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Bahram Namjou,
Chan-Bum Choi, Isaac T W Harley,
Marta E Alarcón-Riquelme,
Jennifer A Kelly,
Stuart B Glenn,
Joshua O Ojwang,
Adam Adler,
Kwangwoo Kim,
Caroline J Gallant, [......],
Adrienne H Williams,
Mary E Comeau,
John D Reveille,
Changwon Kang,
Judith A James,
R Hal Scofield,
Carl D Langefeld,
Kenneth M Kaufman,
John B Harley,
Sang-Cheol Bae
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ABSTRACT: 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 TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development.
Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 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. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated.
Evidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 × 10(-5) and P = 4.73 × 10(-5) , respectively) without significant heterogeneity among populations (P = 0.67 and P = 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(2) = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 × 10(-4) , OR 0.89 [95% CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 × 10(-6) , 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 (P = 0.02) under a dominant model.
Our data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.
Arthritis & Rheumatism 01/2012; 64(6):1960-9. · 7.87 Impact Factor
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Eric M Schauberger,
Susan L Ewart,
Syed H Arshad,
Marianne Huebner,
Wilfried Karmaus,
John W Holloway,
Karen H Friderici,
Julie T Ziegler,
Hongmei Zhang,
Matthew J Rose-Zerilli, [......],
Pedro C Avila,
William Rodriguez-Cintrón,
Jose R Rodriguez-Santana,
Donglei Hu,
Christopher Gignoux,
Isabelle Romieu,
Stephanie J London,
Esteban G Burchard,
Carl D Langefeld,
Marsha Wills-Karp
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ABSTRACT: Asthma is a common disease of children with a complex genetic origin. Understanding the genetic basis of asthma susceptibility will allow disease prediction and risk stratification.
We sought to identify asthma susceptibility genes in children.
A nested case-control genetic association study of children of Caucasian European ancestry from a birth cohort was conducted. Single nucleotide polymorphisms (SNPs, n = 116,024) were genotyped in pools of DNA samples from cohort children with physician-diagnosed asthma (n = 112) and normal controls (n = 165). A genomic region containing the ATPAF1 gene was found to be significantly associated with asthma. Additional SNPs within this region were genotyped in individual samples from the same children and in 8 independent study populations of Caucasian, African American, Hispanic, or other ancestries. SNPs were also genotyped or imputed in 2 consortia control populations. ATPAF1 expression was measured in bronchial biopsies from asthmatic patients and controls.
Asthma was found to be associated with a cluster of SNPs and SNP haplotypes containing the ATPAF1 gene, with 2 SNPs achieving significance at a genome-wide level (P = 2.26 × 10(-5) to 2.2 × 10(-8)). Asthma severity was also found to be associated with SNPs and SNP haplotypes in the primary population. SNP and/or gene-level associations were confirmed in the 4 non-Hispanic populations. Haplotype associations were also confirmed in the non-Hispanic populations (P = .045-.0009). ATPAF1 total RNA expression was significantly (P < .01) higher in bronchial biopsies from asthmatic patients than from controls.
Genetic variation in the ATPAF1 gene predisposes children of different ancestries to asthma.
The Journal of allergy and clinical immunology 06/2011; 128(4):753-760.e11. · 9.17 Impact Factor
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Isaac T W Harley,
Timothy B Niewold,
Rebecca M Stormont,
Kenneth M Kaufman,
Stuart B Glenn,
Beverly S Franek,
Jennifer A Kelly,
Jeffrey R Kilpatrick,
David Hutchings,
Jasmin Divers, [......],
Chaim O Jacob,
Graciela S Alarcón,
Kathy L Moser,
Patrick M Gaffney,
Robert P Kimberly,
Sang-Cheol Bae,
Carl D Langefeld,
John B Harley,
Joel M Guthridge,
Judith A James
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ABSTRACT: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio = 1.93, P = 2.5 x 10(-4)), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.
Journal of Biomedicine and Biotechnology 01/2010; 2010. · 2.44 Impact Factor
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[show abstract]
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ABSTRACT: Genome-wide association studies and fine mapping of candidate regions have rapidly advanced our understanding of the genetic basis of systemic lupus erythematosus (SLE). More than 20 robust associations have now been identified and confirmed, providing insights at the molecular level that refine our understanding of the involvement of host immune response processes. In addition, genes with unknown roles in SLE pathophysiology have been identified. These findings may provide new routes towards improved clinical management of this complex disease.
Nature Reviews Genetics 05/2009; 10(5):285-90. · 38.08 Impact Factor
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YuanYuan Gu, Isaac T W Harley,
Lindsay B Henderson,
Bruce J Aronow,
Ilja Vietor,
Lukas A Huber,
John B Harley,
Jeffrey R Kilpatrick,
Carl D Langefeld,
Adrienne H Williams, [......],
S Hasan Arshad,
Susan L Ewart,
Chloe L Thio,
Leah M Flick,
Marie-Dominique Filippi,
H Leighton Grimes,
Mitchell L Drumm,
Garry R Cutting,
Michael R Knowles,
Christopher L Karp
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ABSTRACT: Lung disease is the major cause of morbidity and mortality in cystic fibrosis, an autosomal recessive disease caused by mutations in CFTR. In cystic fibrosis, chronic infection and dysregulated neutrophilic inflammation lead to progressive airway destruction. The severity of cystic fibrosis lung disease has considerable heritability, independent of CFTR genotype. To identify genetic modifiers, here we performed a genome-wide single nucleotide polymorphism scan in one cohort of cystic fibrosis patients, replicating top candidates in an independent cohort. This approach identified IFRD1 as a modifier of cystic fibrosis lung disease severity. IFRD1 is a histone-deacetylase-dependent transcriptional co-regulator expressed during terminal neutrophil differentiation. Neutrophils, but not macrophages, from Ifrd1-deficient mice showed blunted effector function, associated with decreased NF-kappaB p65 transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and disease-a phenotype primarily dependent on haematopoietic cell expression, or lack of expression, of IFRD1. In humans, IFRD1 polymorphisms were significantly associated with variation in neutrophil effector function. These data indicate that IFRD1 modulates the pathogenesis of cystic fibrosis lung disease through the regulation of neutrophil effector function.
Nature 03/2009; 458(7241):1039-42. · 36.28 Impact Factor
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Shizhong Han,
Joel M Guthridge, Isaac T W Harley,
Andrea L Sestak,
Xana Kim-Howard,
Kenneth M Kaufman,
Bahram Namjou,
Harshal Deshmukh,
Gail Bruner,
Luis R Espinoza,
Gary S Gilkeson,
John B Harley,
Judith A James,
Swapan K Nath
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ABSTRACT: Osteopontin (SPP1) is an important bone matrix mediator found to have key roles in inflammation and immunity. SPP1 genetic polymorphisms and increased osteopontin protein levels have been reported to be associated with SLE in small patient collections. The present study evaluates association between SPP1 polymorphisms and SLE in a large cohort of 1141 unrelated SLE patients [707 European-American (EA) and 434 African-American (AA)], and 2009 unrelated controls (1309 EA and 700 AA). Population-based case-control association analyses were performed. To control for potential population stratification, admixture adjusted logistic regression, genomic control (GC), structured association (STRAT), and principal components analysis (PCA) were applied. Combined analysis of 2 ethnic groups, showed the minor allele of 2 SNPs (rs1126616T and rs9138C) significantly associated with higher risk of SLE in males (P = 0.0005, OR = 1.73, 95% CI = 1.28-2.33), but not in females. Indeed, significant gene-gender interactions in the 2 SNPs, rs1126772 and rs9138, were detected (P = 0.001 and P = 0.0006, respectively). Further, haplotype analysis identified rs1126616T-rs1126772A-rs9138C which demonstrated significant association with SLE in general (P = 0.02, OR = 1.30, 95%CI 1.08-1.57), especially in males (P = 0.0003, OR = 2.42, 95%CI 1.51-3.89). Subgroup analysis with single SNPs and haplotypes also identified a similar pattern of gender-specific association in AA and EA. GC, STRAT, and PCA results within each group showed consistent associations. Our data suggest SPP1 is associated with SLE, and this association is especially stronger in males. To our knowledge, this report serves as the first association of a specific autosomal gene with human male lupus.
PLoS ONE 02/2008; 3(3):e0001757. · 4.09 Impact Factor
