scholarly journals The immunogenetics of viral antigen response is associated with sub-type specific glioma risk and survival

2021 ◽  
Author(s):  
Geno Guerra ◽  
Linda Kachuri ◽  
George Wendt ◽  
Helen M Hansen ◽  
Steven J Mack ◽  
...  
Keyword(s):  
Antibody Response ◽  
Multiple Testing ◽  
Viral Antigen ◽  
Human Leukocyte ◽  
Systematic Investigation ◽  
Barr Virus ◽  
Increased Risk ◽  
Multiple Testing Adjustment ◽  
Glioma Risk ◽  
Hla Dqa1

Background Multiple studies have implicated infections in glioma susceptibility, but the evidence remains inconsistent. Genetic variants in the human leukocyte antigen (HLA) region modulate host response to infection and have been linked to glioma risk. In this study we leveraged genetic predictors of antibody response to 10 viral antigens to investigate the relationship and glioma risk and survival. Methods Genetic reactivity scores (GRS) for each antigen were derived from genome-wide significant (p<5x10-8) variants associated with immunoglobulin G antibody response in the UK Biobank cohort. We conducted parallel analyses of glioma risk and survival for each GRS and HLA alleles imputed at two-field resolution using data from 3418 glioma patients and 8156 controls. Results Genetic reactivity scores to Epstein-Barr virus (EBV) ZEBRA and EBNA antigens and Merkel cell polyomavirus (MCV) VP1 antigen were suggestively associated with glioma risk and survival (unadjusted p<0.05). GRSZEBRA and GRSMCV were associated in opposite directions with risk of IDH wild type gliomas (Odds ratio ORZEBRA=0.91, p=0.007 / ORMCV=1.11, p=0.005). GRSEBNA was associated with both increased risk for IDH mutated gliomas (OR=1.09, p=0.04) and improved survival (Hazard ratio HR=0.86, p=0.01). HLA-DQA1*03:01 was significantly associated with decreased risk of glioma overall (OR=0.85, p=3.96x10-4) after multiple testing adjustment. Conclusion This first systematic investigation of the role of genetic determinants of viral antigen reactivity in glioma risk and survival provides insight into complex immunogenomic mechanisms of glioma pathogenesis. These results may also inform applications of antiviral based therapies in the treatment of glioma.

scholarly journals Elevated risk of invasive group A streptococcal disease and host genetic variation in the human leukocyte antigen locus

2019 ◽  
Author(s):  
Tom Parks ◽  
Katherine Elliott ◽  
Theresa Lamagni ◽  
Kathryn Auckland ◽  
Alexander J. Mentzer ◽  
...  
Keyword(s):  
Case Fatality ◽  
Human Leukocyte ◽  
Hla Typing ◽  
Bacterial Disease ◽  
Invasive Group ◽  
Increased Risk ◽  
Group A ◽  
Host Genetic ◽  
Hla Dqa1 ◽  
Human Leukocyte Antigen Locus

AbstractInvasive group A streptococcal (GAS) disease is uncommon but carries a high case-fatality rate relative to other infectious diseases. Given the ubiquity of mild GAS infections, it remains unclear why healthy individuals will occasionally develop life-threatening infections, raising the possibility of host genetic predisposition. Here, we present the results of a case-control study including 43 invasive GAS cases and 1,540 controls. Using HLA imputation and linear mixed-models, we find each copy of theHLA-DQA1*01:03 allele associates with a two-fold increased risk of disease (odds ratio 2.3, 95% confidence interval 1.3-4.4,P=0.009), an association which persists with classical HLA typing of a subset of cases and analysis with an alternative large control dataset with validated HLA data. Moreover, we propose the association is driven by the allele itself rather than the background haplotype. Overall this finding provides impetus for further investigation of the immunogenetic basis of this devastating bacterial disease.

Effects of infectious mononucleosis and HLA-DRB1*15 in multiple sclerosis

2009 ◽  
Vol 15 (4) ◽  
pp. 431-436 ◽  
Author(s):  
TR Nielsen ◽  
K Rostgaard ◽  
J Askling ◽  
R Steffensen ◽  
A Oturai ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Infectious Mononucleosis ◽  
Human Leukocyte ◽  
Epstein Barr Virus Infection ◽  
Leukocyte Antigen ◽  
Barr Virus ◽  
Increased Risk ◽  
History Of ◽  
Epstein Barr ◽  
Barr Virus Infection

Background Both human leukocyte antigen (HLA)-DRB1*15 and Epstein-Barr virus infection presenting as infectious mononucleosis (IM) are recognized as risk factors for multiple sclerosis (MS). However, their combined effect and possible interaction on MS risk is not known. Objective To assess the association between HLA-DRB1*15 and risk of MS in persons with and without IM. Methods We compared the prevalence of DRB1*15 in MS patients with ( n = 76) and without ( n = 1,836) IM with the corresponding distributions in blood donors with ( n = 62) and without ( n = 484) IM histories. This allowed us to estimate the relative risk of MS associated with DRB1*15 in the presence and absence, respectively, of previous IM. We then estimated the interaction between DRB1*15 and IM as the ratio of the two individual odds ratios. Results In IM-naïve individuals, DRB1*15 carried a 2.4-fold (95% confidence interval [CI], 2.0–3.0) increased MS risk. In contrast, among persons with IM history, DRB1*15 was associated with a 7.0-fold (95% CI, 3.3–15.4) increased MS risk. Thus, the MS risk conferred by HLA-DRB1*15 was 2.9 (95% CI, 1.3–6.5)-fold stronger in the presence than in the absence of IM. Combined with previous results, this result indicates that DRB1*15-positive persons with a history of IM may be at a 10.0-fold (95% CI, 6.0–17.9) increased risk of MS compared with persons who are DRB1*15 and IM-naïve. Conclusion DRB1*15 and IM may act in synergy causing MS.

scholarly journals Sarcopenia and Variation in the Human Leukocyte Antigen Complex

2019 ◽  
Vol 75 (2) ◽  
pp. 301-308 ◽  
Author(s):  
Garan Jones ◽  
Luke C Pilling ◽  
Chia-Ling Kuo ◽  
George Kuchel ◽  
Luigi Ferrucci ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Human Leukocyte Antigen ◽  
Grip Strength ◽  
Muscle Mass ◽  
Genetic Variants ◽  
Multiple Testing ◽  
Human Leukocyte ◽  
Nucleotide Polymorphisms ◽  
Leukocyte Antigen ◽  
Hla Dqa1

Abstract Background Aging is characterized by chronic inflammation plus loss of muscle mass and strength, termed sarcopenia. Human leukocyte antigen (HLA) types are drivers of autoimmune disease, although with limited penetrance. We tested whether autoimmune diagnoses are associated with sarcopenia, and whether HLA types and related genetic variants are associated with sarcopenia in autoimmune disease-free older people. Methods Data were collected from 181,301 UK Biobank European descent volunteers aged 60–70 with measured hand grip strength and impedance. Logistic regression analysis estimated HLA type and sarcopenia associations, adjusted for confounders and multiple testing. Results Having any autoimmune diagnosis was associated with sarcopenia (odds ratio [OR] 1.83, 95% confidence interval (CI) 1.74–1.92, p = 4.0*10−125). After excluding autoimmune diagnoses, 6 of 100 HLA types (allele frequency &gt;1%) were associated with sarcopenia (low grip strength and muscle mass). Having two HLA-DQA1*03:01 alleles increased odds of sarcopenia by 19.3% (OR 1.19, CI 1.09–1.29, p = 2.84*10–5), compared to no alleles. Having ≥6 of the 12 HLA alleles increased sarcopenia odds by 23% (OR 1.23, CI 1.12–1.35, p = 7.28*10–6). Of 658 HLA region non-coding genetic variants previously implicated in disease, 4 were associated with sarcopenia, including rs41268896 and rs29268645 (OR 1.08, CI 1.05–1.11, p = 1.06*10–8 and 1.07, CI 1.04–1.09, p = 1.5*10–6, respectively). Some HLA associations with sarcopenia were greater in female participants. Conclusion Autoimmune diagnoses are strongly associated with sarcopenia in 60- to 70-year olds. Variation in specific HLA types and non-coding single nucleotide polymorphisms is also associated with sarcopenia in older carriers free of diagnosed autoimmune diseases. Patients with sarcopenia might benefit from targeted treatment of autoimmune processes.

scholarly journals Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis

2019 ◽  
Author(s):  
Elin Engdahl ◽  
Rasmus Gustafsson ◽  
Jesse Huang ◽  
Martin Biström ◽  
Izaura Lima Bomfim ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Human Herpesvirus ◽  
Human Leukocyte ◽  
Antibody Responses ◽  
Serological Response ◽  
Barr Virus ◽  
Early Protein ◽  
Increased Risk ◽  
Epstein Barr ◽  
Main Association

ABSTRACTHuman herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) etiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses.A novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8742 persons with MS and 7215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further.The IgG response against IE1A was positively associated with MS (OR = 1.55, p = 9×10−22), and increased risk of future MS (OR = 2.22, p = 2×10−5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6×10−6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6×10−11). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the Human Leukocyte Antigen (HLA) region and the strongest association for IE1A was the DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04.In conclusion a role for HHV-6A in MS etiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.

scholarly journals Differences in the Epstein-Barr Virus gp350 IgA Antibody Response Are Associated With Increased Risk for Coinfection With a Second Strain of Epstein-Barr Virus

2018 ◽  
Vol 219 (6) ◽  
pp. 955-963 ◽  
Author(s):  
Nicholas A Smith ◽  
Paul C Baresel ◽  
Conner L Jackson ◽  
Sidney Ogolla ◽  
Eunice N Toko ◽  
...  
Keyword(s):  
Antibody Response ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Increased Risk ◽  
Iga Antibody ◽  
Epstein Barr

scholarly journals The landscape of host genetic factors involved in infection to common viruses and SARS-CoV-2

2020 ◽  
Author(s):  
Linda Kachuri ◽  
Stephen S. Francis ◽  
Maike Morrison ◽  
Taylor B. Cavazos ◽  
Sara R. Rashkin ◽  
...  
Keyword(s):  
Antibody Response ◽  
Viral Infection ◽  
Human Herpesvirus ◽  
Complex Diseases ◽  
Human Leukocyte ◽  
Class Ii ◽  
Human Polyomavirus ◽  
Nuclear Antigen ◽  
Varicella Zoster ◽  
Barr Virus

ABSTRACTHumans and viruses have co-evolved for millennia resulting in genetic polymorphisms that affect response to viral infection. We conducted a comprehensive study in the UK biobank linking germline genetic variation and gene expression with 28 antigens for 16 viruses in 7924 subjects. We discovered 7 novel loci associated with antibody response (P<5.0×10−8), including FUT2 for human polyomavirus BKV, TMEM173 for Merkel cell polyomavirus (MCV), and TBKBP1 for human herpesvirus 7. Transcriptome-wide analyses identified 114 genes association with response to viral infection, including ECSCR: P=5.0×10−15 (MCV), NTN5: P=1.1×10−9 (BKV), and P2RY13: P=1.1×10−8 (Epstein-Barr virus nuclear antigen). Signals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We also link viral response genes with complex diseases, such as C4A expression in varicella zoster virus and schizophrenia. Lastly, based on 1028 subjects tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we identify 7 class II HLA susceptibility alleles (5 associated with other viruses). We also observe that genetic determinants of ACE2 expression may influence SARS-CoV-2 susceptibility. Our findings elucidate the genetic architecture of host response to viral infection, with potential implications for complex diseases and COVID-19.

scholarly journals Antibody response to common viruses and human leukocyte antigen-DRB1 in pediatric multiple sclerosis

2012 ◽  
Vol 19 (7) ◽  
pp. 891-895 ◽  
Author(s):  
Emmanuelle Waubant ◽  
Ellen M Mowry ◽  
Lauren Krupp ◽  
Tanuja Chitnis ◽  
E Ann Yeh ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Antibody Response ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Humoral Response ◽  
Nuclear Antigen ◽  
Leukocyte Antigen ◽  
Epstein Barr ◽  
Humoral Responses ◽  
Hsv 1

Background: As remote infections with common herpes viruses are associated with modulation of the risk of multiple sclerosis (MS), we hypothesized that antibody concentrations against these viruses may further modify risk. As many common viruses are first encountered during childhood, pediatric MS offer a unique opportunity to investigate more closely their influence on susceptibility. Our aim was to determine if MS patients who were positive for these viruses had higher levels of antibodies to these viruses. We also assessed whether human leukocyte antigen (HLA)-DRB1*1501 genotype influenced viral antibody levels. Methods: Antibody response levels toward Epstein Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV)-1, and HLA-DRB1*1501 status were determined in pediatric MS patients ( n=189) and controls ( n=38). Multivariate analyses were used, adjusted for age, gender, race, ethnicity and use of disease-modifying therapies. Results: The antibody concentrations against EBV (Epstein-Barr nuclear antigen 1 (EBNA-1), viral capsid antigen (VCA) and early antigen (EA)), CMV and HSV-1 were similar between pediatric MS patients and controls positive for seroconversion against the virus of interest. EBNA-1 humoral responses were higher in HLA-DRB1 positive individuals ( p=0.005) whereas other viral humoral responses were similar in HLA-DRB1 positive and negative individuals. Conclusion: Among those positive for EBNA-1, MS patients did not have higher levels of antibody response to EBNA-1: however, titers for EBNA-1 were higher in those who were HLA-DRB1 positive. This suggests that genotype might influence the humoral response to EBV. Whether other genotypes influence antibody response to other viruses remains to be determined.

scholarly journals Recommendations on multiple testing adjustment in multi-arm trials with a shared control group

2016 ◽  
Vol 27 (5) ◽  
pp. 1513-1530 ◽  
Author(s):  
Dena R Howard ◽  
Julia M Brown ◽  
Susan Todd ◽  
Walter M Gregory
Keyword(s):  
False Positive ◽  
Multiple Testing ◽  
Shared Control ◽  
Control Group ◽  
Type I ◽  
False Positive Error ◽  
Control Data ◽  
Experimental Therapies ◽  
Multiple Testing Adjustment ◽  
Independent Trials

Multi-arm clinical trials assessing multiple experimental treatments against a shared control group can offer efficiency advantages over independent trials through assessing an increased number of hypotheses. Published opinion is divided on the requirement for multiple testing adjustment to control the family-wise type-I error rate (FWER). The probability of a false positive error in multi-arm trials compared to equivalent independent trials is affected by the correlation between comparisons due to sharing control data. We demonstrate that this correlation in fact leads to a reduction in the FWER, therefore FWER adjustment is not recommended solely due to sharing control data. In contrast, the correlation increases the probability of multiple false positive outcomes across the hypotheses, although standard FWER adjustment methods do not control for this. A stringent critical value adjustment is proposed to maintain equivalent evidence of superiority in two correlated comparisons to that obtained within independent trials. FWER adjustment is only required if there is an increased chance of making a single claim of effectiveness by testing multiple hypotheses, not due to sharing control data. For competing experimental therapies, the correlation between comparisons can be advantageous as it eliminates bias due to the experimental therapies being compared to different control populations.

scholarly journals Prevalence of autoimmune diseases in in-patients with schizophrenia: nationwide population-based study

2012 ◽  
Vol 200 (5) ◽  
pp. 374-380 ◽  
Author(s):  
Shaw-Ji Chen ◽  
Yu-Lin Chao ◽  
Chuan-Yu Chen ◽  
Chia-Ming Chang ◽  
Erin Chia-Hsuan Wu ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Multiple Testing ◽  
Pernicious Anaemia ◽  
Population Based ◽  
Control Group ◽  
Research Database ◽  
Population Based Study ◽  
Hypersensitivity Vasculitis ◽  
Increased Risk ◽  
Specific Variation

BackgroundThe association between autoimmune diseases and schizophrenia has rarely been systematically investigated.AimsTo investigate the association between schizophrenia and a variety of autoimmune diseases and to explore possible gender variation in any such association.MethodTaiwan's National Health Insurance Research Database was used to identify 10 811 hospital in-patients with schizophrenia and 108 110 age-matched controls. Univariate and multiple logistic regression analyses were performed, separately, to evaluate the association between autoimmune diseases and schizophrenia. We applied the false discovery rate to correct for multiple testing.ResultsWhen compared with the control group, the in-patients with schizophrenia had an increased risk of Graves' disease (odds ratio (OR) = 1.32, 95% CI 1.04–1.67), psoriasis (OR = 1.48, 95% CI 1.07–2.04), pernicious anaemia (OR = 1.71, 95% CI 1.04–2.80), celiac disease (OR = 2.43, 95% CI 1.12–5.27) and hypersensitivity vasculitis (OR = 5.00, 95% CI 1.64–15.26), whereas a reverse association with rheumatoid arthritis (OR = 0.52, 95% CI 0.35–0.76) was also observed. Gender-specific variation was found for Sjögren syndrome, hereditary haemolytic anaemia, myasthenia gravis, polymyalgia rheumatica and dermatomyositis.ConclusionsSchizophrenia was associated with a greater variety of autoimmune diseases than was anticipated. Further investigation is needed to gain a better understanding of the aetiology of schizophrenia and autoimmune diseases.

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