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MR-PheWAS: exploring the causal effect of SUA level on multiple disease outcomes by using genetic instruments in UK Biobank.
Li X, Meng X, Spiliopoulou A, Timofeeva M, Wei WQ, Gifford A, Shen X, He Y, Varley T, McKeigue P, Tzoulaki I, Wright AF, Joshi P, Denny JC, Campbell H, Theodoratou E
(2018) Ann Rheum Dis 77: 1039-1047
MeSH Terms: Adult, Arthritis, Autoimmune Diseases, Biological Specimen Banks, Celiac Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Gout, Humans, Hypertension, Male, Mendelian Randomization Analysis, Middle Aged, Multimorbidity, Myocardial Infarction, Prognosis, Risk Assessment, United Kingdom, Uric Acid
Show Abstract · Added March 14, 2018
OBJECTIVES - We aimed to investigate the role of serum uric acid (SUA) level in a broad spectrum of disease outcomes using data for 120 091 individuals from UK Biobank.
METHODS - We performed a phenome-wide association study (PheWAS) to identify disease outcomes associated with SUA genetic risk loci. We then implemented conventional Mendelianrandomisation (MR) analysis to investigate the causal relevance between SUA level and disease outcomes identified from PheWAS. We next applied MR Egger analysis to detect and account for potential pleiotropy, which conventional MR analysis might mistake for causality, and used the HEIDI (heterogeneity in dependent instruments) test to remove cross-phenotype associations that were likely due to genetic linkage.
RESULTS - Our PheWAS identified 25 disease groups/outcomes associated with SUA genetic risk loci after multiple testing correction (P<8.57e-05). Our conventional MR analysis implicated a causal role of SUA level in three disease groups: inflammatory polyarthropathies (OR=1.22, 95% CI 1.11 to 1.34), hypertensive disease (OR=1.08, 95% CI 1.03 to 1.14) and disorders of metabolism (OR=1.07, 95% CI 1.01 to 1.14); and four disease outcomes: gout (OR=4.88, 95% CI 3.91 to 6.09), essential hypertension (OR=1.08, 95% CI 1.03 to 1.14), myocardial infarction (OR=1.16, 95% CI 1.03 to 1.30) and coeliac disease (OR=1.41, 95% CI 1.05 to 1.89). After balancing pleiotropic effects in MR Egger analysis, only gout and its encompassing disease group of inflammatory polyarthropathies were considered to be causally associated with SUA level. Our analysis highlighted a locus () that may influence SUA level and multiple cardiovascular and autoimmune diseases via pleiotropy.
CONCLUSIONS - Elevated SUA level is convincing to cause gout and inflammatory polyarthropathies, and might act as a marker for the wider range of diseases with which it associates. Our findings support further investigation on the clinical relevance of SUA level with cardiovascular, metabolic, autoimmune and respiratory diseases.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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20 MeSH Terms
Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.
Jiang X, O'Reilly PF, Aschard H, Hsu YH, Richards JB, Dupuis J, Ingelsson E, Karasik D, Pilz S, Berry D, Kestenbaum B, Zheng J, Luan J, Sofianopoulou E, Streeten EA, Albanes D, Lutsey PL, Yao L, Tang W, Econs MJ, Wallaschofski H, Völzke H, Zhou A, Power C, McCarthy MI, Michos ED, Boerwinkle E, Weinstein SJ, Freedman ND, Huang WY, Van Schoor NM, van der Velde N, Groot LCPGM, Enneman A, Cupples LA, Booth SL, Vasan RS, Liu CT, Zhou Y, Ripatti S, Ohlsson C, Vandenput L, Lorentzon M, Eriksson JG, Shea MK, Houston DK, Kritchevsky SB, Liu Y, Lohman KK, Ferrucci L, Peacock M, Gieger C, Beekman M, Slagboom E, Deelen J, Heemst DV, Kleber ME, März W, de Boer IH, Wood AC, Rotter JI, Rich SS, Robinson-Cohen C, den Heijer M, Jarvelin MR, Cavadino A, Joshi PK, Wilson JF, Hayward C, Lind L, Michaëlsson K, Trompet S, Zillikens MC, Uitterlinden AG, Rivadeneira F, Broer L, Zgaga L, Campbell H, Theodoratou E, Farrington SM, Timofeeva M, Dunlop MG, Valdes AM, Tikkanen E, Lehtimäki T, Lyytikäinen LP, Kähönen M, Raitakari OT, Mikkilä V, Ikram MA, Sattar N, Jukema JW, Wareham NJ, Langenberg C, Forouhi NG, Gundersen TE, Khaw KT, Butterworth AS, Danesh J, Spector T, Wang TJ, Hyppönen E, Kraft P, Kiel DP
(2018) Nat Commun 9: 260
MeSH Terms: Amidohydrolases, Autoimmune Diseases, Cohort Studies, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Vesicular Transport Proteins, Vitamin D
Show Abstract · Added January 3, 2019
Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 at rs8018720 in SEC23A, and P = 1.9×10 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
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Bruton's Tyrosine Kinase Deficiency Inhibits Autoimmune Arthritis in Mice but Fails to Block Immune Complex-Mediated Inflammatory Arthritis.
Nyhoff LE, Barron BL, Johnson EM, Bonami RH, Maseda D, Fensterheim BA, Han W, Blackwell TS, Crofford LJ, Kendall PL
(2016) Arthritis Rheumatol 68: 1856-68
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, Antigen-Antibody Complex, Arthritis, Autoimmune Diseases, Male, Mice, Protein-Tyrosine Kinases
Show Abstract · Added October 12, 2016
OBJECTIVE - Bruton's tyrosine kinase (BTK) is a B cell signaling protein that also contributes to innate immunity. BTK inhibitors prevent autoimmune arthritis but have off-target effects, and the mechanisms of protection remain unknown. We undertook these studies using genetic deletion to investigate the role of BTK in adaptive and innate immune responses that drive inflammatory arthritis.
METHODS - BTK-deficient K/BxN mice were generated to study the role of BTK in a spontaneous model that requires both adaptive and innate immunity. The K/BxN serum-transfer model was used to bypass the adaptive system and elucidate the role of BTK in innate immune contributions to arthritis.
RESULTS - BTK deficiency conferred disease protection to K/BxN mice, confirming outcomes of BTK inhibitors. B lymphocytes were profoundly reduced, more than in other models of BTK deficiency. Subset analysis revealed loss of B cells at all developmental stages. Germinal center B cells were also decreased, with downstream effects on numbers of follicular helper T cells and greatly reduced autoantibodies. In contrast, total IgG was only mildly decreased. Strikingly, and in contrast to small molecule inhibitors, BTK deficiency had no effect in the serum-transfer model of arthritis.
CONCLUSION - BTK contributes to autoimmune arthritis primarily through its role in B cell signaling and not through innate immune components.
© 2016, American College of Rheumatology.
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The role of Bruton's tyrosine kinase in autoimmunity and implications for therapy.
Crofford LJ, Nyhoff LE, Sheehan JH, Kendall PL
(2016) Expert Rev Clin Immunol 12: 763-73
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, Anti-Inflammatory Agents, Autoantibodies, Autoimmune Diseases, Autoimmunity, B-Lymphocytes, Humans, Immune Tolerance, Lymphocyte Activation, Protein-Tyrosine Kinases, Receptors, Antigen, B-Cell, Signal Transduction
Show Abstract · Added July 18, 2017
Bruton's tyrosine kinase (BTK) mediates B cell signaling and is also present in innate immune cells but not T cells. BTK propagates B cell receptor (BCR) responses to antigen-engagement as well as to stimulation via CD40, toll-like receptors (TLRs), Fc receptors (FCRs) and chemokine receptors. Importantly, BTK can modulate signaling, acting as a "rheostat" rather than an "on-off" switch; thus, overexpression leads to autoimmunity while decreased levels improve autoimmune disease outcomes. Autoreactive B cells depend upon BTK for survival to a greater degree than normal B cells, reflected as loss of autoantibodies with maintenance of total antibody levels when BTK is absent. This review describes contributions of BTK to immune tolerance, including studies testing BTK-inhibitors for treatment of autoimmune diseases.
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13 MeSH Terms
A case of subepidermal blistering disease with autoantibodies to multiple laminin subunits who developed later autoantibodies to alpha-5 chain of type IV collagen associated with membranous glomerulonephropathy.
Sueki H, Sato Y, Ohtoshi S, Nakada T, Yoshimura A, Tateishi C, Borza DB, Fader W, Ghohestani RF, Hirako Y, Koga H, Ishii N, Tsuchisaka A, Qian H, Li X, Hashimoto T
(2015) Acta Derm Venereol 95: 826-9
MeSH Terms: Aged, Autoantibodies, Autoimmune Diseases, Biopsy, Blister, Collagen Type IV, Female, Fluorescent Antibody Technique, Glomerulonephritis, Membranous, Glucocorticoids, Humans, Kidney, Laminin, Plasma Exchange, Predictive Value of Tests, Protein Subunits, Skin, Time Factors
Show Abstract · Added December 2, 2016
We report a 68-year-old Japanese female patient with subepidermal blistering disease with autoantibodies to multiple laminins, who subsequently developed membranous glomerulonephropathy. At skin disease stage, immunofluorescence demonstrated IgG anti-basement membrane zone antibodies reactive with dermal side of NaCl-split skin. Immunoblotting of human dermal extract, purified laminin-332, hemidesmosome-rich fraction and laminin-521 trimer recombinant protein (RP) detected laminin γ-1 and α-3 and γ-2 subunits of laminin-332. Three years after skin lesions disappeared, nephrotic symptoms developed. Antibodies to α-3 chain of type IV collagen (COL4A3) were negative, thus excluding the diagnosis of Goodpasture syndrome. All anti-laminin antibodies disappeared. Additional IB and ELISA studies of RPs of various COL4 chains revealed reactivity with COL4A5, but not with COL4A6 or COL4A3. Although diagnosis of anti-laminin γ-1 (p200) pemphigoid or anti-laminin-332-type mucous membrane pemphigoid could not be made, this case was similar to previous cases with autoantibodies to COL4A5 and/or COL4A6.
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18 MeSH Terms
Impact of premature ovarian failure on mortality and morbidity among Chinese women.
Wu X, Cai H, Kallianpur A, Li H, Yang G, Gao J, Xiang YB, Ji BT, Yu-Tang , Zheng W, Shu XO
(2014) PLoS One 9: e89597
MeSH Terms: Adult, Aged, Asian Continental Ancestry Group, Autoimmune Diseases, Breast Neoplasms, China, Cohort Studies, Female, Humans, Incidence, Logistic Models, Middle Aged, Morbidity, Mortality, Prevalence, Primary Ovarian Insufficiency, Proportional Hazards Models, Waist-Hip Ratio, Women's Health
Show Abstract · Added March 10, 2014
OBJECTIVE - To evaluate associations of premature ovarian failure (POF) with mortality and morbidity in Asian populations.
METHODS - We identified 1,003 cases of POF among 36,402 postmenopausal women who participated in the Shanghai Women's Health Study, a population-based cohort study. Cox regression and logistic regression models were applied in data analysis.
RESULTS - After adjustment for potential confounding factors, we found that POF increased the risk of total and cancer-specific mortality (HR (95%CIs): 1.29 (1.08-1.54) and 1.38 (1.05-1.81), respectively). POF was also associated with high prevalence of autoimmune disease (OR (95%CI): 1.56 (1.04-2.35)) but decreased incidence of breast cancer (OR (95%CI): 0.59 (0.38-0.91)). Similar results were observed when hormone replacement therapy users were excluded from the analysis. POF is associated with high waist-to-hip ratio.
CONCLUSIONS - Our results suggest that women with POF experience increased mortality and that these women may benefit from heightened surveillance and appropriate interventions.
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Clinical predictors of autoimmune and severe atopic disease in pediatric heart transplant recipients.
Mouledoux JH, Albers EL, Lu Z, Saville BR, Moore DJ, Dodd DA
(2014) Pediatr Transplant 18: 197-203
MeSH Terms: Adolescent, Autoimmune Diseases, Child, Child, Preschool, Female, Heart Failure, Heart Transplantation, Humans, Hypersensitivity, Immediate, Immunosuppressive Agents, Infant, Infant, Newborn, Male, Molecular Sequence Data, Retrospective Studies, Risk Factors
Show Abstract · Added May 27, 2014
Autoimmune and allergic diseases cause morbidity and diminished quality of life in pediatric organ transplant recipients. We hypothesize that younger age at transplantation and immunosuppression regimen play a role in the development of immune-mediated disease following heart transplant. A single institution retrospective review identified all patients undergoing heart transplant at ≤18 yr of age from 1987 to 2010 who survived ≥1 yr. Using medical record and database review, patients were evaluated for development of autoimmune or severe allergic disease. Of 129 patients who met criteria, seven patients (5.4%) with autoimmune or severe atopic disease were identified. Immune-mediated diseases included inflammatory bowel disease (n = 3), eosinophilic esophagitis/colitis (n = 4), and chronic bullous disease of childhood (n = 1). Patients <1 yr of age at transplant were at greater risk of developing autoimmune disease than patients 1-18 yr at transplant (OR = 9.3, 95% CI 1.1-79.2, p = 0.02). All affected patients underwent thymectomy at <1 yr of age (7/71 vs. 0/58, p = 0.02). In our experience, heart transplantation in infancy is associated with the development of immune-mediated gastrointestinal and dermatologic diseases. Further study is needed to determine risk factors for the development of immune-mediated disease to identify best practices to decrease incidence.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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16 MeSH Terms
Non-viral opportunistic infections in new users of tumour necrosis factor inhibitor therapy: results of the SAfety Assessment of Biologic ThERapy (SABER) study.
Baddley JW, Winthrop KL, Chen L, Liu L, Grijalva CG, Delzell E, Beukelman T, Patkar NM, Xie F, Saag KG, Herrinton LJ, Solomon DH, Lewis JD, Curtis JR
(2014) Ann Rheum Dis 73: 1942-8
MeSH Terms: Adult, Aged, Antirheumatic Agents, Arthritis, Rheumatoid, Autoimmune Diseases, Biological Products, Biological Therapy, Female, Humans, Immunocompromised Host, Immunosuppressive Agents, Male, Middle Aged, Opportunistic Infections, Retrospective Studies, Tumor Necrosis Factor-alpha, United States
Show Abstract · Added July 27, 2018
OBJECTIVES - To determine among patients with autoimmune diseases in the USA whether the risk of non-viral opportunistic infections (OI) was increased among new users of tumour necrosis factor α inhibitors (TNFI), when compared to users of non-biological agents used for active disease.
METHODS - We identified new users of TNFI among cohorts of rheumatoid arthritis (RA), inflammatory bowel disease and psoriasis-psoriatic arthritis-ankylosing spondylitis patients during 1998-2007 using combined data from Kaiser Permanente Northern California, two pharmaceutical assistance programmes for the elderly, Tennessee Medicaid and US Medicaid/Medicare programmes. We compared incidence of non-viral OI among new TNFI users and patients initiating non-biological disease-modifying antirheumatic drugs (DMARD) overall and within each disease cohort. Cox regression models were used to compare propensity-score and steroid- adjusted OI incidence between new TNFI and non-biological DMARD users.
RESULTS - Within a cohort of 33 324 new TNFI users we identified 80 non-viral OI, the most common of which was pneumocystosis (n=16). In the combined cohort, crude rates of non-viral OI among new users of TNFI compared to those initiating non-biological DMARD was 2.7 versus 1.7 per 1000-person-years (aHR 1.6, 95% CI 1.0 to 2.6). Baseline corticosteroid use was associated with non-viral OI (aHR 2.5, 95% CI 1.5 to 4.0). In the RA cohort, rates of non-viral OI among new users of infliximab were higher when compared to patients newly starting non-biological DMARD (aHR 2.6, 95% CI 1.2 to 5.6) or new etanercept users (aHR 2.9, 95% CI 1.5 to 5.4).
CONCLUSIONS - In the USA, the rate of non-viral OI was higher among new users of TNFI with autoimmune diseases compared to non-biological DMARD users.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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Type 2 diabetes mellitus--an autoimmune disease?
Velloso LA, Eizirik DL, Cnop M
(2013) Nat Rev Endocrinol 9: 750-5
MeSH Terms: Autoimmune Diseases, Diabetes Mellitus, Type 2, Humans, Insulin Resistance, Obesity
Show Abstract · Added August 14, 2013
Inflammation-induced inhibition of the insulin signalling pathway can lead to insulin resistance and contribute to the development of type 2 diabetes mellitus (T2DM). Obesity and insulin resistance are associated with a chronic but subclinical inflammatory process that impairs insulin action in most tissues and could also hamper pancreatic β-cell function. The involvement of monocytic cells and the profiles of the chemokines and cytokines induced by this inflammation suggest an innate immune response. However, emerging data indicate that elements of the adaptive immune system could also be involved. As activation of an adaptive response requires antigen specificity, some researchers have hypothesized that T2DM evolves from an innate immune response to an autoimmune condition. In this Perspectives article, we present the arguments for and against this hypothesis and discuss which mechanisms could be involved in a putative switch from innate immunity to autoimmunity.
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5 MeSH Terms
Association between the initiation of anti-tumor necrosis factor therapy and the risk of herpes zoster.
Winthrop KL, Baddley JW, Chen L, Liu L, Grijalva CG, Delzell E, Beukelman T, Patkar NM, Xie F, Saag KG, Herrinton LJ, Solomon DH, Lewis JD, Curtis JR
(2013) JAMA 309: 887-95
MeSH Terms: Adult, Aged, Antirheumatic Agents, Arthritis, Rheumatoid, Autoimmune Diseases, Case-Control Studies, Cohort Studies, Databases, Factual, Female, Herpes Zoster, Humans, Immunocompromised Host, Incidence, Male, Middle Aged, Retrospective Studies, Risk, Tumor Necrosis Factor-alpha, United States
Show Abstract · Added July 27, 2018
IMPORTANCE - Herpes zoster reactivation disproportionately affects patients with rheumatoid arthritis (RA). It is unclear whether anti-tumor necrosis factor (anti-TNF) therapy elevates herpes zoster risk.
OBJECTIVES - To ascertain whether initiation of anti-TNF therapy compared with nonbiologic comparators is associated with increased herpes zoster risk.
DESIGN, SETTING, AND PATIENTS - We identified new users of anti-TNF therapy among cohorts of patients with RA, inflammatory bowel disease, and psoriasis, psoriatic arthritis, or ankylosing spondylitis from 1998 through 2007 within a large US multi-institutional collaboration combining data from Kaiser Permanente Northern California, Pharmaceutical Assistance Contract for the Elderly, Tennessee Medicaid, and national Medicaid/Medicare programs. We compared herpes zoster incidence between new anti-TNF users (n=33,324) and patients initiating nonbiologic disease-modifying antirheumatic drugs (DMARDs) (n=25,742) within each inflammatory disease cohort (last participant follow-up December 31, 2007). Within these cohorts, we used Cox regression models to compare propensity score-adjusted herpes zoster incidence between new anti-TNF and nonbiologic DMARD users while controlling for baseline corticosteroid use.
MAIN OUTCOME MEASURES - Incidence of herpes zoster cases occurring after initiation of new anti-TNF or nonbiologic DMARD therapy.
RESULTS - Among 33,324 new users of anti-TNF therapy, we identified 310 herpes zoster cases. Crude incidence rates among anti-TNF users were 12.1 per 1000 patient-years (95% CI, 10.7-13.6) for RA, 11.3 per 1000 patient-years (95% CI, 7.7-16.7) for inflammatory bowel disease, and 4.4 per 1000 patient-years (95% CI, 2.8-7.0) for psoriasis, psoriatic arthritis, or ankylosing spondylitis. Baseline use of corticosteroids of 10 mg/d or greater among all disease indications was associated with elevated risk (adjusted hazard ratio [HR], 2.13 [95% CI, 1.64-2.75]) compared with no baseline use. For patients with RA, adjusted incidence rates were similar between anti-TNF and nonbiologic DMARD initiators (adjusted HR, 1.00 [95% CI, 0.77-1.29]) and comparable between all 3 anti-TNF therapies studied. Across all disease indications, the adjusted HR was 1.09 (95% CI, 0.88-1.36).
CONCLUSION AND RELEVANCE - Among patients with RA and other inflammatory diseases, those who initiated anti-TNF therapies were not at higher risk of herpes zoster compared with patients who initiated nonbiologic treatment regimens.
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