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2.  Fine Mapping of Xq28: Both MECP2 and IRAK1 Contribute to Risk for Systemic Lupus Erythematosus in Multiple Ancestral Groups 
Annals of the rheumatic diseases  2012;72(3):437-444.
Objectives
The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE.
Methods
We fine-mapped ≥136 SNPs in a ~227kb region on Xq28, containing IRAK1, MECP2 and 7 adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15,783 case-control subjects derived from 4 different ancestral groups.
Results
Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at P<5×10−8 with consistent association in subjects with African ancestry. Of these, 6 SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all 4 ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest P value in trans-ancestral meta-analysis (Pmeta=1.3×10−27, OR=1.43), and thus was considered to be the most-likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (P=0.0012) and healthy controls (P=0.0064).
Conclusion
These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.
doi:10.1136/annrheumdis-2012-201851
PMCID: PMC3567234  PMID: 22904263
Systemic Lupus Erythematosus; Gene Polymorphism; Xq28; IRAK1; MECP2
3.  Identification and Characterization of a Peptide Mimetic That May Detect a Species of Disease-Associated Anticardiolipin Antibodies in Patients With the Antiphospholipid Syndrome 
Arthritis and rheumatism  2003;48(3):737-745.
Objective
To test the feasibility of applying a mimetic (specific for a patient-derived prothrombotic anticardiolipin antibody [aCL]) to study the homologous, disease-associated aCL in patients with antiphospholipid syndrome (APS).
Methods
We used the CL15 monoclonal aCL to screen 17 phage-display peptide libraries. Peptides (corresponding to recurrent peptide sequences) and their derivatives were synthesized and analyzed for binding to CL15 and for their abilities to inhibit CL15 from binding to cardiolipin. A peptide was chosen and used to study CL15-like IgG aCL in plasma samples from patients with APS, patients with systemic lupus erythematosus (SLE) but without APS, and normal healthy donors.
Results
Library screening with CL15 yielded 4 recurrent peptide sequences. Analyses of peptides showed that peptide CL154C reacted with antibody CL15 and inhibited binding of CL15 to cardiolipin, indicating that peptide CL154C may be a peptide mimetic for the CL15 aCL. Initial studies with plasma samples revealed that CL154C-reactive IgG was present (positivity defined as the mean + 3 SD optical density of the 25 normal controls) in 15 of 21 APS patients and 1 of 12 SLE patients.
Conclusion
These findings suggest that it is feasible to develop a specific enzyme-linked immunosorbent assay for each immunologically and functionally distinct disease-associated aCL. Additional testing of CL154C with a larger number of APS patients and SLE patients, as well as identification of peptide mimetics for each distinct aCL, will reveal the diagnostic potential of CL154C and other mimetics in identifying patients with aCL who are at risk of developing life-threatening thrombosis.
doi:10.1002/art.10836
PMCID: PMC2206208  PMID: 12632428
4.  Low Physical Activity is Associated with Proinflammatory High Density Lipoprotein and Increased Subclinical Atherosclerosis in Women with Systemic Lupus Erythematosus 
Arthritis care & research  2010;62(2):258-265.
Objective
To investigate the association between physical activity, functional activity of HDL, and subclinical cardiovascular disease in patients with Systemic Lupus Erythematosus (SLE).
Methods
242 SLE patients (all women) participated in this cross-sectional study from February 2004 to February 2008. Carotid plaque and intima-media thickness (IMT), antioxidant function of HDL, and traditional cardiac risk factors were measured. Physical activity was assessed from self-reports by calculating the metabolic equivalent-minutes (METs) per week and by the physical function domain of the Medical Outcomes Study Short Form-36 (SF-36). Data were analyzed using bivariate and multivariate regression analyses.
Results
Number of METs per week spent performing strenuous exercise was negatively correlated with IMT (r = −.30, P = 0.002) and number of plaques (r = −.30, P = 0.0001). Physical function as assessed by the SF-36 was also negatively correlated with IMT (r = .14, P = 0.03) and number of plaques (r = −.14, P = 0.04). In multivariate analyses, number of strenuous exercise METs was significantly associated with IMT (t = −2.2, P = 0.028) and number of plaques (t = −2.5, P = 0.014) when controlling for markers of SLE disease activity and damage, but not after controlling for traditional cardiac risk factors. Low physical activity, defined as < 225 total METs per week, was associated with presence of piHDL (P = 0.03).
Conclusion
Low physical activity is associated with increased subclinical atherosclerosis and with piHDL in patients with SLE. Increased strenuous exercise may reduce the risk of atherosclerosis in SLE.
doi:10.1002/acr.20076
PMCID: PMC2853476  PMID: 20191526
5.  Measurement Uncertainty in Racial and Ethnic Identification Among Adolescents of Mixed Ancestry: A Latent Variable Approach 
In this article, we operationalize identification of mixed racial and ethnic ancestry among adolescents as a latent variable to (a) account for measurement uncertainty, and (b) compare alternative wording formats for racial and ethnic self-categorization in surveys. Two latent variable models were fit to multiple mixed-ancestry indicator data from 1,738 adolescents in New England. The first, a mixture factor model, accounts for the zero-inflated mixture distribution underlying mixed-ancestry identification. Alternatively, a latent class model allows classification distinction between relatively ambiguous versus unambiguous mixed-ancestry responses. Comparison of individual indicators reveals that the Census 2000 survey version estimates higher prevalence of mixed ancestry but is less sensitive to relative certainty of identification than are alternate survey versions (i.e., offering a “mixed” check box option, allowing a written response). Ease of coding and missing data are also considered in discussing the relative merit of individual mixed-ancestry indicators among adolescents.
doi:10.1080/10705510903439094
PMCID: PMC3050510  PMID: 21394232
6.  Importance of race-ethnicity: An exploration of Asian, Black, Latino, and Multiracial adolescent identity 
This mixed-method study used a grounded theory approach to explore the meanings underlying the importance adolescents attach to their racial-ethnic identities. The sample consisted of 923 9th–12th grade students from Black, Latino, Asian, and Multiracial backgrounds. Thematic findings identified a broad range of explanations for adolescents’ racial-ethnic centrality, ranging from pride and cultural connection to ambivalence and colorblind attitudes. While racial-ethnic groups differed in reported levels of racial-ethnic centrality, few group differences were identified in participants’ thematic explanations, with the exception of racial-ethnic and gender differences for Positive Regard and Disengagement. These findings highlight the diversity of meanings adolescents attribute to their racial-ethnic centrality as well as the many commonalities among adolescents across gender and racial-ethnic groups.
doi:10.1037/a0018668
PMCID: PMC2868515  PMID: 20438152
racial identity; ethnic identity; gender and race; grounded theory
7.  Race, Context, and Privilege: White Adolescents' Explanations of Racial-ethnic Centrality 
Journal of youth and adolescence  2008;38(2):139-152.
This mixed-methods exploratory study examined the diverse content and situated context of White adolescents' racial-ethnic identities. The sample consisted of 781 9th–12th grade White adolescents from three New England schools, which varied in racial and economic make-up. Open-ended responses provided a range of thematic categories regarding the importance of race-ethnicity to the adolescents' identities, representing the diverse ideologies of White adolescents' explanations, ranging from colorblind claims to ethnic pride. This study also found significant relationships between racial-ethnic identity importance (centrality) and parents' education for White adolescents. These findings highlight the diversity of White adolescents' understanding of their racial-ethnic identities and the importance of context in shaping racial-ethnic centrality.
doi:10.1007/s10964-008-9330-7
PMCID: PMC2864535  PMID: 19636713
White racial identity; White privilege; Social class; School
8.  Antibodies Against the Activated Coagulation Factor X (FXa) in the Antiphospholipid Syndrome that Interfere With the FXa Inactivation by Antithrombin 
Antiphospholipid Ab (aPL) have been shown to promote thrombosis and fetal loss in the antiphospholipid syndrome (APS). Previously, we found IgG anti-thrombin Ab in some APS patients that could interfere with inactivation of thrombin by antithrombin (AT). Considering that activated coagulation factor X (FXa) is homologous to thrombin in the catalytic domains and is also regulated primarily by AT, we hypothesized that some thrombin-reactive Ab may bind to FXa and interfere with AT inactivation of FXa. To test these hypotheses, we studied reactivity of 8 patient-derived monoclonal IgG aPL with FXa and the presence of IgG anti-FXa Ab in APS patients, and investigated the effects of FXa-reactive mAb on AT inactivation of FXa. The results revealed that 6/6 thrombin-reactive IgG mAb bound to FXa, and that the levels of plasma IgG anti-FXa Ab in 38 APS patients were significantly higher than those in 30 normal controls (p < 0.001). When the mean plus 3 standard deviations of the 30 normal controls was used as the cutoff, 5/38 APS patients (13.2%) had IgG anti-FXa Ab. Importantly, 3/6 FXa-reactive mAb significantly inhibited AT inactivation of FXa. Combined, these results indicate that anti-FXa Ab may contribute to thrombosis by interfering with the anticoagulant function of AT on FXa in some APS patients.
PMCID: PMC1950736  PMID: 17114499
human; autoimmunity; antibodies
9.  A thrombin-crossreactive anti-cardiolipin antibody binds to activated protein C and inhibits the anticoagulant function of activated protein C 
Arthritis and rheumatism  2003;48(6):1622-1630.
Objective
To test the hypotheses that some thrombin-reactive anti-cardiolipin antibodies (aCL) may bind to protein C (PC) and/or activated PC (APC), and that some of the PC- and APC-reactive aCL may inhibit PC activation and/or the function of APC.
Methods
We studied the reactivity of patient-derived monoclonal aCL with PC and APC. Of the reactive antibodies, we examined their effects on PC activation and the activity of APC in plasma coagulation.
Results
Five of five patient-derived thrombin-reactive monoclonal aCL bind to PC and APC. In addition, one patient-derived monoclonal anti-prothrombin antibody (aPT) that displays aCL activity and reacts with thrombin also binds to PC and APC. Of these 6 PC- and APC-reactive aCL/aPT, all failed to inhibit PC activation, but one (CL15) shortened the plasma coagulation time in the presence of exogenous APC and thus inhibited the anticoagulant function of APC.
Conclusion
Most of the thrombin-reactive aCL in APS patients may bind to PC and APC. Of the APC-reactive aCL, some (like CL15) may inhibit the anticoagulant function of APC and thus are likely to be prothrombotic in the host.
doi:10.1002/art.10983
PMCID: PMC1978198  PMID: 12794830
10.  PARP alleles within the linked chromosomal region are associated with systemic lupus erythematosus 
Journal of Clinical Investigation  1999;103(8):1135-1140.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by various autoantibodies that recognize autoantigens displayed on the surface of cells undergoing apoptosis. The genetic contribution to SLE susceptibility has been widely recognized. We previously reported evidence for linkage to SLE of the human chromosome 1q41–q42 region and have now narrowed it from 15 to 5 cM in an extended sample using multipoint linkage analysis. Candidate genes within this region include (a) PARP, poly(ADP-ribose) polymerase, encoding a zinc-finger DNA-binding protein that is involved in DNA repair and apoptosis; (b) TGFB2, encoding a transforming growth factor that regulates cellular interactions and responses; and (c) HLX1, encoding a homeobox protein that may regulate T-cell development. Using a multiallelic, transmission-disequilibrium test (TDT), we found overall skewing of transmission of PARP alleles to affected offspring in 124 families (P = 0.00008), preferential transmission of a PARP allele to affected offspring (P = 0.0003), and lack of transmission to unaffected offspring (P = 0.004). Similar TDT analyses of TGFB2 and HLX1 polymorphisms yielded no evidence for association with SLE. These results suggest that PARP may be (or is close to) the susceptibility gene within the chromosome 1q41–q42 region linked to SLE.
PMCID: PMC408279  PMID: 10207165
11.  Plasma levels of osteopontin identify patients at risk for organ damage in systemic lupus erythematosus 
Introduction
Osteopontin (OPN) has been implicated as a mediator of Th17 regulation via type I interferon (IFN) receptor signaling and in macrophage activity at sites of tissue repair. This study assessed whether increased circulating plasma OPN (cOPN) precedes development of organ damage in pediatric systemic lupus erythematosus (pSLE) and compared it to circulating plasma neutrophil gelatinase-associated lipocalin (cNGAL), a predictor of increased SLE disease activity.
Methods
cOPN and cNGAL were measured in prospectively followed pSLE (n = 42) and adult SLE (aSLE; n = 23) patients and age-matched controls. Time-adjusted cumulative disease activity and disease damage were respectively assessed using adjusted-mean SLE disease activity index (SLEDAI) (AMS) and SLICC/ACR damage index (SDI).
Results
Compared to controls, elevated cOPN and cNGAL were observed in pSLE and aSLE. cNGAL preceded worsening SLEDAI by 3-6 months (P = 0.04), but was not associated with increased 6-month AMS. High baseline cOPN, which was associated with high IFNalpha activity and expression of autoantibodies to nucleic acids, positively correlated with 6-month AMS (r = 0.51 and 0.52, P = 0.001 and 0.01 in pSLE and aSLE, respectively) and was associated with SDI increase at 12 months in pSLE (P = 0.001). Risk factors for change in SDI in pSLE were cOPN (OR 7.5, 95% CI [2.9-20], P = 0.03), but not cNGAL, cumulative prednisone, disease duration, immunosuppression use, gender or ancestry using univariate and multivariate logistic regression. The area under the curve (AUC) when generating the receiver-operating characteristic (ROC) of baseline cOPN sensitivity and specificity for the indication of SLE patients with an increase of SDI over a 12 month period is 0.543 (95% CI 0.347-0.738; positive predictive value 95% and negative predictive value 38%).
Conclusion
High circulating OPN levels preceded increased cumulative disease activity and organ damage in SLE patients, especially in pSLE, and its value as a predictor of poor outcome should be further validated in large longitudinal cohorts.
doi:10.1186/ar4150
PMCID: PMC3672798  PMID: 23343383
12.  Association of a functional IRF7 variant with systemic lupus erythematosus 
Arthritis and Rheumatism  2011;63(3):749-754.
Objective
Previous genome wide association study conducted in a population of European ancestry identified rs4963128, a KIAA1542 SNP 23kb telomeric to IRF7, in strong association with SLE. This study was undertaken to investigate whether genetic polymorphism within IRF7 is a risk factor for the development of SLE.
Methods
We genotyped one KIAA1542 SNP rs4963128 and one IRF7 SNP rs1131665 (Q412R) in an Asian population (cases vs. controls: 1302 vs.1479) to assess their association with SLE using custom-designed Beadstation Infinium II platform (Illumina). Subsequently, rs1131665 was further genotyped in independent panels of Chinese (528 vs.527), European American (EA) (446 vs.461) and African American (AA) (159 vs.115) by Taqman genotyping assay to seek confirmation of association in various ethnic groups. Luciferase reporter assay was used to assess the effect of Q412R polymorphism on the activation of IRF7.
Results
Consistent association of rs1131665 (Q412R) with SLE was identified in Asian, EA and AA populations (case vs. control: 2435 vs. 2582; Pmeta = 6.18×10−6, OR = 1.42[1.22–1.65]). Expression of IRF7 412Q risk allele resulted in a 2-fold increase in ISRE transcriptional activity compared with expression of IRF7 412R (P = 0.0003), suggesting IRF7 412Q confers elevated IRF7 activity and may therefore affect downstream IFN pathway.
Conclusion
We showed that the major allele of a nonsynonymous SNP rs1131665 (412Q) in IRF7 confers elevated IRF7 activation and predisposes to the development of SLE in multiple ethnic groups. This result provides direct genetic evidence supporting IRF7 may be a risk gene for human SLE.
doi:10.1002/art.30193
PMCID: PMC3063317  PMID: 21360504

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