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2. Integrative Analysis of Glucometabolic Traits, Adipose Tissue DNA Methylation and Gene Expression Identifies Epigenetic Regulatory Mechanisms of Insulin Resistance and Obesity in African Americans

Author

Sharma, Neeraj K, Comeau, Mary E, Montoya, Dennis, Pellegrini, Matteo, Howard, Timothy D, Langefeld, Carl D, and Das, Swapan K

Subjects
Biomedical and Clinical Sciences, Obesity, Diabetes, Nutrition, Genetics, Biotechnology, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Adipose Tissue, Adult, Black or African American, Computational Biology, DNA Methylation, Epigenesis, Genetic, Female, Gene Expression Regulation, Glucose, Humans, Insulin Resistance, Male, Transcriptome, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in type 2 diabetes. We hypothesize that differential DNA methylation (DNAm) controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating AT DNAm profiles with transcript profile data measured in a cohort of 230 African Americans (AAs) from the African American Genetics of Metabolism and Expression cohort, we performed cis-expression quantitative trait methylation (cis-eQTM) analysis to identify epigenetic regulatory loci for glucometabolic trait-associated transcripts. We identified significantly associated cytosine-guanine dinucleotide regions for 82 transcripts (false discovery rate [FDR]-P < 0.05). The strongest eQTM locus was observed for the proopiomelanocortin (POMC; ρ = -0.632, P = 4.70 × 10-27) gene. Epigenome-wide association studies (EWAS) further identified 155, 46, and 168 cytosine-guanine dinucleotide regions associated (FDR-P < 0.05) with the Matsuda index, SI, and BMI, respectively. Intersection of EWAS, transcript level to trait association, and eQTM results, followed by causal inference test identified significant eQTM loci for 23 genes that were also associated with Matsuda index, SI, and/or BMI in EWAS. These associated genes include FERMT3, ITGAM, ITGAX, and POMC In summary, applying an integrative multiomics approach, our study provides evidence for DNAm-mediated regulation of gene expression at both previously identified and novel loci for many key AT transcripts influencing insulin resistance and obesity.

Published
2020

7. Transancestral mapping and genetic load in systemic lupus erythematosus.

Author

Langefeld, Carl D, Ainsworth, Hannah C, Cunninghame Graham, Deborah S, Kelly, Jennifer A, Comeau, Mary E, Marion, Miranda C, Howard, Timothy D, Ramos, Paula S, Croker, Jennifer A, Morris, David L, Sandling, Johanna K, Almlöf, Jonas Carlsson, Acevedo-Vásquez, Eduardo M, Alarcón, Graciela S, Babini, Alejandra M, Baca, Vicente, Bengtsson, Anders A, Berbotto, Guillermo A, Bijl, Marc, Brown, Elizabeth E, Brunner, Hermine I, Cardiel, Mario H, Catoggio, Luis, Cervera, Ricard, Cucho-Venegas, Jorge M, Dahlqvist, Solbritt Rantapää, D'Alfonso, Sandra, Da Silva, Berta Martins, de la Rúa Figueroa, Iñigo, Doria, Andrea, Edberg, Jeffrey C, Endreffy, Emőke, Esquivel-Valerio, Jorge A, Fortin, Paul R, Freedman, Barry I, Frostegård, Johan, García, Mercedes A, de la Torre, Ignacio García, Gilkeson, Gary S, Gladman, Dafna D, Gunnarsson, Iva, Guthridge, Joel M, Huggins, Jennifer L, James, Judith A, Kallenberg, Cees GM, Kamen, Diane L, Karp, David R, Kaufman, Kenneth M, Kottyan, Leah C, Kovács, László, Laustrup, Helle, Lauwerys, Bernard R, Li, Quan-Zhen, Maradiaga-Ceceña, Marco A, Martín, Javier, McCune, Joseph M, McWilliams, David R, Merrill, Joan T, Miranda, Pedro, Moctezuma, José F, Nath, Swapan K, Niewold, Timothy B, Orozco, Lorena, Ortego-Centeno, Norberto, Petri, Michelle, Pineau, Christian A, Pons-Estel, Bernardo A, Pope, Janet, Raj, Prithvi, Ramsey-Goldman, Rosalind, Reveille, John D, Russell, Laurie P, Sabio, José M, Aguilar-Salinas, Carlos A, Scherbarth, Hugo R, Scorza, Raffaella, Seldin, Michael F, Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D, Toloza, Sergio MA, Truedsson, Lennart, Tusié-Luna, Teresa, Vasconcelos, Carlos, Vilá, Luis M, Wallace, Daniel J, Weisman, Michael H, Wither, Joan E, Bhangale, Tushar, Oksenberg, Jorge R, Rioux, John D, Gregersen, Peter K, Syvänen, Ann-Christine, Rönnblom, Lars, Criswell, Lindsey A, Jacob, Chaim O, Sivils, Kathy L, Tsao, Betty P, Schanberg, Laura E, and Behrens, Timothy W

Subjects
Humans, Lupus Erythematosus, Systemic, HLA Antigens, Logistic Models, Case-Control Studies, Mutagenesis, Insertional, Age of Onset, Sequence Deletion, Genetic Load, Multifactorial Inheritance, Polymorphism, Single Nucleotide, African Continental Ancestry Group, American Native Continental Ancestry Group, European Continental Ancestry Group, Hispanic Americans, Lupus Erythematosus, Systemic, Mutagenesis, Insertional, Polymorphism, Single Nucleotide
Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P

Published
2017

8. Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

Author

Rusu, Victor, Hoch, Eitan, Mercader, Josep M, Tenen, Danielle E, Gymrek, Melissa, Hartigan, Christina R, DeRan, Michael, von Grotthuss, Marcin, Fontanillas, Pierre, Spooner, Alexandra, Guzman, Gaelen, Deik, Amy A, Pierce, Kerry A, Dennis, Courtney, Clish, Clary B, Carr, Steven A, Wagner, Bridget K, Schenone, Monica, Ng, Maggie CY, Chen, Brian H, Consortium, MEDIA, Shriner, Daniel, Li, Jiang, Chen, Wei-Min, Guo, Xiuqing, Liu, Jiankang, Bielinski, Suzette J, Yanek, Lisa R, Nalls, Michael A, Comeau, Mary E, Rasmussen-Torvik, Laura J, Jensen, Richard A, Evans, Daniel S, Sun, Yan V, An, Ping, Patel, Sanjay R, Lu, Yingchang, Long, Jirong, Armstrong, Loren L, Wagenknecht, Lynne, Yang, Lingyao, Snively, Beverly M, Palmer, Nicholette D, Mudgal, Poorva, Langefeld, Carl D, Keene, Keith L, Freedman, Barry I, Mychaleckyj, Josyf C, Nayak, Uma, Raffel, Leslie J, Goodarzi, Mark O, Chen, Y-D Ida, Taylor, Herman A, Correa, Adolfo, Sims, Mario, Couper, David, Pankow, James S, Boerwinkle, Eric, Adeyemo, Adebowale, Doumatey, Ayo, Chen, Guanjie, Mathias, Rasika A, Vaidya, Dhananjay, Singleton, Andrew B, Zonderman, Alan B, Igo, Robert P, Sedor, John R, Consortium, the FIND, Kabagambe, Edmond K, Siscovick, David S, McKnight, Barbara, Rice, Kenneth, Liu, Yongmei, Hsueh, Wen-Chi, Zhao, Wei, Bielak, Lawrence F, Kraja, Aldi, Province, Michael A, Bottinger, Erwin P, Gottesman, Omri, Cai, Qiuyin, Zheng, Wei, Blot, William J, Lowe, William L, Pacheco, Jennifer A, Crawford, Dana C, Consortium, the eMERGE, Consortium, the DIAGRAM, Grundberg, Elin, Consortium, the MuTHER, Rich, Stephen S, Hayes, M Geoffrey, Shu, Xiao-Ou, Loos, Ruth JF, Borecki, Ingrid B, Peyser, Patricia A, Cummings, Steven R, and Psaty, Bruce M

Subjects
Biological Sciences, Genetics, Clinical Research, Diabetes, Digestive Diseases, Liver Disease, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Basigin, Cell Membrane, Chromosomes, Human, Pair 17, Diabetes Mellitus, Type 2, Gene Knockdown Techniques, Haplotypes, Hepatocytes, Heterozygote, Histone Code, Humans, Liver, Models, Molecular, Monocarboxylic Acid Transporters, MEDIA Consortium, SIGMA T2D Consortium, MCT11, SLC16A11, disease mechanism, fatty acid metabolism, genetics, lipid metabolism, monocarboxylates, precision medicine, solute carrier, type 2 diabetes, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT.

Published
2017

9. Deep Resequencing of the 1q22 Locus in Non‐Lobar Intracerebral Hemorrhage

Author

Parodi, Livia, primary, Comeau, Mary E., additional, Georgakis, Marios K., additional, Mayerhofer, Ernst, additional, Chung, Jaeyoon, additional, Falcone, Guido J., additional, Malik, Rainer, additional, Demel, Stacie L., additional, Worrall, Bradford B., additional, Koch, Sebastian, additional, Testai, Fernando D., additional, Kittner, Steven J., additional, McCauley, Jacob L., additional, Hall, Christiana E., additional, Mayson, Douglas J., additional, Elkind, Mitchell S.V., additional, James, Michael L., additional, Woo, Daniel, additional, Rosand, Jonathan, additional, Langefeld, Carl D., additional, and Anderson, Christopher D., additional

Published
2023
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10. Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

Author

Iyengar, Sudha K, Sedor, John R, Freedman, Barry I, Kao, WH Linda, Kretzler, Matthias, Keller, Benjamin J, Abboud, Hanna E, Adler, Sharon G, Best, Lyle G, Bowden, Donald W, Burlock, Allison, Chen, Yii-Der Ida, Cole, Shelley A, Comeau, Mary E, Curtis, Jeffrey M, Divers, Jasmin, Drechsler, Christiane, Duggirala, Ravi, Elston, Robert C, Guo, Xiuqing, Huang, Huateng, Hoffmann, Michael Marcus, Howard, Barbara V, Ipp, Eli, Kimmel, Paul L, Klag, Michael J, Knowler, William C, Kohn, Orly F, Leak, Tennille S, Leehey, David J, Li, Man, Malhotra, Alka, März, Winfried, Nair, Viji, Nelson, Robert G, Nicholas, Susanne B, O'Brien, Stephen J, Pahl, Madeleine V, Parekh, Rulan S, Pezzolesi, Marcus G, Rasooly, Rebekah S, Rotimi, Charles N, Rotter, Jerome I, Schelling, Jeffrey R, Seldin, Michael F, Shah, Vallabh O, Smiles, Adam M, Smith, Michael W, Taylor, Kent D, Thameem, Farook, Thornley-Brown, Denyse P, Truitt, Barbara J, Wanner, Christoph, Weil, E Jennifer, Winkler, Cheryl A, Zager, Philip G, Igo, Robert P, Hanson, Robert L, Langefeld, Carl D, and Family Investigation of Nephropathy and Diabetes (FIND)

Subjects
Family Investigation of Nephropathy and Diabetes, Humans, Diabetic Nephropathies, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, RNA-Binding Proteins, African Americans, Indians, North American, European Continental Ancestry Group, Hispanic Americans, United States, Genome-Wide Association Study, Diabetes, Genetics, Human Genome, Clinical Research, Kidney Disease, American Indian or Alaska Native, Prevention, 2.1 Biological and endogenous factors, Metabolic and endocrine, Renal and urogenital, Developmental Biology
Abstract

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

Published
2015

11. Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression

Author

Lu, Xiaoming, Zoller, Erin E, Weirauch, Matthew T, Wu, Zhiguo, Namjou, Bahram, Williams, Adrienne H, Ziegler, Julie T, Comeau, Mary E, Marion, Miranda C, Glenn, Stuart B, Adler, Adam, Shen, Nan, Nath, Swapan K, Stevens, Anne M, Freedman, Barry I, Tsao, Betty P, Jacob, Chaim O, Kamen, Diane L, Brown, Elizabeth E, Gilkeson, Gary S, Alarcón, Graciela S, Reveille, John D, Anaya, Juan-Manuel, James, Judith A, Sivils, Kathy L, Criswell, Lindsey A, Vilá, Luis M, Alarcón-Riquelme, Marta E, Petri, Michelle, Scofield, R Hal, Kimberly, Robert P, Ramsey-Goldman, Rosalind, Bin Joo, Young, Choi, Jeongim, Bae, Sang-Cheol, Boackle, Susan A, Graham, Deborah Cunninghame, Vyse, Timothy J, Guthridge, Joel M, Gaffney, Patrick M, Langefeld, Carl D, Kelly, Jennifer A, Greis, Kenneth D, Kaufman, Kenneth M, Harley, John B, and Kottyan, Leah C

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Biotechnology, Lupus, Autoimmune Disease, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Alleles, Animals, Asian People, Bayes Theorem, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Lupus Erythematosus, Systemic, Mice, Protein Binding, Proto-Oncogene Protein c-ets-1, STAT1 Transcription Factor, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1.

Published
2015

12. Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.

Author

Ng, Maggie CY, Shriner, Daniel, Chen, Brian H, Li, Jiang, Chen, Wei-Min, Guo, Xiuqing, Liu, Jiankang, Bielinski, Suzette J, Yanek, Lisa R, Nalls, Michael A, Comeau, Mary E, Rasmussen-Torvik, Laura J, Jensen, Richard A, Evans, Daniel S, Sun, Yan V, An, Ping, Patel, Sanjay R, Lu, Yingchang, Long, Jirong, Armstrong, Loren L, Wagenknecht, Lynne, Yang, Lingyao, Snively, Beverly M, Palmer, Nicholette D, Mudgal, Poorva, Langefeld, Carl D, Keene, Keith L, Freedman, Barry I, Mychaleckyj, Josyf C, Nayak, Uma, Raffel, Leslie J, Goodarzi, Mark O, Chen, Y-D Ida, Taylor, Herman A, Correa, Adolfo, Sims, Mario, Couper, David, Pankow, James S, Boerwinkle, Eric, Adeyemo, Adebowale, Doumatey, Ayo, Chen, Guanjie, Mathias, Rasika A, Vaidya, Dhananjay, Singleton, Andrew B, Zonderman, Alan B, Igo, Robert P, Sedor, John R, FIND Consortium, Kabagambe, Edmond K, Siscovick, David S, McKnight, Barbara, Rice, Kenneth, Liu, Yongmei, Hsueh, Wen-Chi, Zhao, Wei, Bielak, Lawrence F, Kraja, Aldi, Province, Michael A, Bottinger, Erwin P, Gottesman, Omri, Cai, Qiuyin, Zheng, Wei, Blot, William J, Lowe, William L, Pacheco, Jennifer A, Crawford, Dana C, eMERGE Consortium, DIAGRAM Consortium, Grundberg, Elin, MuTHER Consortium, Rich, Stephen S, Hayes, M Geoffrey, Shu, Xiao-Ou, Loos, Ruth JF, Borecki, Ingrid B, Peyser, Patricia A, Cummings, Steven R, Psaty, Bruce M, Fornage, Myriam, Iyengar, Sudha K, Evans, Michele K, Becker, Diane M, Kao, WH Linda, Wilson, James G, Rotter, Jerome I, Sale, Michèle M, Liu, Simin, Rotimi, Charles N, Bowden, Donald W, and MEta-analysis of type 2 DIabetes in African Americans Consortium

Subjects
FIND Consortium, eMERGE Consortium, DIAGRAM Consortium, MuTHER Consortium, MEta-analysis of type 2 DIabetes in African Americans Consortium, Humans, Diabetes Mellitus, Type 2, HMGA2 Protein, HLA-B27 Antigen, Polymorphism, Single Nucleotide, African Americans, Mutant Chimeric Proteins, KCNQ1 Potassium Channel, Genome-Wide Association Study, Transcription Factor 7-Like 2 Protein, Human Genome, Diabetes, Genetics, 2.1 Biological and endogenous factors, Metabolic and endocrine, Developmental Biology
Abstract

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)

Published
2014

13. End‐Stage Renal Disease in African Americans With Lupus Nephritis Is Associated With APOL1

Author

Freedman, Barry I, Langefeld, Carl D, Andringa, Kelly K, Croker, Jennifer A, Williams, Adrienne H, Garner, Neva E, Birmingham, Daniel J, Hebert, Lee A, Hicks, Pamela J, Segal, Mark S, Edberg, Jeffrey C, Brown, Elizabeth E, Alarcón, Graciela S, Costenbader, Karen H, Comeau, Mary E, Criswell, Lindsey A, Harley, John B, James, Judith A, Kamen, Diane L, Lim, S Sam, Merrill, Joan T, Sivils, Kathy L, Niewold, Timothy B, Patel, Neha M, Petri, Michelle, Ramsey‐Goldman, Rosalind, Reveille, John D, Salmon, Jane E, Tsao, Betty P, Gibson, Keisha L, Byers, Joyce R, Vinnikova, Anna K, Lea, Janice P, Julian, Bruce A, Kimberly, Robert P, and Consortium, on behalf of the Lupus Nephritis–End‐Stage Renal Disease

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Kidney Disease, Genetic Testing, Clinical Research, Autoimmune Disease, Lupus, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Adult, Black or African American, Alleles, Apolipoprotein L1, Apolipoproteins, Disease Progression, Female, Genetic Predisposition to Disease, Genotype, Humans, Kidney Failure, Chronic, Lipoproteins, HDL, Logistic Models, Lupus Nephritis, Male, Middle Aged, Risk Factors, White People, Lupus Nephritis–End‐Stage Renal Disease Consortium, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveLupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.MethodsAPOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression.ResultsNinety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10(-9)), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10(-6)). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ∼2 years earlier among individuals with APOL1 risk genotypes (P = 0.01).ConclusionAPOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans.

Published
2014

14. Deep Resequencing of the 1q22 Locus in Non‐Lobar Intracerebral Hemorrhage.

Author

Parodi, Livia, Comeau, Mary E., Georgakis, Marios K., Mayerhofer, Ernst, Chung, Jaeyoon, Falcone, Guido J., Malik, Rainer, Demel, Stacie L., Worrall, Bradford B., Koch, Sebastian, Testai, Fernando D., Kittner, Steven J., McCauley, Jacob L., Hall, Christiana E., Mayson, Douglas J., Elkind, Mitchell S.V., James, Michael L., Woo, Daniel, Rosand, Jonathan, and Langefeld, Carl D.

Subjects
*LACUNAR stroke, *CEREBRAL small vessel diseases, *CEREBRAL hemorrhage, *BASE pairs, *GENOME-wide association studies, *LOCUS (Genetics)
Abstract

Objective: Genome‐wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases, including non‐lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study, we performed targeted high‐depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown. Methods: A total of 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44, and PMF1/PMF1‐BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non‐lobar) and 1,078 controls. Firth regression and Rare Variant Influential Filtering Tool analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi‐C, chromatin immunoprecipitation followed by sequencing, and chromatin interaction analysis with paired‐end tag databases. Multivariable Mendelian randomization assessed whether alterations in gene‐specific expression relative to regionally co‐expressed genes at 1q22 could be causally related to ICH risk. Results: Common and rare variant analyses prioritized variants in SEMA4A 5′‐UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi‐C data analysis determined that 1q22 is spatially organized in a single chromatin loop, and that the genes therein belong to the same topologically associating domain. Chromatin immunoprecipitation followed by sequencing and chromatin interaction analysis with paired‐end tag data analysis highlighted the presence of long‐range interactions between the SEMA4A‐promoter and PMF1‐enhancer regions prioritized by association testing. Multivariable Mendelian randomization analyses demonstrated that PMF1 overexpression could be causally related to non‐lobar ICH risk. Interpretation: Altered promoter–enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non‐lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and cerebral small vessel disease. ANN NEUROL 2024;95:325–337 [ABSTRACT FROM AUTHOR]

Published
2024
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16. Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups

Author

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, Glenn, Stuart B, Cantor, Rita M, Grossman, Jennifer M, Hahn, Bevra H, Song, Yeong Wook, Yu, Chack-Yung, James, Judith A, Guthridge, Joel M, Brown, Elizabeth E, Alarcón, Graciela S, Kimberly, Robert P, Edberg, Jeffrey C, Ramsey-Goldman, Rosalind, Petri, Michelle A, Reveille, John D, Vilá, Luis M, Anaya, Juan-Manuel, Boackle, Susan A, Stevens, Anne M, Freedman, Barry I, Criswell, Lindsey A, Group, Bernardo A Pons-Estel on behalf of the Argentine Collaborative, Lee, Joo-Hyun, Lee, Ji-Seon, Chang, Deh-Ming, Scofield, R Hal A, Gilkeson, Gary S, Merrill, Joan T, Niewold, Timothy B, Vyse, Timothy James, Bae, Sang-Cheol, network, Marta E Alarcón-Riquelme on behalf of the BIOLUPUS, Jacob, Chaim O, Sivils, Kathy Moser, Gaffney, Patrick M, Harley, John B, Sawalha, Amr H, and Tsao, Betty P

Subjects
Human Genome, Autoimmune Disease, Lupus, Genetics, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Base Sequence, Chromosome Mapping, Chromosomes, Human, X, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Interleukin-1 Receptor-Associated Kinases, Lupus Erythematosus, Systemic, Methyl-CpG-Binding Protein 2, Molecular Sequence Data, Polymorphism, Single Nucleotide, Racial Groups, Real-Time Polymerase Chain Reaction, Risk Factors, Argentine Collaborative Group, BIOLUPUS network, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology
Abstract

ObjectivesThe 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.MethodsWe 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.ResultsMultiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p

Published
2013

17. Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus

Author

Adrianto, Indra, Wang, Shaofeng, Wiley, Graham B, Lessard, Christopher J, Kelly, Jennifer A, Adler, Adam J, Glenn, Stuart B, Williams, Adrienne H, Ziegler, Julie T, Comeau, Mary E, Marion, Miranda C, Wakeland, Benjamin E, Liang, Chaoying, Kaufman, Kenneth M, Guthridge, Joel M, Alarcón‐Riquelme, Marta E, Networks, BIOLUPUS and GENLES, Alarcón, Graciela S, Anaya, Juan‐Manuel, Bae, Sang‐Cheol, Kim, Jae‐Hoon, Bin Joo, Young, Boackle, Susan A, Brown, Elizabeth E, Petri, Michelle A, Ramsey‐Goldman, Rosalind, Reveille, John D, Vilá, Luis M, Criswell, Lindsey A, Edberg, Jeffrey C, Freedman, Barry I, Gilkeson, Gary S, Jacob, Chaim O, James, Judith A, Kamen, Diane L, Kimberly, Robert P, Martín, Javier, Merrill, Joan T, Niewold, Timothy B, Pons‐Estel, Bernardo A, Scofield, R Hal, Stevens, Anne M, Tsao, Betty P, Vyse, Timothy J, Langefeld, Carl D, Harley, John B, Wakeland, Edward K, Moser, Kathy L, Montgomery, Courtney G, and Gaffney, Patrick M

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Human Genome, Lupus, Autoimmune Disease, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Adaptor Proteins, Signal Transducing, Black or African American, Asian, B-Lymphocytes, Cell Line, Transformed, DNA-Binding Proteins, Female, Genetic Markers, Genetic Predisposition to Disease, Haplotypes, Hispanic or Latino, Humans, Intracellular Signaling Peptides and Proteins, Lupus Erythematosus, Systemic, Male, Neoplasm Proteins, Polymorphism, Single Nucleotide, Risk Factors, United States, White People, BIOLUPUS and GENLES Networks, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway.MethodsWe analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively.ResultsWe found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression.ConclusionOur results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.

Published
2012

18. Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian–European populations

Author

Sánchez, Elena, Rasmussen, Astrid, Riba, Laura, Acevedo‐Vasquez, Eduardo, Kelly, Jennifer A, Langefeld, Carl D, Williams, Adrianne H, Ziegler, Julie T, Comeau, Mary E, Marion, Miranda C, La Torre, Ignacio García‐De, Maradiaga‐Ceceña, Marco A, Cardiel, Mario H, Esquivel‐Valerio, Jorge A, Rodriguez‐Amado, Jacqueline, Moctezuma, José Francisco, Miranda, Pedro, Perandones, Carlos E, Castel, Cecilia, Laborde, Hugo A, Alba, Paula, Musuruana, Jorge L, Goecke, I Annelise, Anaya, Juan‐Manuel, Kaufman, Kenneth M, Adler, Adam, Glenn, Stuart B, Brown, Elizabeth E, Alarcón, Graciela S, Kimberly, Robert P, Edberg, Jeffrey C, Vilá, Luis M, Criswell, Lindsey A, Gilkeson, Gary S, Niewold, Timothy B, Martín, Javier, Vyse, Timothy J, Boackle, Susan A, Ramsey‐Goldman, Rosalind, Scofield, R Hal, Petri, Michelle, Merrill, Joan T, Reveille, John D, Tsao, Betty P, Orozco, Lorena, Baca, Vicente, Moser, Kathy L, Gaffney, Patrick M, James, Judith A, Harley, John B, Tusié‐Luna, Teresa, Pons‐Estel, Bernardo A, Jacob, Chaim O, and Alarcón‐Riquelme, Marta E

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Health Sciences, Genetics, Autoimmune Disease, Clinical Research, Lupus, Kidney Disease, American Indian or Alaska Native, Inflammatory and immune system, Adolescent, Adult, Child, Female, Genetic Predisposition to Disease, Genotype, Humans, Indians, North American, Indians, South American, Lupus Erythematosus, Systemic, Lupus Nephritis, Male, Middle Aged, Morbidity, Prevalence, Risk Factors, Socioeconomic Factors, White People, Young Adult, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveAmerican Indian-Europeans, Asians, and African Americans have an excess morbidity from systemic lupus erythematosus (SLE) and a higher prevalence of lupus nephritis than do Caucasians. The aim of this study was to analyze the relationship between genetic ancestry and sociodemographic characteristics and clinical features in a large cohort of American Indian-European SLE patients.MethodsA total of 2,116 SLE patients of American Indian-European origin and 4,001 SLE patients of European descent for whom we had clinical data were included in the study. Genotyping of 253 continental ancestry-informative markers was performed on the Illumina platform. Structure and Admixture software were used to determine genetic ancestry proportions of each individual. Logistic regression was used to test the association between genetic ancestry and sociodemographic and clinical characteristics. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs).ResultsThe average American Indian genetic ancestry of 2,116 SLE patients was 40.7%. American Indian genetic ancestry conferred increased risks of renal involvement (P < 0.0001, OR 3.50 [95% CI 2.63- 4.63]) and early age at onset (P < 0.0001). American Indian ancestry protected against photosensitivity (P < 0.0001, OR 0.58 [95% CI 0.44-0.76]), oral ulcers (P < 0.0001, OR 0.55 [95% CI 0.42-0.72]), and serositis (P < 0.0001, OR 0.56 [95% CI 0.41-0.75]) after adjustment for age, sex, and age at onset. However, age and sex had stronger effects than genetic ancestry on malar rash, discoid rash, arthritis, and neurologic involvement.ConclusionIn general, American Indian genetic ancestry correlates with lower sociodemographic status and increases the risk of developing renal involvement and SLE at an earlier age.

Published
2012

19. Evaluation of TRAF6 in a large multiancestral lupus cohort

Author

Namjou, Bahram, Choi, Chan‐Bum, Harley, Isaac TW, Alarcón‐Riquelme, Marta E, Network, BIOLUPUS, Kelly, Jennifer A, Glenn, Stuart B, Ojwang, Joshua O, Adler, Adam, Kim, Kwangwoo, Gallant, Caroline J, Boackle, Susan A, Criswell, Lindsey A, Kimberly, Robert P, Brown, Elizabeth E, Edberg, Jeffrey, Alarcón, Graciela S, Stevens, Anne M, Jacob, Chaim O, Gilkeson, Gary S, Kamen, Diane L, Tsao, Betty P, Anaya, Juan‐Manuel, Kim, Eun‐Mi, Park, So‐Yeon, Sung, Yoon‐Kyoung, Guthridge, Joel M, Merrill, Joan T, Petri, Michelle, Ramsey‐Goldman, Rosalind, Vilá, Luis M, Niewold, Timothy B, Martin, Javier, Pons‐Estel, Bernardo A, Network, Genoma en Lupus, Vyse, Timothy J, Freedman, Barry I, Moser, Kathy L, Gaffney, Patrick M, Williams, Adrienne H, Comeau, Mary E, Reveille, John D, Kang, Changwon, James, Judith A, Scofield, R Hal, Langefeld, Carl D, Kaufman, Kenneth M, Harley, John B, and Bae, Sang‐Cheol

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Lupus, Clinical Research, Arthritis, Autoimmune Disease, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Alleles, Case-Control Studies, Cohort Studies, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Lupus Erythematosus, Systemic, Male, Polymorphism, Single Nucleotide, TNF Receptor-Associated Factor 6, BIOLUPUS Network, Genoma en Lupus Network, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveSystemic 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.MethodsFifteen 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.ResultsEvidence 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.ConclusionOur 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.

Published
2012

20. A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap.

Author

Ramos, Paula S, Criswell, Lindsey A, Moser, Kathy L, Comeau, Mary E, Williams, Adrienne H, Pajewski, Nicholas M, Chung, Sharon A, Graham, Robert R, Zidovetzki, Raphael, Kelly, Jennifer A, Kaufman, Kenneth M, Jacob, Chaim O, Vyse, Timothy J, Tsao, Betty P, Kimberly, Robert P, Gaffney, Patrick M, Alarcón-Riquelme, Marta E, Harley, John B, Langefeld, Carl D, and International Consortium on the Genetics of Systemic Erythematosus

Subjects
International Consortium on the Genetics of Systemic Erythematosus, Humans, Arthritis, Rheumatoid, Colitis, Ulcerative, Crohn Disease, Lupus Erythematosus, Systemic, Diabetes Mellitus, Type 1, Autoimmune Diseases, Genetic Predisposition to Disease, Receptors, Interleukin, Case-Control Studies, Cohort Studies, Polymorphism, Single Nucleotide, European Continental Ancestry Group, OX40 Ligand, Interleukin-2 Receptor alpha Subunit, Genome-Wide Association Study, Genetic Pleiotropy, V-Set Domain-Containing T-Cell Activation Inhibitor 1, Arthritis, Rheumatoid, Colitis, Ulcerative, Lupus Erythematosus, Systemic, Diabetes Mellitus, Type 1, Receptors, Interleukin, Polymorphism, Single Nucleotide, Genetics, Developmental Biology
Abstract

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.

Published
2011

23. 1401 A Genome Wide Association Scan of SLE genetic risk in a cohort of African-American persons

Author

Harley, Isaac TW, primary, Sun, Celi, additional, Williams, Adrienne H, additional, Ziegler, Julie T, additional, Comeau, Mary E, additional, Marion, Miranda C, additional, Glenn, Stuart B, additional, Adler, Adam, additional, Frank-Pearce, Summer G, additional, Shen, Nan, additional, Kelly, Jennifer A, additional, Namjou-Khales, Bahram, additional, Petri, Michelle, additional, Alarcon-Riquelme, Marta, additional, Joseph McCune, W, additional, Gaffney, Patrick, additional, Sivils, Kathy, additional, Salmon, Jane E, additional, Weisman, Michael H, additional, Edberg, Jeffrey C, additional, Brown, Elizabeth E, additional, Utset, Tammy, additional, Criswell, Lindsey A, additional, Jacob, Chaim O, additional, Tsao, Betty, additional, Vyse, Timothy J, additional, James, Judith A, additional, Gilkeson, Gary S, additional, Kamen, Diane L, additional, Montgomery, Courtney, additional, Merrill, Joan T, additional, Nath, Swapan K, additional, Laurynenka, Viktoryia, additional, Chepelev, Iouri, additional, Harris-Lewis, Valerie, additional, Hal Scofield, R, additional, Kimberly, Robert P, additional, Langefeld, Carl D, additional, Harley, John B, additional, and Kaufman, Kenneth M, additional

Published
2022
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24. COVID-19 and systemic lupus erythematosus genetics: A balance between autoimmune disease risk and protection against infection

Author

Wang, Yuxuan, primary, Guga, Suri, additional, Wu, Kejia, additional, Khaw, Zoe, additional, Tzoumkas, Konstantinos, additional, Tombleson, Phil, additional, Comeau, Mary E., additional, Langefeld, Carl D., additional, Cunninghame Graham, Deborah S., additional, Morris, David L., additional, and Vyse, Timothy J., additional

Published
2022
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27. Genome‐Wide Association Meta‐Analysis Reveals Novel Juvenile Idiopathic Arthritis Susceptibility Loci

Author

McIntosh, Laura A., Marion, Miranda C., Sudman, Marc, Comeau, Mary E., Becker, Mara L., Bohnsack, John F., Fingerlin, Tasha E., Griffin, Thomas A., Haas, J. Peter, Lovell, Daniel J., Maier, Lisa A., Nigrovic, Peter A., Prahalad, Sampath, Punaro, Marilynn, Rosé, Carlos D., Wallace, Carol A., Wise, Carol A., Moncrieffe, Halima, Howard, Timothy D., Langefeld, Carl D., and Thompson, Susan D.

Published
2017
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28. Mapping adipose and muscle tissue expression quantitative trait loci in African Americans to identify genes for type 2 diabetes and obesity

Author

Sajuthi, Satria P., Sharma, Neeraj K., Chou, Jeff W., Palmer, Nicholette D., McWilliams, David R., Beal, John, Comeau, Mary E., Ma, Lijun, Calles-Escandon, Jorge, Demons, Jamehl, Rogers, Samantha, Cherry, Kristina, Menon, Lata, Kouba, Ethel, Davis, Donna, Burris, Marcie, Byerly, Sara J., Ng, Maggie C. Y., Maruthur, Nisa M., Patel, Sanjay R., Bielak, Lawrence F., Lange, Leslie A., Guo, Xiuqing, Sale, Michèle M., Chan, Kei Hang K., Monda, Keri L., Chen, Gary K., Taylor, Kira, Palmer, Cameron, Edwards, Todd L., North, Kari E., Haiman, Christopher A., Bowden, Donald W., Freedman, Barry I., Langefeld, Carl D., and Das, Swapan K.

Published
2016
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29. Transcriptome-wide analyses of adipose tissue in outbred rats reveal genetic regulatory mechanisms relevant for human obesity

Author

Crouse, Wesley L., primary, Das, Swapan K., additional, Le, Thu, additional, Keele, Gregory, additional, Holl, Katie, additional, Seshie, Osborne, additional, Craddock, Ann L., additional, Sharma, Neeraj K., additional, Comeau, Mary E., additional, Langefeld, Carl D., additional, Hawkins, Gregory A., additional, Mott, Richard, additional, Valdar, William, additional, and Solberg Woods, Leah C., additional

Published
2022
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30. A Genomic Risk Score Identifies Individuals at High Risk for Intracerebral Hemorrhage

Author

Myserlis, Evangelos Pavlos, primary, Georgakis, Marios K., additional, Demel, Stacie L., additional, Sekar, Padmini, additional, Chung, Jaeyoon, additional, Malik, Rainer, additional, Hyacinth, Hyacinth I., additional, Comeau, Mary E., additional, Falcone, Guido, additional, Langefeld, Carl D., additional, Rosand, Jonathan, additional, Woo, Daniel, additional, and Anderson, Christopher D., additional

Published
2022
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31. Risk Factors Associated With Mortality and Neurologic Disability After Intracerebral Hemorrhage in a Racially and Ethnically Diverse Cohort

Author

Woo, Daniel, primary, Comeau, Mary E., additional, Venema, Simone Uniken, additional, Anderson, Christopher D., additional, Flaherty, Matthew, additional, Testai, Fernando, additional, Kittner, Steven, additional, Frankel, Michael, additional, James, Michael L., additional, Sung, Gene, additional, Elkind, Mitchell, additional, Worrall, Bradford, additional, Kidwell, Chelsea, additional, Gonzales, Nicole, additional, Koch, Sebastian, additional, Hall, Christiana, additional, Birnbaum, Lee, additional, Mayson, Douglas, additional, Coull, Bruce, additional, Malkoff, Marc, additional, Sheth, Kevin N., additional, McCauley, Jacob L., additional, Osborne, Jennifer, additional, Morgan, Misty, additional, Gilkerson, Lee, additional, Behymer, Tyler, additional, Coleman, Elisheva R., additional, Rosand, Jonathan, additional, Sekar, Padmini, additional, Moomaw, Charles J., additional, and Langefeld, Carl D., additional

Published
2022
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32. Abstract TP10: Inflammatory And Neurodegenerative Gene Expression Changes Occur Long-term After ICH

Author

Hooper, Destiny, primary, Howard, Timothy D, additional, Williamson, Brady J, additional, BEHYMER, Tyler P, additional, Comeau, Mary E, additional, Zimmerman, Kip, additional, Khandwala, Vivek, additional, Gilkerson, Lee A, additional, Kittner, Steven J, additional, Roh, David J, additional, James, Michael L, additional, Testai, Fernando D, additional, Vahidy, Farhaan S, additional, Bagga, Ranjit S, additional, Thornton, James B, additional, Maloney, Thomas, additional, Sawyer, Russell P. P, additional, Shatz, Rhonna S, additional, Boyne, Pierce, additional, Dunning, Kari, additional, Vagal, Achala, additional, Langefeld, Carl D. D, additional, and Woo, Daniel, additional

Published
2022
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33. Tissue-Specific and Genetic Regulation of Insulin Sensitivity-Associated Transcripts in African Americans

Author

Sharma, Neeraj K., Sajuthi, Satria P., Chou, Jeff W., Calles-Escandon, Jorge, Demons, Jamehl, Rogers, Samantha, Ma, Lijun, Palmer, Nicholette D., McWilliams, David R., Beal, John, Comeau, Mary E., Cherry, Kristina, Hawkins, Gregory A., Menon, Lata, Kouba, Ethel, Davis, Donna, Burris, Marcie, Byerly, Sara J., Easter, Linda, Bowden, Donald W., Freedman, Barry I., Langefeld, Carl D., and Das, Swapan K.

Published
2016

34. Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture

Author

Alarcón-Riquelme, Marta E., Ziegler, Julie T., Molineros, Julio, Howard, Timothy D., Moreno-Estrada, Andrés, Sánchez-Rodríguez, Elena, Ainsworth, Hannah C., Ortiz-Tello, Patricia, Comeau, Mary E., Rasmussen, Astrid, Kelly, Jennifer A., Adler, Adam, Acevedo-Vázquez, Eduardo M., Mariano Cucho-Venegas, Jorge, García-De la Torre, Ignacio, Cardiel, Mario H., Miranda, Pedro, Catoggio, Luis J., Maradiaga-Ceceña, Marco, Gaffney, Patrick M., Vyse, Timothy J., Criswell, Lindsey A., Tsao, Betty P., Sivils, Kathy L., Bae, Sang-Cheol, James, Judith A., Kimberly, Robert P., Kaufman, Kenneth M., Harley, John B., Esquivel-Valerio, Jorge A., Moctezuma, José F., García, Mercedes A., Berbotto, Guillermo A., Babini, Alejandra M., Scherbarth, Hugo, Toloza, Sergio, Baca, Vicente, Nath, Swapan K., Aguilar Salinas, Carlos, Orozco, Lorena, Tusié-Luna, Teresa, Zidovetzki, Raphael, Pons-Estel, Bernardo A., Langefeld, Carl D., and Jacob, Chaim O.

Published
2016
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35. Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA

Author

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

Published
2016
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37. Ethnic and Racial Variation in Intracerebral Hemorrhage Risk Factors and Risk Factor Burden

Author

Kittner, Steven J., primary, Sekar, Padmini, additional, Comeau, Mary E., additional, Anderson, Christopher D., additional, Parikh, Gunjan Y., additional, Tavarez, Tachira, additional, Flaherty, Matthew L., additional, Testai, Fernando D., additional, Frankel, Michael R., additional, James, Michael L., additional, Sung, Gene, additional, Elkind, Mitchell S. V., additional, Worrall, Bradford B., additional, Kidwell, Chelsea S., additional, Gonzales, Nicole R., additional, Koch, Sebastian, additional, Hall, Christiana E., additional, Birnbaum, Lee, additional, Mayson, Douglas, additional, Coull, Bruce, additional, Malkoff, Marc D., additional, Sheth, Kevin N., additional, McCauley, Jacob L., additional, Osborne, Jennifer, additional, Morgan, Misty, additional, Gilkerson, Lee A., additional, Behymer, Tyler P., additional, Demel, Stacie L., additional, Moomaw, Charles J., additional, Rosand, Jonathan, additional, Langefeld, Carl D., additional, and Woo, Daniel, additional

Published
2021
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38. Apolipoprotein L1 Risk Variants Underlie Racial Disparities in Lupus Nephritis-Induced End-Stage Renal Disease.: 729

Author

Kimberly, Robert P., Freedman, Barry I., Langfeld, Carl D., Absher, Devin, Andringa, Kelly K., Birmingham, Daniel, Brown, Elizabeth E., Comeau, Mary E., Costenbader, Karen H., Criswell, Lindsey A., Edberg, Jeffrey C., Harley, John B., James, Judith A., Kamen, Diane L., Merrill, Joan T., Niewold, Timothy B., Patel, Neha, Petri, Michelle A., Ramsey-Goldman, Rosalind, Salmon, Jane E., Segal, Mark, Sivils, Kathy Moser, Tsao, Betty P., Julian, Bruce A., and Consortium, Lupus Nephritis-ESRD

Published
2012

40. Identification of Novel Genetic Susceptibility Loci in African American Lupus Patients in a Candidate Gene Association Study

Author

Sánchez, Elena, Comeau, Mary E., Freedman, Barry I., Kelly, Jennifer A., Kaufman, Kenneth M., Langefeld, Carl D., Brown, Elizabeth E., Alarcón, Graciela S., Kimberly, Robert P., Edberg, Jeffrey C., Ramsey-Goldman, Rosalind, Petri, Michelle, Reveille, John D., Vilá, Luis M., Merrill, Joan T., Tsao, Betty P., Kamen, Diane L., Gilkeson, Gary S., James, Judith A., Vyse, Timothy J., Gaffney, Patrick M., Jacob, Chaim O., Niewold, Timothy B., Richardson, Bruce C., Harley, John B., Alarcón-Riquelme, Marta E., and Sawalha, Amr H.

Published
2011
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41. Association of PPP2CA polymorphisms with systemic lupus erythematosus susceptibility in multiple ethnic groups

Author

Tan, Wenfeng, Sunahori, Katsue, Zhao, Jian, Deng, Yun, Kaufman, Kenneth M., Kelly, Jennifer A., Langefeld, Carl D., Williams, Adrienne H., Comeau, Mary E., Ziegler, Julie T., Marion, Miranda C., Bae, Sang-Cheol, Lee, Joo Hyun, Lee, Ji-Seon, Chang, Deh-Ming, Song, Yeong Wook, Yu, Chack-Yung, Kimberly, Robert P., Edberg, Jeffrey C., Brown, Elizabeth E., Petri, Michelle A., Ramsey-Goldman, Rosalind, Vilá, Luis M., Reveille, John D., Alarcón-Riquelme, Marta E., Harley, John B., Boackle, Susan A., Stevens, Anne M., Scofield, Hal R., Merrill, Joan T., Freedman, Barry I., Anaya, Juan-Manuel, Criswell, Lindsey A., Jacob, Chaim O., Vyse, Timothy J., Niewold, Timothy B., Gaffney, Patrick M., Moser, Kathy L., Gilkeson, Gary S., Kamen, Diane L., James, Judith A., Grossman, Jennifer M., Hahn, Bevra H., Tsokos, George C., and Tsao, Betty P.

Published
2011
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42. Genetic analyses of interferon pathway–related genes reveal multiple new loci associated with systemic lupus erythematosus

Author

Ramos, Paula S., Williams, Adrienne H., Ziegler, Julie T., Comeau, Mary E., Guy, Richard T., Lessard, Christopher J., Li, He, Edberg, Jeffrey C., Zidovetzki, Raphael, Criswell, Lindsey A., Gaffney, Patrick M., Graham, Deborah Cunninghame, Graham, Robert R., Kelly, Jennifer A., Kaufman, Kenneth M., Brown, Elizabeth E., Alarcón, Graciela S., Petri, Michelle A., Reveille, John D., McGwin, Gerald, Vilá, Luis M., Ramsey-Goldman, Rosalind, Jacob, Chaim O., Vyse, Timothy J., Tsao, Betty P., Harley, John B., Kimberly, Robert P., Alarcón-Riquelme, Marta E., Langefeld, Carl D., and Moser, Kathy L.

Published
2011
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46. The susceptibility loci juvenile idiopathic arthritis shares with other autoimmune diseases extend to PTPN2, COG6, and ANGPT1

Author

Thompson, Susan D., Sudman, Marc, Ramos, Paula S., Marion, Miranda C., Ryan, Mary, Tsoras, Monica, Weiler, Tracey, Wagner, Michael, Keddache, Mehdi, Haas, Peter J., Mueller, Cornelia, Prahalad, Sampath, Bohnsack, John, Wise, Carol A., Punaro, Marilynn, Zhang, Dongping, Rosé, Carlos D., Comeau, Mary E., Divers, Jasmin, Glass, David N., and Langefeld, Carl D.

Published
2010

48. The genetic profile of RF-positive polyarticular juvenile idiopathic arthritis (JIA) resembles adult rheumatoid arthritis (RA)

Author

Hinks, Anne, Marion, Miranda C., Cobb, Joanna, Comeau, Mary E., Sudman, Marc, Ainsworth, Hannah C, Bowes, John, Becker, Mara L, Bohnsack, John F., Haas, Johannes-Peter, Lovell, Daniel J, Mellins, Elizabeth D, Nelson, J. Lee, Nordal, Ellen, Punaro, Marilynn, Reed, Ann M., Rosé, Carlos D., Rosenberg, Alan M, Rygg, Marite, Smith, Samantha L, Stevens, Anne M, Videm, Vibeke, Wallace, Carol A., Wedderburn, Lucy R, Yarwood, Annie, Yeung, Rae S M, Langefeld, Carl D., Thompson, Susan D., Thomson, Wendy, and Prahalad, Sampath

Subjects
musculoskeletal diseases, genetic structures, immune system diseases, skin and connective tissue diseases, eye diseases
Abstract

Objective: Juvenile idiopathic arthritis (JIA) is comprised of seven heterogeneous categories of chronic childhood arthritides. About 5% of children with JIA have rheumatoid factor (RF) positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF-positive polyarticular JIA with RA, and selected other JIA categories, to more fully understand the pathophysiological relationships of inflammatory arthropathies. Methods: RF-positive polyarticular JIA cases (n=340) and controls (n=14,412) were genotyped using the Immunochip array. Single nucleotide polymorphisms (SNPs) were tested for association using a logistic regression model adjusting for admixture proportions. Weighted genetic risk scores (wGRS) of published RA and JIA risk loci were calculated and their ability to predict RF-positive polyarticular JIA were compared. Results: As expected, the HLA region was strongly associated with RF-positive polyarticular JIA (p=5.51x10-31). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF-negative polyarticular JIA risk loci were associated (p70 years. Conclusions: RF-positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood-onset presentation of autoantibody positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies.

Published
2018

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