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Kaufman, Kenneth M,Zhao, Jian,Kelly, Jennifer A,Hughes, Travis,Adler, Adam,Sanchez, Elena,Ojwang, Joshua O,Langefeld, Carl D,Ziegler, Julie T,Williams, Adrienne H,Comeau, Mary E,Marion, Miranda C,Glen British Medical Association 2013 Annals of the Rheumatic Diseases Vol.72 No.3
<P>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.</P>
Kim, Kwangwoo,Brown, Elizabeth E,Choi, Chan-Bum,Alarc?n-Riquelme, Marta E,Kelly, Jennifer A,Glenn, Stuart B,Ojwang, Joshua O,Adler, Adam,Lee, Hye-Soon,Boackle, Susan A,Criswell, Lindsey A,Alarc?n, Gra British Medical Association 2012 Annals of the Rheumatic Diseases Vol.71 No.11
<P>Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin α(M) (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.</P>
Han, S.,Kim-Howard, X.,Deshmukh, H.,Kamatani, Y.,Viswanathan, P.,Guthridge, J. M.,Thomas, K.,Kaufman, K. M.,Ojwang, J.,Rojas-Villarraga, A.,Baca, V.,Orozco, L.,Rhodes, B.,Choi, C.-B.,Gregersen, P. K. Oxford University Press 2009 Human Molecular Genetics Vol.18 No.6
<P>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 x 10(-8)) and Hispanic-Americans (P = 2.9 x 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 (log(10)Bayes factor=20, P = 6.17 x 10(-24)). Thirdly, we determined the robustness of rs1143679 association with SLE across three additional case-control samples, including UK (P = 6.2 x 10(-8)), Colombian (P = 3.6 x 10(-7)), Mexican (P = 0.002), as well as two independent sets of trios from UK (P(TDT) = 1.4 x 10(-5)) and Mexico (P(TDT) = 0.015). A meta-analysis combing all independent data sets greatly reinforces the association (P(meta) = 7.1 x 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.</P>
Identification of new SLE-associated genes with a two-step Bayesian study design
Armstrong, D L,Reiff, A,Myones, B L,Quismorio Jr, F P,Klein-Gitelman, M,McCurdy, D,Wagner-Weiner, L,Silverman, E,Ojwang, J O,Kaufman, K M,Kelly, J A,Merrill, J T,Harley, J B,Bae, S-C,Vyse, T J,Gilkeso Macmillan Publishers Limited 2009 GENES AND IMMUNITY Vol.10 No.5
In our earlier study, we utilized a Bayesian design to probe the association of ∼1000 genes (∼10 000 single-nucleotide polymorphisms (SNPs)) with systemic lupus erythematosus (SLE) on a moderate number of trios of parents and children with SLE. Two genes associated with SLE, with a multitest-corrected false discovery rate (FDR) of <0.05, were identified, and a number of noteworthy genes with FDR of <0.8 were also found, pointing out a future direction for the study. In this report, using a large population of controls and adult- or childhood-onset SLE cases, we have extended the earlier investigation to explore the SLE association of 10 of these noteworthy genes (109 SNPs). We have found that seven of these genes exhibit a significant (FDR<0.05) association with SLE, both confirming some genes that have earlier been found to be associated with SLE (PTPN22 and IRF5) and presenting novel findings of genes (KLRG1, interleukin-16, protein tyrosine phosphatase receptor type T, toll-like receptor (TLR)8 and CASP10), which have not been reported earlier. The results signify that the two-step candidate pathway design is an efficient way to study the genetic foundations of complex diseases. Furthermore, the novel genes identified in this study point to new directions in both the diagnosis and the eventual treatment of this debilitating disease.Genes and Immunity (2009) 10, 446–456; doi:10.1038/gene.2009.38; published online 14 May 2009
Evaluation of <i>TRAF6</i> in a large multiancestral lupus cohort
Namjou, Bahram,Choi, Chan‐,Bum,Harley, Isaac T. W.,Alarcó,n‐,Riquelme, Marta E.,Kelly, Jennifer A.,Glenn, Stuart B.,Ojwang, Joshua O.,Adler, Adam,Kim, Kwangwoo,Gallant, Caroline J.,B Wiley Subscription Services, Inc., A Wiley Company 2012 Vol.64 No.6
<P><B>Abstract</B></P><P><B>Objective</B></P><P>Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of <I>TRAF6</I> as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development.</P><P><B>Methods</B></P><P>Fifteen single‐nucleotide polymorphisms (SNPs) across <I>TRAF6</I> were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population‐based case–control association analyses and meta‐analyses were performed. <I>P</I> values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated.</P><P><B>Results</B></P><P>Evidence of associations was detected in multiple SNPs. The best overall <I>P</I> values were obtained for SNPs rs5030437 and rs4755453 (<I>P</I> = 7.85 × 10<SUP>−5</SUP> and <I>P</I> = 4.73 × 10<SUP>−5</SUP>, respectively) without significant heterogeneity among populations (<I>P</I> = 0.67 and <I>P</I> = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r<SUP>2</SUP> = 0.95) and demonstrated evidence of association with SLE in the same direction (meta‐analysis <I>P</I> = 9.15 × 10<SUP>−4</SUP>, OR 0.89 [95% CI 0.83–0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta‐analysis <I>P</I> = 1.99 × 10<SUP>−6</SUP>, OR 0.57 [95% CI 0.45–0.72], for rs5030470). Finally, evidence of family‐based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (<I>P</I> = 0.02) under a dominant model.</P><P><B>Conclusion</B></P><P>Our data indicate the presence of association of <I>TRAF6</I> with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of <I>TRAF6</I> in the pathogenesis of autoimmunity.</P>
Jacob, Chaim O,Zhu, Jiankun,Armstrong, Don L,Yan, Mei,Han, Jie,Zhou, Xin J,Thomas, James A,Reiff, Andreas,Myones, Barry L,Ojwang, Joshua O,Kaufman, Kenneth M,Klein-Gitelman, Marisa,McCurdy, Deborah,Wa National Academy of Sciences 2009 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.106 No.15
<P>A combined forward and reverse genetic approach was undertaken to test the candidacy of IRAK1 (interleukin-1 receptor associated kinase-1) as an X chromosome-encoded risk factor for systemic lupus erythematosus (SLE). In studying approximately 5,000 subjects and healthy controls, 5 SNPs spanning the IRAK1 gene showed disease association (P values reaching 10(-10), odds ratio >1.5) in both adult- and childhood-onset SLE, in 4 different ethnic groups, with a 4 SNP haplotype (GGGG) being strongly associated with the disease. The functional role of IRAK1 was next examined by using congenic mouse models bearing the disease loci: Sle1 or Sle3. IRAK1 deficiency abrogated all lupus-associated phenotypes, including IgM and IgG autoantibodies, lymphocytic activation, and renal disease in both models. In addition, the absence of IRAK1 reversed the dendritic cell 'hyperactivity' associated with Sle3. Collectively, the forward genetic studies in human SLE and the mechanistic studies in mouse models establish IRAK1 as a disease gene in lupus, capable of modulating at least 2 key checkpoints in disease development. This demonstration of an X chromosome gene as a disease susceptibility factor in human SLE raises the possibility that the gender difference in SLE may in part be attributed to sex chromosome genes.</P>