of the complexity of their patients lives at a variety of levels. In particular, ethnic disparities in the risk of serious kidney disease remain to be addressed.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus page on lupus
Lupus Foundation of America
American College of Rheumatology pages on lupus
Wikipedia entry on lupus (note: Wikipedia is a free Internet encyclopedia that anyone can edit)
PMCID: PMC1626549  PMID: 17076550
4.  Early disease onset is predicted by a higher genetic risk for lupus and is associated with a more severe phenotype in lupus patients 
Annals of the rheumatic diseases  2010;70(1):151-156.
Systemic lupus erythematosus (SLE) is a chronic, multiorgan, autoimmune disease that affects people of all ages and ethnicities.
To explore the relationship between age at disease onset and many of the diverse manifestations of SLE. Additionally, to determine the relationship between age of disease onset and genetic risk in patients with SLE.
The relationship between the age at disease onset and SLE manifestations were explored in a multiracial cohort of 1317 patients. Patients with SLE were genotyped across 19 confirmed genetic susceptibility loci for SLE. Logistic regression was used to determine the relationships between the number of risk alleles present and age of disease onset.
Childhood-onset SLE had higher odds of proteinuria, malar rash, anti-dsDNA antibody, haemolytic anaemia, arthritis and leucopenia (OR=3.03, 2.13, 2.08, 2.50, 1.89, 1.53, respectively; p values <0.0001, 0.0004, 0.0005, 0.0024, 0.0114, 0.045, respectively). In female subjects, the odds of having cellular casts were 2.18 times higher in childhood-onset than in adult-onset SLE (p=0.0027). With age of onset ≥50, the odds of having proteinuria, cellular casts, anti-nRNP antibody, anti-Sm antibody, anti-dsDNA antibody and seizures were reduced. However, late adult-onset patients with SLE have higher odds of developing photosensitivity than early adult-onset patients. Each SLE-susceptibility risk allele carried within the genome of patients with SLE increased the odds of having a childhood-onset disease in a race-specific manner: by an average of 48% in Gullah and 25% in African-Americans, but this was not significant in Hispanic and European-American lupus patients.
The genetic contribution towards predicting early-onset disease in patients with SLE is quantified for the first time. A more severe SLE phenotype is found in patients with early-onset disease in a large multi-racial cohort, independent of gender, race and disease duration.
PMCID: PMC3034281  PMID: 20881011
5.  Polymorphisms of the ITGAM Gene Confer Higher Risk of Discoid Cutaneous Than of Systemic Lupus Erythematosus 
PLoS ONE  2010;5(12):e14212.
Lupus erythematosus (LE) is a heterogeneous disease ranging from mainly skin-restricted manifestations (discoid LE [DLE] and subacute cutaneous LE) to a progressive multisystem disease (systemic LE [SLE]). Genetic association studies have recently identified several strong susceptibility genes for SLE, including integrin alpha M (ITGAM), also known as CD11b, whereas the genetic background of DLE is less clear.
Principal Findings
To specifically investigate whether ITGAM is a susceptibility gene not only for SLE, but also for cutaneous DLE, we genotyped 177 patients with DLE, 85 patients with sporadic SLE, 190 index cases from SLE families and 395 population control individuals from Finland for nine genetic markers at the ITGAM locus. SLE patients were further subdivided by the presence or absence of discoid rash and renal involvement. In addition, 235 Finnish and Swedish patients positive for Ro/SSA-autoantibodies were included in a subphenotype analysis. Analysis of the ITGAM coding variant rs1143679 showed highly significant association to DLE in patients without signs of systemic disease (P-value  = 4.73×10−11, OR  = 3.20, 95% CI  = 2.23–4.57). Significant association was also detected to SLE patients (P-value  = 8.29×10−6, OR  = 2.14, 95% CI  = 1.52–3.00), and even stronger association was found when stratifying SLE patients by presence of discoid rash (P-value  = 3.59×10−8, OR  = 3.76, 95% CI  = 2.29–6.18).
We propose ITGAM as a novel susceptibility gene for cutaneous DLE. The risk effect is independent of systemic involvement and has an even stronger genetic influence on the risk of DLE than of SLE.
PMCID: PMC2996302  PMID: 21151989
6.  Specificity of the STAT4 Genetic Association for Severe Disease Manifestations of Systemic Lupus Erythematosus 
PLoS Genetics  2008;4(5):e1000084.
Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the STAT4 gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the STAT4 region genotyped in 4 independent SLE case series (total n = 1398) and 2560 healthy controls, along with clinical data for the cases. Using conditional testing, we confirmed the most significant STAT4 haplotype for SLE risk. We then studied a SNP marking this haplotype for association with specific SLE subphenotypes, including autoantibody production, nephritis, arthritis, mucocutaneous manifestations, and age at diagnosis. To prevent possible type-I errors from population stratification, we reanalyzed the data using a subset of subjects determined to be most homogeneous based on principal components analysis of genome-wide data. We confirmed that four SNPs in very high LD (r2 = 0.94 to 0.99) were most strongly associated with SLE, and there was no compelling evidence for additional SLE risk loci in the STAT4 region. SNP rs7574865 marking this haplotype had a minor allele frequency (MAF) = 31.1% in SLE cases compared with 22.5% in controls (OR = 1.56, p = 10−16). This SNP was more strongly associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p<10−19), nephritis (MAF = 34.3%, OR = 1.80, p<10−11), and age at diagnosis<30 years (MAF = 33.8%, OR = 1.77, p<10−13). An association with severe nephritis was even more striking (MAF = 39.2%, OR = 2.35, p<10−4 in the homogeneous subset of subjects). In contrast, STAT4 was less strongly associated with oral ulcers, a manifestation associated with milder disease. We conclude that this common polymorphism of STAT4 contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease.
Author Summary
Systemic lupus erythematosus is a chronic disabling autoimmune disease, most commonly striking women in their thirties or forties. It can cause a wide variety of clinical manifestations, including kidney disease, arthritis, and skin disorders. Prognosis varies greatly depending on these clinical features, with kidney disease and related characteristics leading to greater morbidity and mortality. It is also complex genetically; while lupus runs in families, genes increase one’s risk for lupus but do not fully determine the outcome. It is thought that the interactions of multiple genes and/or interactions between genes and environmental factors may cause lupus, but the causes and disease pathways of this very heterogeneous disease are not well understood. By examining relationships between subtypes of lupus and specific genes, we hope to better understand how lupus is triggered and by what biological pathways it progresses. We show in this work that the STAT4 gene, very recently identified as a lupus risk gene, predisposes specifically to severe manifestations of lupus, including kidney disease.
PMCID: PMC2377340  PMID: 18516230
7.  Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus 
Arthritis and Rheumatism  2012;64(2):485-492.
Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis is established in lupus. We test for gene-gene interactions in a number of known lupus susceptibility loci.
Eighteen SNPs tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 lupus patients and 3,818 normal healthy controls of European descent. Epistasis was tested using a 2-step approach utilizing both parametric and non-parametric methods. The false discovery rate (FDR) method was used to correct for multiple testing.
We detected and confirmed gene-gene interactions between the HLA region and CTLA4, IRF5, and ITGAM, and between PDCD1 and IL21 in lupus patients. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (Interaction odds ratio=1.19, z-score= 3.95, P= 7.8×10−5 (FDR≤0.05), PMDR= 5.9×10−45). Importantly, our data suggest that in lupus patients the presence of the HLA lupus-risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus-risk allele in IRF5 (rs2070197) by 17% and 16%, respectively (P= 0.0028 and 0.0047).
We provide evidence for gene-gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability.
PMCID: PMC3268866  PMID: 21952918
8.  Differential Genetic Associations for Systemic Lupus Erythematosus Based on Anti–dsDNA Autoantibody Production 
PLoS Genetics  2011;7(3):e1001323.
Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti–dsDNA autoantibody production, a SLE–related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti–dsDNA autoantibody positive (anti–dsDNA +, n = 811) and anti–dsDNA autoantibody negative (anti–dsDNA –, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti–dsDNA + SLE. Far fewer and weaker associations were observed for anti–dsDNA – SLE. For example, rs7574865 in STAT4 had an OR for anti–dsDNA + SLE of 1.77 (95% CI 1.57–1.99, p = 2.0E-20) compared to an OR for anti–dsDNA – SLE of 1.26 (95% CI 1.12–1.41, p = 2.4E-04), with pheterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti–dsDNA + SLE and were not associated with anti–dsDNA – SLE. In conclusion, we identified differential genetic associations with SLE based on anti–dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti–dsDNA – SLE.
Author Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can involve virtually any organ system. SLE patients produce antibodies that bind to their own cells and proteins (autoantibodies) which can cause irreversible organ damage. One particular SLE–related autoantibody directed at double-stranded DNA (anti–dsDNA) is associated with kidney involvement and more severe disease. Previous genome-wide association studies (GWAS) in SLE have studied SLE itself, not particular SLE manifestations. Therefore, we conducted this GWAS of anti–dsDNA autoantibody production to identify genetic associations with this clinically important autoantibody. We found that many previously identified SLE–associated genes are more strongly associated with anti–dsDNA autoantibody production than SLE itself, and they may be more accurately described as autoantibody propensity genes. No strong genetic associations were observed for SLE patients who do not produce anti–dsDNA autoantibodies, suggesting that other factors may have more influence in developing this type of SLE. Further investigation of these autoantibody propensity genes may lead to greater insight into the causes of autoantibody production and organ damage in SLE.
PMCID: PMC3048371  PMID: 21408207
9.  Genetically Determined Amerindian Ancestry Correlates with Increased Frequency of Risk Alleles for Systemic Lupus Erythematosus 
Arthritis and rheumatism  2010;62(12):3722-3729.
To analyze if genetically determined Amerindian ancestry predicts the increased presence of risk alleles of known susceptibility genes for systemic lupus erythematosus.
Single nucleotide polymorphisms within 16 confirmed genetic susceptibility loci for SLE were genotyped in a set of 804 Mestizo lupus patients and 667 Mestizo normal healthy controls. In addition, 347 admixture informative markers were genotyped. Individual ancestry proportions were determined using STRUCTURE. Association analysis was performed using PLINK, and correlation of the presence of risk alleles with ancestry was done using linear regression.
A meta-analysis of the genetic association of the 16 SNPs across populations showed that TNFSF4, STAT4, PDCD1, ITGAM, and IRF5 were associated with lupus in a Hispanic-Mestizo cohort enriched for European and Amerindian ancestry. In addition, two SNPs within the MHC region, previously associated in a genome-wide association study in Europeans, were also associated in Mestizos. Using linear regression we predict an average increase of 2.34 risk alleles when comparing a lupus patient with 100% Amerindian ancestry to an SLE patient with 0% American Indian Ancestry (p<0.0001). SLE patients with 43% more Amerindian ancestry are predicted to carry one additional risk allele.
Amerindian ancestry increased the number of risk alleles for lupus.
PMCID: PMC3078084  PMID: 20848568
10.  ITGAM coding variant (rs1143679) influences the risk of renal disease, discoid rash, and immunologic manifestations in lupus patients with European ancestry 
Annals of the rheumatic diseases  2009;69(7):1329-1332.
We hypothesized that the coding variant (R77H), rs1143679, within ITGAM could predict specific clinical manifestations associated with lupus.
To assess genetic association, 2366 lupus cases and 2931 unaffected controls with European ancestry were analyzed. Lupus patients were coded by the presence or absence of individual ACR criteria. Logistic regression and Pearson chi-square tests were used to assess statistical significance.
First, for overall case-control analysis, we detected highly significant (p=2.22×10−21, OR=1.73) association. Second, using case-only analysis we detected significant association with renal criteria (p=0.0003), discoid rash (p=0.02), and immunologic criteria (p=0.04). Third, we compared them with healthy controls, the association became stronger for renal (p=4.69×10−22, OR=2.15), discoid (p=1.77×10−14, OR=2.03), and immunologic (p=3.49×10−22, OR = 1.86) criteria. Risk allele frequency increased from 10.6% (controls) to 17.0% (lupus), 20.4% (renal), 18.1% (immunologic), and 19.5% (discoid).
These results demonstrated a strong association between the risk allele (A) at rs1143679 and renal disease, discoid rash, and immunological manifestations of lupus.
PMCID: PMC2891778  PMID: 19939855
11.  Resequencing the susceptibility gene, ITGAM, identifies two functionally deleterious rare variants in systemic lupus erythematosus cases 
Arthritis Research & Therapy  2014;16(3):R114.
The majority of the genetic variance of systemic lupus erythematosus (SLE) remains unexplained by the common disease-common variant hypothesis. Rare variants, which are not detectable by genome-wide association studies because of their low frequencies, are predicted to explain part of this ”missing heritability.” However, recent studies identifying rare variants within known disease-susceptibility loci have failed to show genetic associations because of their extremely low frequencies, leading to the questioning of the contribution of rare variants to disease susceptibility. A common (minor allele frequency = 17.4% in cases) nonsynonymous coding variant rs1143679 (R77H) in ITGAM (CD11b), which forms half of the heterodimeric integrin receptor, complement receptor 3 (CR3), is robustly associated with SLE and has been shown to impair CR3-mediated phagocytosis.
We resequenced ITGAM in 73 SLE cases and identified two previously unidentified, case-specific nonsynonymous variants, F941V and G1145S. Both variants were genotyped in 2,107 and 949 additional SLE cases, respectively, to estimate their frequencies in a disease population. An in vitro model was used to assess the impact of F941V and G1145S, together with two nonsynonymous ITGAM polymorphisms, A858V (rs1143683) and M441T (rs11861251), on CR3-mediated phagocytosis. A paired two-tailed t test was used to compare the phagocytic capabilities of each variant with that of wild-type CR3.
Both rare variants, F941V and G1145S, significantly impair CR3-mediated phagocytosis in an in vitro model (61% reduction, P = 0.006; 26% reduction, P = 0.0232). However, neither of the common variants, M441T and A858V, had an effect on phagocytosis. Neither rare variant was observed again in the genotyping of additional SLE cases, suggesting that there frequencies are extremely low.
Our results add further evidence to the functional importance of ITGAM in SLE pathogenesis through impaired phagocytosis. Additionally, this study provides a new example of the identification of rare variants in common-allele-associated loci, which, because of their extremely low frequencies, are not statistically associated. However, the demonstration of their functional effects adds support to their contribution to disease risk, and questions the current notion of dismissing the contribution of very rare variants on purely statistical analyses.
PMCID: PMC4060450  PMID: 24886912
12.  Recent insights into the genetic basis of systemic lupus erythematosus 
Genes and immunity  2009;10(5):373-379.
Genetic variation was first shown to be part of the cause of systemic lupus erythematosus (SLE or lupus) in the 1970s with associations in the human leukocyte antigen (HLA) region. Almost four decades later, and with the help of increasingly powerful genetic approaches, more than 25 genes are now known to contribute to the mechanisms that predispose individuals to lupus. Over half of these loci have been discovered in the past two years, underscoring the extraordinary success of recent genome-wide association approaches in SLE. The now well established genetic risk factors include alleles in the MHC region (multiple genes), IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFAIP3, SPP1, ATG5, XKR6, PXK, some of the Fcγ receptors, and deficiencies in several complement components, including C1q, C4, and C2. As reviewed here, many of these genes fall into key pathways that are consistent with previous studies implicating immune complexes, host immune signal transduction, and interferon pathways in the pathogenesis of SLE. Other genetic loci have no known function or apparent immunological role and have the potential to reveal novel disease mechanisms. Certainly, as our understanding of the genetic etiology of SLE continues to mature, important new opportunities will emerge for developing more targeted and effective diagnostic and clinical management tools for this complex autoimmune disease.
PMCID: PMC3144759  PMID: 19440199
13.  Association Study of ITGAM, ITGAX, and CD58 Autoimmune Risk Loci in Systemic Sclerosis: Results from 2 Large European Caucasian Cohorts 
The Journal of Rheumatology  2011;38(6):1033-1038.
Accumulating evidence shows that shared autoimmunity is critical for the pathogenesis of many autoimmune diseases. Systemic sclerosis (SSc) belongs to the connective tissue disorders, and recent data have highlighted strong associations with autoimmunity genes shared with other autoimmune diseases. To determine whether novel risk loci associated with systemic lupus erythematosus or multiple sclerosis may confer susceptibility to SSc, we tested single-nucleotide polymorphisms (SNP) from ITGAM, ITGAX, and CD58 for associations.
SNP harboring associations with autoimmune diseases, ITGAM rs9937837, ITGAX rs11574637, and CD58 rs12044852, were genotyped in 2 independent cohorts of European Caucasian ancestry: 1031 SSc patients and 1014 controls from France and 1038 SSc patients and 691 controls from the USA, providing a combined study population of 3774 individuals. ITGAM rs1143679 was additionally genotyped in the French cohort.
The 4 polymorphisms were in Hardy-Weinberg equilibrium in the 2 control populations, and allelic frequencies were similar to those expected in European Caucasian populations. Allelic and genotypic frequencies for these 3 SNP were found to be statistically similar in SSc patients and controls. Subphenotype analyses for subgroups having diffuse cutaneous subtype disease, specific autoantibodies, or fibrosing alveolitis did not reveal any difference between SSc patients and controls.
These results obtained through 2 large cohorts of SSc patients of European Caucasian ancestry do not support the implication of ITGAM, ITGAX, and CD58 genes in the genetic susceptibility of SSc, although they were recently identified as autoimmune disease risk genes.
PMCID: PMC3404507  PMID: 21362770
14.  Variation in the ICAM1–ICAM4–ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries 
Annals of the rheumatic diseases  2012;71(11):1809-1814.
Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin αΜ (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM.
The authors examined several markers in the ICAM1–ICAM4–ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case–control study of 17 481 unrelated participants from four ancestry populations. The single marker association and gene–gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed.
The A-allele of ICAM1–ICAM4–ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (ORmeta=1.16, 95% CI 1.11 to 1.22; p=4.88×10−10 and ORmeta=1.67, 95% CI 1.55 to 1.79; p=3.32×10−46, respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91×10−5).
These findings are the first to suggest that an ICAM–integrin-mediated pathway contributes to susceptibility to SLE.
PMCID: PMC3466387  PMID: 22523428
15.  Evaluation of genetic association between an ITGAM non-synonymous SNP (rs1143679) and multiple autoimmune diseases 
Autoimmunity Reviews  2011;11(4):276-280.
Many autoimmune diseases (ADs) share similar underlying pathology and have a tendency to cluster within families, supporting the involvement of shared susceptibility genes. To date, most of the genetic variants associated with systemic lupus erythematosus (SLE) susceptibility also show association with others ADs. ITGAM and its associated ‘predisposing’ variant (rs1143679, Arg77His), predicted to alter the tertiary structures of the ligand-binding domain of ITGAM, may play a key role for SLE pathogenesis. The aim of this study is to examine whether the ITGAM variant is also associated with other ADs. We evaluated case-control association between rs1143679 and ADs (N=18,457) including primary Sjögren’s syndrome, systemic sclerosis, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, celiac disease, and type-1 diabetes. We also performed meta-analyses using our data in addition to available published data. Although the risk allele ‘A’ is relatively more frequent among cases for each disease, it was not significantly associated with any other ADs tested in this study. However, the meta-analysis for systemic sclerosis was associated with rs1143679 (pmeta=0.008). In summary, this study explored the role of ITGAM in general autoimmunity in seven non-lupus ADs, and only found association for systemic sclerosis when our results were combined with published results. Thus ITGAM may not be a general autoimmunity gene but this variant may be specifically associated with SLE and systemic sclerosis.
PMCID: PMC3224188  PMID: 21840425
ITGAM; autoimmune diseases; genetic susceptibility
Indian Journal of Dermatology  2009;54(2):132-136.
Systemic lupus erythematosus (SLE) is an autoimmune disease with multiorgan involvement. The skin is the second most commonly affected organ. SLE with skin lesions can produce considerable morbidity resulting from painful skin lesions, alopecia, disfigurement, etc. Skin lesions in patients with lupus may be specific (LE specific) or may be non specific (LE non specific). Acute cutaneous LE (Lupus specific) has a strong association with systemic disease and non-specific skin lesions always indicate disease activity for which patients present to rheumatologists and internists. Therefore, a thorough understanding of the cutaneous manifestations of SLE is essential for most efficient management.
The aims of this study were to evaluate the patterns and prevalence of skin lesions in patients with SLE and to assess the relationship between skin lesions and other systemic involvement.
Materials and Methods:
At the Department of Rheumatology and Clinical Immunology, IPGME&R in Kolkata, 150 patients with SLE fulfilling the clinical and laboratory criteria of the American Rheumatology Association (updated 1982) were examined and followed-up for cutaneous manifestations between January 2002 and January 2007.
Skin lesions were important clinical features. About 45 patients (30%) presented with skin lesions although all patients had skin lesions during the follow-up period. Skin changes noted were as follows: Lupus specific lesions: malar rash in 120 patients (80%), photosensitive dermatitis in 75 patients (50%), generalized maculopapular rash in 40 patients (26.67%), discoid rash in 30 patients (20%), subacute cutaneous lupus erythematosus (SCLE) in 5 patients (3.34%), lupus profundus in 5 patients (3.34%). The lupus non-specific lesions were non-scarring alopecia in 130 patients (86.67%), oral ulcers in 85 patients (56.67%), vasculitic lesions in 50 patients (33.34%), bullous lesions in 15 patients (10%), Raynaud's phenomenon in 10 patients (6.67%), pyoderma gangrenosum in 2 patients (1.34%), erythema multiforme in 10 patients (6.67%), and nail fold infarcts in 2 patients (1.34%); however, mucosal discoid lupus, lichenoid discoid lupus, livedo reticularis, sclerodactyly, etc. were not detected. Patients having lupus-specific skin lesions e.g., malar rash were associated with systemic involvement, whereas those having lupus non-specific skin lesions were associated with disease flare.
Skin lesions in patients with SLE are important disease manifestations and proper understanding is essential for diagnosis and efficient management.
PMCID: PMC2807152  PMID: 20101308
Cutaneous manifestations; systemic lupus erythematosus; organ involvement
17.  Association of STAT4 Polymorphism with Severe Renal Insufficiency in Lupus Nephritis 
PLoS ONE  2013;8(12):e84450.
Lupus nephritis is a cause of significant morbidity in systemic lupus erythematosus (SLE) and its genetic background has not been completely clarified. The aim of this investigation was to analyze single nucleotide polymorphisms (SNPs) for association with lupus nephritis, its severe form proliferative nephritis and renal outcome, in two Swedish cohorts. Cohort I (n = 567 SLE cases, n =  512 controls) was previously genotyped for 5676 SNPs and cohort II (n = 145 SLE cases, n = 619 controls) was genotyped for SNPs in STAT4, IRF5, TNIP1 and BLK.
Case-control and case-only association analyses for patients with lupus nephritis, proliferative nephritis and severe renal insufficiency were performed. In the case-control analysis of cohort I, four highly linked SNPs in STAT4 were associated with lupus nephritis with genome wide significance with p = 3.7×10−9, OR 2.20 for the best SNP rs11889341. Strong signals of association between IRF5 and an HLA-DR3 SNP marker were also detected in the lupus nephritis case versus healthy control analysis (p <0.0001). An additional six genes showed an association with lupus nephritis with p <0.001 (PMS2, TNIP1, CARD11, ITGAM, BLK and IRAK1). In the case-only meta-analysis of the two cohorts, the STAT4 SNP rs7582694 was associated with severe renal insufficiency with p  = 1.6×10−3 and OR 2.22. We conclude that genetic variations in STAT4 predispose to lupus nephritis and a worse outcome with severe renal insufficiency.
PMCID: PMC3873995  PMID: 24386384
18.  Association of FCGR3A and FCGR3B Copy Number Variations With Systemic Lupus Erythematosus and Rheumatoid Arthritis in Taiwanese Patients 
To determine whether copy number variations (CNVs) in FCGR3A and FCGR3B are associated with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Taiwanese individuals.
FCGR3A and FCGR3B CNV genotypes were determined in 846 patients with SLE, 948 patients with RA, and 1,420 healthy control subjects, using custom TaqMan CNV assays. The FCGR3A and FCGR3B CNV genotypes were compared between healthy control subjects and patients and among patients stratified according to clinical characteristics.
A low (<2) FCGR3A copy number was significantly associated with SLE (for <2 copies versus 2 copies, P = 5.06 × 10−4, false discovery rate–corrected P [PFDR] = 0.001, odds ratio [OR] 3.26, 95% confidence interval [95% CI] 1.68−6.35) and RA (for <2 copies versus 2 copies, P = 5.83 × 10−4, PFDR = 0.0012, OR 2.82, 95% CI 1.56−5.1). A low FCGR3B copy number was also significantly associated with SLE (for <2 copies versus 2 copies, P = 0.0032, PFDR = 0.0032, OR 1.59, 95% CI 1.17−2.18). Notably, a high (>2) FCGR3A copy number was also associated with SLE (for >2 copies versus 2 copies, P = 0.003, PFDR = 0.0061, OR 1.6, 95% CI 1.17−2.18). Additionally, the FCGR3A low copy number genotype was significantly enriched in subsets of patients with SLE (those with ulcer, arthritis, rash, discoid rash, photosensitivity, nephritis, leukopenia, thrombocytopenia, depressed complement levels, and autoantibody positivity) and patients with RA (those positive for rheumatoid factor) compared with healthy control subjects. The FCGR3B low copy number genotype was also significantly enriched in SLE patients with ulcer, rash, discoid rash, photosensitivity, ascites, nephritis, complement level depression, and anti–double-stranded DNA antibody positivity compared with control subjects. However, FCGR3B CNVs were not associated with RA susceptibility (for <2 copy numbers versus 2 copy numbers, P = 0.3584, OR 1.15, 95% CI 0.85–1.55) and clinical characteristics.
In Taiwanese individuals, a low FCGR3A copy number is a common risk factor for SLE and RA, while a low FCGR3B copy number confers a risk of SLE but not RA.
PMCID: PMC4232894  PMID: 25154742
19.  Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus 
PLoS Genetics  2011;7(10):e1002341.
Systemic lupus erythematosus (SLE) is a complex trait characterised by the production of a range of auto-antibodies and a diverse set of clinical phenotypes. Currently, ∼8% of the genetic contribution to SLE in Europeans is known, following publication of several moderate-sized genome-wide (GW) association studies, which identified loci with a strong effect (OR>1.3). In order to identify additional genes contributing to SLE susceptibility, we conducted a replication study in a UK dataset (870 cases, 5,551 controls) of 23 variants that showed moderate-risk for lupus in previous studies. Association analysis in the UK dataset and subsequent meta-analysis with the published data identified five SLE susceptibility genes reaching genome-wide levels of significance (Pcomb<5×10−8): NCF2 (Pcomb = 2.87×10−11), IKZF1 (Pcomb = 2.33×10−9), IRF8 (Pcomb = 1.24×10−8), IFIH1 (Pcomb = 1.63×10−8), and TYK2 (Pcomb = 3.88×10−8). Each of the five new loci identified here can be mapped into interferon signalling pathways, which are known to play a key role in the pathogenesis of SLE. These results increase the number of established susceptibility genes for lupus to ∼30 and validate the importance of using large datasets to confirm associations of loci which moderately increase the risk for disease.
Author Summary
Genome-wide association studies have revolutionised our ability to identify common susceptibility alleles for systemic lupus erythematosus (SLE). In complex diseases such as SLE, where many different genes make a modest contribution to disease susceptibility, it is necessary to perform large-scale association studies to combine results from several datasets, to have sufficient power to identify highly significant novel loci (P<5×10−8). Using a large SLE collection of 870 UK SLE cases and 5,551 UK unaffected individuals, we firstly replicated ten moderate-risk alleles (P<0.05) from a US–Swedish study of 3,273 SLE cases and 12,188 healthy controls. Combining our results with the US-Swedish data identified five new loci, which crossed the level for genome-wide significance: NCF2 (neutrophil cytosolic factor 2), IKZF1 (Ikaros family zinc-finger 1), IRF8 (interferon regulatory factor 8), IFIH1 (interferon-induced helicase C domain-containing protein 1), and TYK2 (tyrosine kinase 2). Each of these five genes regulates a different aspect of the immune response and contributes to the production of type-I and type-II interferons. Although further studies will be required to identify the causal alleles within these loci, the confirmation of five new susceptibility genes for lupus makes a significant step forward in our understanding of the genetic contribution to SLE.
PMCID: PMC3203198  PMID: 22046141
20.  Study of the common genetic background for rheumatoid arthritis and systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2010;70(3):463-468.
Evidence is beginning to emerge that there may be susceptibility loci for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) that are common to both diseases.
To investigate single nucleotide polymorphisms that have been reported to be associated with SLE in a UK cohort of patients with RA and controls.
3962 patients with RA and 9275 controls were included in the study. Eleven SNPs mapping to confirmed SLE loci were investigated. These mapped to the TNFSF4, BANK1, TNIP1, PTTG1, UHRF1BP1, ATG5, JAZF1, BLK, KIAA1542, ITGAM and UBE2L3 loci. Genotype frequencies were compared between patients with RA and controls using the trend test.
The SNPs mapping to the BLK and UBE2L3 loci showed significant evidence for association with RA. Two other SNPs, mapping to ATG5 and KIAA1542, showed nominal evidence for association with RA (p=0.02 and p=0.02, respectively) but these were not significant after applying a Bonferroni correction. Additionally, a significant global enrichment in carriage of SLE alleles in patients with RA compared with controls (p=9.1×10−7) was found. Meta-analysis of this and previous studies confirmed the association of the BLK and UBE2L3 gene with RA at genome-wide significance levels (p<5×10−8). Together, the authors estimate that the SLE and RA overlapping loci, excluding HLA-DRB1 alleles, identified so far explain ∼5.8% of the genetic susceptibility to RA as a whole.
The findings confirm the association of the BLK and UBE2L3 loci with RA, thus adding to the list of loci showing overlap between RA and SLE.
PMCID: PMC3033530  PMID: 21068098
21.  A Comprehensive Analysis of Shared Loci between Systemic Lupus Erythematosus (SLE) and Sixteen Autoimmune Diseases Reveals Limited Genetic Overlap 
PLoS Genetics  2011;7(12):e1002406.
In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non–Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, P = 2.02×10−06) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohn's disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non–MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases.
Author Summary
It is well known that multiple autoimmune disorders cluster in families. However, all of the genetic variants that explain this clustering have not been discovered, and the specific genetic variants shared between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) are not known. In order to better understand the genetic factors that explain this predisposition to autoimmunity, we performed a comprehensive evaluation of shared autoimmune genetic variants. First we considered results from 17 ADs and compiled a list with 446 significant genetic variants from these studies. We identified some genetic variants extensively shared between ADs, as well as the ADs that share the most variants. The genetic overlap between SLE and other ADs was modest. Next we tested how important all the 446 genetic variants were in our collection with a minimum of 1,500 SLE patients. Among the most significant variants in SLE, the majority had already been identified in previous studies, but we also discovered variants in two important immune genes. In summary, our data identified diseases with common genetic risk factors and novel SLE effects, and this supports a relatively distinct genetic susceptibility for SLE. This study helps delineate the genetic architecture of ADs.
PMCID: PMC3234215  PMID: 22174698
22.  Evaluation of imputation-based association in and around the integrin-α-M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE) 
Human Molecular Genetics  2009;18(6):1171-1180.
We recently identified a novel non-synonymous variant, rs1143679, at exon 3 of the ITGAM gene associated with systemic lupus erythematosus (SLE) susceptibility in European-Americans (EAs) and African-Americans. Using genome-wide association approach, three other studies also independently reported an association between SLE susceptibility and ITGAM or ITGAM-ITGAX region. The primary objectives of this study are to assess whether single or multiple causal variants from the same gene or any nearby gene(s) are involved in SLE susceptibility and to confirm a robust ITGAM association across nine independent data sets (n = 8211). First, we confirmed our previously reported association of rs1143679 (risk allele ‘A’) with SLE in EAs (P = 1.0 × 10−8) and Hispanic-Americans (P = 2.9 × 10−5). Secondly, using a comprehensive imputation-based association test, we found that ITGAM is one of the major non-human leukocyte antigen susceptibility genes for SLE, and the strongest association for EA is the same coding variant rs1143679 (log10Bayes factor=20, P = 6.17 × 10−24). Thirdly, we determined the robustness of rs1143679 association with SLE across three additional case–control samples, including UK (P = 6.2 × 10−8), Colombian (P = 3.6 × 10−7), Mexican (P = 0.002), as well as two independent sets of trios from UK (PTDT = 1.4 × 10−5) and Mexico (PTDT = 0.015). A meta-analysis combing all independent data sets greatly reinforces the association (Pmeta = 7.1 × 10−50, odds ratio = 1.83, 95% confidence interval = 1.69–1.98, n = 10 046). However, this ITGAM association was not observed in the Korean or Japanese samples, in which rs1143679 is monomorphic for the non-risk allele (G). Taken together along with our earlier findings, these results demonstrate that the coding variant, rs1143679, best explains the ITGAM-SLE association, especially in European- and African-derived populations, but not in Asian populations.
PMCID: PMC2649018  PMID: 19129174
23.  Association of STAT4 with Rheumatoid Arthritis in the Korean Population 
Molecular Medicine  2007;13(9-10):455-460.
A recent study in the North American White population has documented the association of a common STAT4 haplotype (tagged by rs7574865) with risk for rheumatoid arthritis (RA) and systemic lupus erythematosus. To replicate this finding in the Korean population, we performed a case-control association study. We genotyped 67 single nucleotide polymorphisms (SNPs) within the STAT1 and STAT4 regions in 1123 Korean patients with RA and 1008 ethnicity-matched controls. The most significant four risk SNPs (rs11889341, rs7574865, rs8179673, and rs10181656 located within the third intron of STAT4) among 67 SNPs are identical with those in the North American study. All four SNPs have modest risk for RA susceptibility (odds ratio 1.21–1.27). A common haplotype defined by these markers (TTCG) carries significant risk for RA in Koreans [34 percent versus 28 percent, P = 0.0027, OR (95 percent CI) = 1.33 (1.10–1.60)]. By logistic regression analysis, this haplotype is an independent risk factor in addition to the classical shared epitope alleles at the HLA-DRB1 locus. There were no significant associations with age of disease onset, radiographic progression, or serologic status using either allelic or haplotypic analysis. Unlike several other risk genes for RA such as PTPN22, PADI4, and FCRL3, a haplotype of the STAT4 gene shows consistent association with RA susceptibility across Whites and Asians, suggesting that this risk haplotype predates the divergence of the major racial groups.
PMCID: PMC2014726  PMID: 17932559
24.  Clinical and serological manifestations associated with interferon-α levels in childhood-onset systemic lupus erythematosus 
Clinics  2012;67(2):157-162.
To determine the serum levels of interferon alpha in childhood-onset systemic lupus erythematosus patients, their first-degree relatives and healthy controls and to evaluate the associations between serum interferon alpha and disease activity, laboratory findings and treatment features.
We screened consecutive childhood-onset systemic lupus erythematosus patients in a longitudinal cohort at the pediatric rheumatology unit of the State University of Campinas between 2009 and 2010. All patients demonstrated disease onset before the age of 16. Disease status was assessed according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Interferon alpha levels were measured using an enzyme-linked immunoabsorbent assay.
We included 57 childhood-onset systemic lupus erythematosus patients (mean age 17.33±4.50), 64 first-degree relatives (mean age 39.95±5.66), and 57 healthy (mean age 19.30±4.97) controls. Serum interferon alpha levels were significantly increased in childhood-onset systemic lupus erythematosus patients compared to their first-degree relatives and healthy controls. Interferon alpha levels were significantly increased in patients with positive dsDNA antibodies, patients with cutaneous vasculitis, patients with new malar rash and patients who were not receiving medication. Interferon alpha levels correlated with C3 levels and systemic lupus erythematosus Disease Activity Index scores. In addition, we observed an inverse correlation between patient age and interferon alpha levels.
Interferon alpha may play a role in the pathogenesis of childhood-onset systemic lupus erythematosus, especially in cutaneous manifestations and dsDNA antibody formation. The observation that interferon alpha levels are increased in patients who are not taking medication should be investigated in longitudinal studies to determine whether elevated interferon alpha levels may predict systemic lupus erythematosus flares.
PMCID: PMC3275113  PMID: 22358241
Interferon alpha (IFN-α); SLEDAI; Childhood-onset; Systemic lupus erythematosus
25.  Replicated associations of TNFAIP3, TNIP1 and ETS1 with systemic lupus erythematosus in a southwestern Chinese population 
Arthritis Research & Therapy  2011;13(6):R186.
Recent genome-wide and candidate gene association studies in large numbers of systemic lupus erythematosus (SLE) patients have suggested approximately 30 susceptibility genes. These genes are involved in three types of biological processes, including immune complex processing, toll-like receptor function and type I interferon production, and immune signal transduction in lymphocytes, and they may contribute to the pathogenesis of SLE. To better understand the genetic risk factors of SLE, we investigated the associations of seven SLE susceptibility genes in a Chinese population, including FCGR3A, FCGR2A, TNFAIP3, TLR9, TREX1, ETS1 and TNIP1.
A total of 20 SNPs spanning the seven SLE susceptibility genes were genotyped in a sample of 564 unrelated SLE patients and 504 unrelated healthy controls recruited from Yunnan, southwestern China. The associations of SNPs with SLE were assessed by statistical analysis.
Five SNPs in two genes (TNFAIP3 and ETS1) were significantly associated with SLE (corrected P values ranging from 0.03 to 5.5 × 10-7). Through stratified analysis, TNFAIP3 and ETS1 showed significant associations with multiple SLE subphenotypes (such as malar rash, arthritis, hematologic disorder and antinuclear antibody) while TNIP1 just showed relatively weak association with onset age. The associations of the SNPs in the other four genes were not replicated.
The replication analysis indicates that TNFAIP3, ETS1 and TNIP1 are probably common susceptibility genes for SLE in Chinese populations, and they may contribute to the pathogenesis of multiple SLE subphenotypes.
PMCID: PMC3334635  PMID: 22087647

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