20 results on '"Alarcón Riquelme, Marta E."'
Search Results
2. A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus
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Márquez, Ana, Vidal-Bralo, Laura, Rodríguez-Rodríguez, Luis, González-Gay, Miguel A, Balsa, Alejandro, González-Álvaro, Isidoro, Carreira, Patricia, Ortego-Centeno, Norberto, Ayala-Gutiérrez, María M, García-Hernández, Francisco José, González-Escribano, M Francisca, Sabio, José Mario, Tolosa, Carles, Suárez, Ana, González, Antonio, Padyukov, Leonid, Worthington, Jane, Vyse, Timothy, Alarcón-Riquelme, Marta E, and Martín, Javier
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- 2017
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3. Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA
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Zhao, Jian, Giles, Brendan M, Taylor, Rhonda L, Yette, Gabriel A, Lough, Kara M, Ng, Han Leng, Abraham, Lawrence J, Wu, Hui, Kelly, Jennifer A, Glenn, Stuart B, Adler, Adam J, Williams, Adrienne H, Comeau, Mary E, Ziegler, Julie T, Marion, Miranda, Alarcón-Riquelme, Marta E, Alarcón, Graciela S, Anaya, Juan-Manuel, Bae, Sang-Cheol, Kim, Dam, Lee, Hye-Soon, Criswell, Lindsey A, Freedman, Barry I, Gilkeson, Gary S, Guthridge, Joel M, Jacob, Chaim O, James, Judith A, Kamen, Diane L, Merrill, Joan T, Sivils, Kathy Moser, Niewold, Timothy B, Petri, Michelle A, Ramsey-Goldman, Rosalind, Reveille, John D, Scofield, R Hal, Stevens, Anne M, Vilá, Luis M, Vyse, Timothy J, Kaufman, Kenneth M, Harley, John B, Langefeld, Carl D, Gaffney, Patrick M, Brown, Elizabeth E, Edberg, Jeffrey C, Kimberly, Robert P, Ulgiati, Daniela, Tsao, Betty P, and Boackle, Susan A
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- 2016
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4. A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus
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Márquez, Ana, primary, Vidal-Bralo, Laura, additional, Rodríguez-Rodríguez, Luis, additional, González-Gay, Miguel A, additional, Balsa, Alejandro, additional, González-Álvaro, Isidoro, additional, Carreira, Patricia, additional, Ortego-Centeno, Norberto, additional, Ayala-Gutiérrez, María M, additional, García-Hernández, Francisco José, additional, González-Escribano, M Francisca, additional, Sabio, José Mario, additional, Tolosa, Carles, additional, Suárez, Ana, additional, González, Antonio, additional, Padyukov, Leonid, additional, Worthington, Jane, additional, Vyse, Timothy, additional, Alarcón-Riquelme, Marta E, additional, and Martín, Javier, additional
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- 2016
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5. IFI44L promoter methylation as a blood biomarker for systemic lupus erythematosus
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Zhao, Ming, primary, Zhou, Yin, additional, Zhu, Bochen, additional, Wan, Mengjie, additional, Jiang, Tingting, additional, Tan, Qiqun, additional, Liu, Yan, additional, Jiang, Juqing, additional, Luo, Shuaihantian, additional, Tan, Yixin, additional, Wu, Haijing, additional, Renauer, Paul, additional, del Mar Ayala Gutiérrez, Maria, additional, Castillo Palma, Maria Jesús, additional, Ortega Castro, Rafaela, additional, Fernández-Roldán, Concepción, additional, Raya, Enrique, additional, Faria, Raquel, additional, Carvalho, Claudia, additional, Alarcón-Riquelme, Marta E, additional, Xiang, Zhongyuan, additional, Chen, Jinwei, additional, Li, Fen, additional, Ling, Guanghui, additional, Zhao, Hongjun, additional, Liao, Xiangping, additional, Lin, Youkun, additional, Sawalha, Amr H, additional, and Lu, Qianjin, additional
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- 2016
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6. Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production
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Deng, Yun, primary, Zhao, Jian, additional, Sakurai, Daisuke, additional, Sestak, Andrea L, additional, Osadchiy, Vadim, additional, Langefeld, Carl D, additional, Kaufman, Kenneth M, additional, Kelly, Jennifer A, additional, James, Judith A, additional, Petri, Michelle A, additional, Bae, Sang-Cheol, additional, Alarcón-Riquelme, Marta E, additional, Alarcón, Graciela S, additional, Anaya, Juan-Manuel, additional, Criswell, Lindsey A, additional, Freedman, Barry I, additional, Kamen, Diane L, additional, Gilkeson, Gary S, additional, Jacob, Chaim O, additional, Merrill, Joan T, additional, Gaffney, Patrick M, additional, Sivils, Kathy Moser, additional, Niewold, Timothy B, additional, Ramsey-Goldman, Rosalind, additional, Reveille, John D, additional, Scofield, R Hal, additional, Stevens, Anne M, additional, Boackle, Susan A, additional, Vilá, Luis M, additional, Sohn, I I Woong, additional, Lee, Seung, additional, Chang, Deh-Ming, additional, Song, Yeong Wook, additional, Vyse, Timothy J, additional, Harley, John B, additional, Brown, Elizabeth E, additional, Edberg, Jeffrey C, additional, Kimberly, Robert P, additional, Cantor, Rita M, additional, Hahn, Bevra H, additional, Grossman, Jennifer M, additional, and Tsao, Betty P, additional
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- 2016
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7. IFI44L promoter methylation as a blood biomarker for systemic lupus erythematosus.
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Ming Zhao, Yin Zhou, Bochen Zhu, Mengjie Wan, Tingting Jiang, Qiqun Tan, Yan Liu, Juqing Jiang, Shuaihantian Luo, Yixin Tan, Haijing Wu, Renauer, Paul, del Mar Ayala Gutiérrez, Maria, Palma, Maria Jesús Castillo, Castro, Rafaela Ortega, Fernández-Roldán, Concepción, Raya, Enrique, Faria, Raquel, Carvalho, Claudia, and Alarcón-Riquelme, Marta E.
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RHEUMATOID arthritis diagnosis ,SYSTEMIC lupus erythematosus diagnosis ,SJOGREN'S syndrome diagnosis ,ANTIGENS ,COMPARATIVE studies ,CYTOSKELETAL proteins ,GENES ,RESEARCH methodology ,MEDICAL cooperation ,RESEARCH ,RESEARCH funding ,RHEUMATOID arthritis ,SJOGREN'S syndrome ,SYSTEMIC lupus erythematosus ,GENETIC markers ,EVALUATION research ,CASE-control method ,DNA methylation - Abstract
Objective: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease with limited reliable diagnostic biomarkers. We investigated whether gene methylation could meet sensitivity and specificity criteria for a robust biomarker.Methods: IFI44L promoter methylation was examined using DNA samples from a discovery set including 377 patients with SLE, 358 healthy controls (HCs) and 353 patients with rheumatoid arthritis (RA). Two independent sets including 1144 patients with SLE, 1350 HCs, 429 patients with RA and 199 patients with primary Sjögren's syndrome (pSS) were used for validation.Results: Significant hypomethylation of two CpG sites within IFI44L promoter, Site1 (Chr1: 79 085 222) and Site2 (Chr1: 79 085 250; cg06872964), was identified in patients with SLE compared with HCs, patients with RA and patients with pSS. In a comparison between patients with SLE and HCs included in the first validation cohort, Site1 methylation had a sensitivity of 93.6% and a specificity of 96.8% at a cut-off methylation level of 75.5% and Site2 methylation had a sensitivity of 94.1% and a specificity of 98.2% at a cut-off methylation level of 25.5%. The IFI44L promoter methylation marker was also validated in an European-derived cohort. In addition, the methylation levels of Site1 and Site2 within IFI44L promoter were significantly lower in patients with SLE with renal damage than those without renal damage. Patients with SLE showed significantly increased methylation levels of Site1 and Site2 during remission compared with active stage.Conclusions: The methylation level of IFI44L promoter can distinguish patients with SLE from healthy persons and other autoimmune diseases, and is a highly sensitive and specific diagnostic marker for SLE. [ABSTRACT FROM AUTHOR]- Published
- 2016
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8. Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA.
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Jian Zhao, Giles, Brendan M., Taylor, Rhonda L., Yette, Gabriel A., Lough, Kara M., Han Leng Ng, Abraham, Lawrence J., Hui Wu, Kelly, Jennifer A., Glenn, Stuart B., Adler, Adam J., Williams, Adrienne H., Comeau, Mary E., Ziegler, Julie T., Marion, Miranda, Alarcón-Riquelme, Marta E., Alarcón, Graciela S., Anaya, Juan-Manuel, Sang-Cheol Bae, and Dam Kim
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AUTOANTIBODIES ,B cells ,CELL receptors ,DISEASE susceptibility ,DNA ,GENETIC polymorphisms ,GENETICS ,RESEARCH funding ,RISK assessment ,SYSTEMIC lupus erythematosus ,TRANSCRIPTION factors ,PHENOTYPES ,CASE-control method ,HAPLOTYPES ,GENOTYPES - Abstract
Objectives: Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association.Methods: Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR.Results: The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10(-4), OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10(-7), OR 0.71; case-only pmeta=1.9×10(-4), OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR.Conclusions: These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications. [ABSTRACT FROM AUTHOR]- Published
- 2016
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9. Fine mapping and conditional analysis identify a new mutation in the autoimmunity susceptibility gene BLK that leads to reduced half-life of the BLK protein
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Delgado-Vega, Angélica M, primary, Dozmorov, Mikhail G, additional, Quirós, Manuel Bernal, additional, Wu, Ying-Yu, additional, Martínez-García, Belén, additional, Kozyrev, Sergey V, additional, Frostegård, Johan, additional, Truedsson, Lennart, additional, de Ramón, Enrique, additional, González-Escribano, María F, additional, Ortego-Centeno, Norberto, additional, Pons-Estel, Bernardo A, additional, D'Alfonso, Sandra, additional, Sebastiani, Gian Domenico, additional, Witte, Torsten, additional, Lauwerys, Bernard R, additional, Endreffy, Emoke, additional, Kovács, László, additional, Vasconcelos, Carlos, additional, da Silva, Berta Martins, additional, Wren, Jonathan D, additional, Martin, Javier, additional, Castillejo-López, Casimiro, additional, and Alarcón-Riquelme, Marta E, additional
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- 2012
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10. Variation in the ICAM1–ICAM4–ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries
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Kim, Kwangwoo, primary, Brown, Elizabeth E, additional, Choi, Chan-Bum, additional, Alarcón-Riquelme, Marta E, additional, Kelly, Jennifer A, additional, Glenn, Stuart B, additional, Ojwang, Joshua O, additional, Adler, Adam, additional, Lee, Hye-Soon, additional, Boackle, Susan A, additional, Criswell, Lindsey A, additional, Alarcón, Graciela S, additional, Edberg, Jeffrey C, additional, Stevens, Anne M, additional, Jacob, Chaim O, additional, Gilkeson, Gary S, additional, Kamen, Diane L, additional, Tsao, Betty P, additional, Anaya, Juan-Manuel, additional, Guthridge, Joel M, additional, Nath, Swapan K, additional, Richardson, Bruce, additional, Sawalha, Amr H, additional, Kang, Young Mo, additional, Shim, Seung Cheol, additional, Suh, Chang-Hee, additional, Lee, Soo-Kon, additional, Kim, Chang-sik, additional, Merrill, Joan T, additional, Petri, Michelle, additional, Ramsey-Goldman, Rosalind, additional, Vilá, Luis M, additional, Niewold, Timothy B, additional, Martin, Javier, additional, Pons-Estel, Bernardo A, additional, Vyse, Timothy J, additional, Freedman, Barry I, additional, Moser, Kathy L, additional, Gaffney, Patrick M, additional, Williams, Adrienne, additional, Comeau, Mary, additional, Reveille, John D, additional, James, Judith A, additional, Scofield, R Hal, additional, Langefeld, Carl D, additional, Kaufman, Kenneth M, additional, Harley, John B, additional, Kang, Changwon, additional, Kimberly, Robert P, additional, and Bae, Sang-Cheol, additional
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- 2012
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11. Analysis of autosomal genes reveals gene–sex interactions and higher total genetic risk in men with systemic lupus erythematosus
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Hughes, Travis, primary, Adler, Adam, additional, Merrill, Joan T, additional, Kelly, Jennifer A, additional, Kaufman, Kenneth M, additional, Williams, Adrienne, additional, Langefeld, Carl D, additional, Gilkeson, Gary S, additional, Sanchez, Elena, additional, Martin, Javier, additional, Boackle, Susan A, additional, Stevens, Anne M, additional, Alarcón, Graciela S, additional, Niewold, Timothy B, additional, Brown, Elizabeth E, additional, Kimberly, Robert P, additional, Edberg, Jeffrey C, additional, Ramsey-Goldman, Rosalind, additional, Petri, Michelle, additional, Reveille, John D, additional, Criswell, Lindsey A, additional, Vilá, Luis M, additional, Jacob, Chaim O, additional, Gaffney, Patrick M, additional, Moser, Kathy L, additional, Vyse, Timothy J, additional, Alarcón-Riquelme, Marta E, additional, James, Judith A, additional, Tsao, Betty P, additional, Scofield, R Hal, additional, Harley, John B, additional, Richardson, Bruce C, additional, and Sawalha, Amr H, additional
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- 2011
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12. IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus
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Niewold, Timothy B, primary, Kelly, Jennifer A, additional, Kariuki, Silvia N, additional, Franek, Beverly S, additional, Kumar, Akaash A, additional, Kaufman, Kenneth M, additional, Thomas, Kenaz, additional, Walker, Daniel, additional, Kamp, Stan, additional, Frost, Jacqueline M, additional, Wong, Andrew K, additional, Merrill, Joan T, additional, Alarcón-Riquelme, Marta E, additional, Tikly, Mohammed, additional, Ramsey-Goldman, Rosalind, additional, Reveille, John D, additional, Petri, Michelle A, additional, Edberg, Jeffrey C, additional, Kimberly, Robert P, additional, Alarcón, Graciela S, additional, Kamen, Diane L, additional, Gilkeson, Gary S, additional, Vyse, Timothy J, additional, James, Judith A, additional, Gaffney, Patrick M, additional, Moser, Kathy L, additional, Crow, Mary K, additional, and Harley, John B, additional
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- 2011
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13. Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK
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Castillejo-López, Casimiro, primary, Delgado-Vega, Angélica M, additional, Wojcik, Jerome, additional, Kozyrev, Sergey V, additional, Thavathiru, Elangovan, additional, Wu, Ying-Yu, additional, Sánchez, Elena, additional, Pöllmann, David, additional, López-Egido, Juan R, additional, Fineschi, Serena, additional, Domínguez, Nicolás, additional, Lu, Rufei, additional, James, Judith A, additional, Merrill, Joan T, additional, Kelly, Jennifer A, additional, Kaufman, Kenneth M, additional, Moser, Kathy L, additional, Gilkeson, Gary, additional, Frostegård, Johan, additional, Pons-Estel, Bernardo A, additional, D'Alfonso, Sandra, additional, Witte, Torsten, additional, Callejas, José Luis, additional, Harley, John B, additional, Gaffney, Patrick M, additional, Martin, Javier, additional, Guthridge, Joel M, additional, and Alarcón-Riquelme, Marta E, additional
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- 2011
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14. Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus
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Sanchez, Elena, primary, Nadig, Ajay, additional, Richardson, Bruce C, additional, Freedman, Barry I, additional, Kaufman, Kenneth M, additional, Kelly, Jennifer A, additional, Niewold, Timothy B, additional, Kamen, Diane L, additional, Gilkeson, Gary S, additional, Ziegler, Julie T, additional, Langefeld, Carl D, additional, Alarcón, Graciela S, additional, Edberg, Jeffrey C, additional, Ramsey-Goldman, Rosalind, additional, Petri, Michelle, additional, Brown, Elizabeth E, additional, Kimberly, Robert P, additional, Reveille, John D, additional, Vilá, Luis M, additional, Merrill, Joan T, additional, Anaya, Juan-Manuel, additional, James, Judith A, additional, Pons-Estel, Bernardo A, additional, Martin, Javier, additional, Park, So-Yeon, additional, Bang, So-Young, additional, Bae, Sang-Cheol, additional, Moser, Kathy L, additional, Vyse, Timothy J, additional, Criswell, Lindsey A, additional, Gaffney, Patrick M, additional, Tsao, Betty P, additional, Jacob, Chaim O, additional, Harley, John B, additional, Alarcón-Riquelme, Marta E, additional, and Sawalha, Amr H, additional
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- 2011
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15. IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus.
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Niewold, Timothy B., Kelly, Jennifer A., Kariuki, Silvia N., Franek, Beverly S., Kumar, Akaash A., Kaufman, Kenneth M., Thomas, Kenaz, Walker, Daniel, Kamp, Stan, Frost, Jacqueline M., Wong, Andrew K., Merrill, Joan T., Alarcón-Riquelme, Marta E., Tikly, Mohammed, Ramsey-Goldm, Rosalind, Reveille, John D., Petri, Michelle A., Edberg, Jeffrey C., Kimberly, Robert P., and Alarcón, Graciela S.
- Published
- 2012
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16. Early disease onset is predicted by a higher genetic risk for lupus and is associated with a more severe phenotype in lupus patients.
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Webb, Ryan, Kelly, Jennifer A, Somers, Emily C, Hughes, Travis, Kaufman, Kenneth M, Sanchez, Elena, Nath, Swapan K, Bruner, Gail, Alarcón-Riquelme, Marta E, Gilkeson, Gary S, Kamen, Diane L, Richardson, Bruce C, Harley, John B, and Sawalha, Amr H
- Abstract
Background Systemic lupus erythematosus (SLE) is a chronic, multiorgan, autoimmune disease that affects people of all ages and ethnicities. Objectives 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. Methods The relationship between the age at disease onset and SLE manifestations were explored in a multi-racial 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. Results 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. Conclusions 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. [ABSTRACT FROM PUBLISHER]
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- 2011
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17. Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications.
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Ombrello MJ, Arthur VL, Remmers EF, Hinks A, Tachmazidou I, Grom AA, Foell D, Martini A, Gattorno M, Özen S, Prahalad S, Zeft AS, Bohnsack JF, Ilowite NT, Mellins ED, Russo R, Len C, Hilario MO, Oliveira S, Yeung RS, Rosenberg AM, Wedderburn LR, Anton J, Haas JP, Rosen-Wolff A, Minden K, Tenbrock K, Demirkaya E, Cobb J, Baskin E, Signa S, Shuldiner E, Duerr RH, Achkar JP, Kamboh MI, Kaufman KM, Kottyan LC, Pinto D, Scherer SW, Alarcón-Riquelme ME, Docampo E, Estivill X, Gül A, Langefeld CD, Thompson S, Zeggini E, Kastner DL, Woo P, and Thomson W
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- Arthritis, Juvenile drug therapy, Case-Control Studies, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Risk Factors, Arthritis, Juvenile genetics, Chromosomes, Human, Pair 1 genetics, Major Histocompatibility Complex genetics
- Abstract
Objectives: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA., Methods: We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes., Results: The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes., Conclusions: The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)
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- 2017
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18. Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups.
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Kaufman KM, Zhao J, Kelly JA, Hughes T, Adler A, Sanchez E, Ojwang JO, Langefeld CD, Ziegler JT, Williams AH, Comeau ME, Marion MC, Glenn SB, Cantor RM, Grossman JM, Hahn BH, Song YW, Yu CY, James JA, Guthridge JM, Brown EE, Alarcón GS, Kimberly RP, Edberg JC, Ramsey-Goldman R, Petri MA, Reveille JD, Vilá LM, Anaya JM, Boackle SA, Stevens AM, Freedman BI, Criswell LA, Pons Estel BA, Lee JH, Lee JS, Chang DM, Scofield RH, Gilkeson GS, Merrill JT, Niewold TB, Vyse TJ, Bae SC, Alarcón-Riquelme ME, Jacob CO, Moser Sivils K, Gaffney PM, Harley JB, Sawalha AH, and Tsao BP
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- Base Sequence, Chromosome Mapping, Genetic Predisposition to Disease genetics, Genotype, Haplotypes, Humans, Molecular Sequence Data, Polymorphism, Single Nucleotide, Real-Time Polymerase Chain Reaction, Risk Factors, Chromosomes, Human, X genetics, Interleukin-1 Receptor-Associated Kinases genetics, Lupus Erythematosus, Systemic genetics, Methyl-CpG-Binding Protein 2 genetics, Racial Groups genetics
- Abstract
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 ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four 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, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p(meta )= 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)., Conclusions: These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.
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- 2013
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19. Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus.
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Hughes T, Adler A, Merrill JT, Kelly JA, Kaufman KM, Williams A, Langefeld CD, Gilkeson GS, Sanchez E, Martin J, Boackle SA, Stevens AM, Alarcón GS, Niewold TB, Brown EE, Kimberly RP, Edberg JC, Ramsey-Goldman R, Petri M, Reveille JD, Criswell LA, Vilá LM, Jacob CO, Gaffney PM, Moser KL, Vyse TJ, Alarcón-Riquelme ME, James JA, Tsao BP, Scofield RH, Harley JB, Richardson BC, and Sawalha AH
- Subjects
- Case-Control Studies, Female, Genotype, Humans, Male, Quantitative Trait Loci, Risk Factors, Sex Factors, Genetic Linkage, Genetic Predisposition to Disease, Lupus Erythematosus, Systemic genetics, Polymorphism, Single Nucleotide
- Abstract
Objectives: Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci., Methods: A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex-gene interaction was further validated using parametric and non-parametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients., Results: A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10-8) A significant sex-gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men., Conclusions: The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.
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- 2012
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20. Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK.
- Author
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Castillejo-López C, Delgado-Vega AM, Wojcik J, Kozyrev SV, Thavathiru E, Wu YY, Sánchez E, Pöllmann D, López-Egido JR, Fineschi S, Domínguez N, Lu R, James JA, Merrill JT, Kelly JA, Kaufman KM, Moser KL, Gilkeson G, Frostegård J, Pons-Estel BA, D'Alfonso S, Witte T, Callejas JL, Harley JB, Gaffney PM, Martin J, Guthridge JM, and Alarcón-Riquelme ME
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Case-Control Studies, Epistasis, Genetic genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Lupus Erythematosus, Systemic immunology, Male, Membrane Proteins metabolism, Polymorphism, Single Nucleotide, Protein Binding genetics, Signal Transduction genetics, Signal Transduction immunology, Adaptor Proteins, Signal Transducing genetics, B-Lymphocytes immunology, Lupus Erythematosus, Systemic genetics, Membrane Proteins genetics, src-Family Kinases genetics
- Abstract
Objectives: Altered signalling in B cells is a predominant feature of systemic lupus erythematosus (SLE). The genes BANK1 and BLK were recently described as associated with SLE. BANK1 codes for a B-cell-specific cytoplasmic protein involved in B-cell receptor signalling and BLK codes for an Src tyrosine kinase with important roles in B-cell development. To characterise the role of BANK1 and BLK in SLE, a genetic interaction analysis was performed hypothesising that genetic interactions could reveal functional pathways relevant to disease pathogenesis., Methods: The GPAT16 method was used to analyse the gene-gene interactions of BANK1 and BLK. Confocal microscopy was used to investigate co-localisation, and immunoprecipitation was used to verify the physical interaction of BANK1 and BLK., Results: Epistatic interactions between BANK1 and BLK polymorphisms associated with SLE were observed in a discovery set of 279 patients and 515 controls from northern Europe. A meta-analysis with 4399 European individuals confirmed the genetic interactions between BANK1 and BLK. As BANK1 was identified as a binding partner of the Src tyrosine kinase LYN, the possibility that BANK1 and BLK could also show a protein-protein interaction was tested. The co-immunoprecipitation and co-localisation of BLK and BANK1 were demonstrated. In a Daudi cell line and primary naive B cells endogenous binding was enhanced upon B-cell receptor stimulation using anti-IgM antibodies., Conclusion: This study shows a genetic interaction between BANK1 and BLK, and demonstrates that these molecules interact physically. The results have important consequences for the understanding of SLE and other autoimmune diseases and identify a potential new signalling pathway.
- Published
- 2012
- Full Text
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