scholarly journals High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility

2021 ◽  
Vol 12 ◽  
Author(s):  
Kazutoyo Osoegawa ◽  
Lisa E. Creary ◽  
Gonzalo Montero-Martín ◽  
Kalyan C. Mallempati ◽  
Sridevi Gangavarapu ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Statistical Significance ◽  
Hla Class I ◽  
Protective Effects ◽  
Genetic Associations ◽  
Hla Alleles ◽  
Hla Genes ◽  
Haplotype Allele ◽  
Family Based ◽  
Hla Haplotypes

Multiple sclerosis (MS) susceptibility shows strong genetic associations with HLA alleles and haplotypes. We genotyped 11 HLA genes in 477 non-Hispanic European MS patients and their 954 unaffected parents using a validated next-generation sequencing (NGS) methodology. HLA haplotypes were assigned unequivocally by tracing HLA allele transmissions. We explored HLA haplotype/allele associations with MS using the genotypic transmission disequilibrium test (gTDT) and multiallelic TDT (mTDT). We also conducted a case-control (CC) study with all patients and 2029 healthy unrelated ethnically matched controls. We performed separate analyses of 54 extended multi-case families by reviewing transmission of haplotype blocks. The haplotype fragment including DRB5*01:01:01~DRB1*15:01:01:01 was significantly associated with predisposition (gTDT: p < 2.20e-16; mTDT: p =1.61e-07; CC: p < 2.22e-16) as reported previously. A second risk allele, DPB1*104:01 (gTDT: p = 3.69e-03; mTDT: p = 2.99e-03; CC: p = 1.00e-02), independent from the haplotype bearing DRB1*15:01 was newly identified. The allele DRB1*01:01:01 showed significant protection (gTDT: p = 8.68e-06; mTDT: p = 4.50e-03; CC: p = 1.96e-06). Two DQB1 alleles, DQB1*03:01 (gTDT: p = 2.86e-03; mTDT: p = 5.56e-02; CC: p = 4.08e-05) and DQB1*03:03 (gTDT: p = 1.17e-02; mTDT: p = 1.16e-02; CC: p = 1.21e-02), defined at two-field level also showed protective effects. The HLA class I block, A*02:01:01:01~C*03:04:01:01~B*40:01:02 (gTDT: p = 5.86e-03; mTDT: p = 3.65e-02; CC: p = 9.69e-03) and the alleles B*27:05 (gTDT: p = 6.28e-04; mTDT: p = 2.15e-03; CC: p = 1.47e-02) and B*38:01 (gTDT: p = 3.20e-03; mTDT: p = 6.14e-03; CC: p = 1.70e-02) showed moderately protective effects independently from each other and from the class II associated factors. By comparing statistical significance of 11 HLA loci and 19 haplotype segments with both untruncated and two-field allele names, we precisely mapped MS candidate alleles/haplotypes while eliminating false signals resulting from ‘hitchhiking’ alleles. We assessed genetic burden for the HLA allele/haplotype identified in this study. This family-based study including the highest-resolution of HLA alleles proved to be powerful and efficient for precise identification of HLA genotypes associated with both, susceptibility and protection to development of MS.

scholarly journals Immunogenetic Epidemiology of Multiple Sclerosis in 14 Continental Western European Countries

2021 ◽  
Vol 5 (2) ◽  
pp. 40-46
Author(s):  
Lisa M. James ◽  
Apostolos P. Georgopoulos
Keyword(s):  
Multiple Sclerosis ◽  
Human Leukocyte ◽  
Hla Class I ◽  
European Countries ◽  
Class I ◽  
Hla Alleles ◽  
Susceptibility Effect ◽  
Pathogen Elimination ◽  
Western European

Human leukocyte antigen (HLA), a system involved in immune response to foreign antigens and in autoimmunity, has been strongly implicated in multiple sclerosis (MS). Prior research has shown that HLA DRB1*15:01 exerts the strongest susceptibility effect, although other HLA alleles have been implicated in both susceptibility to, and protection against, MS. Here we utilized an immunogenetic epidemiological approach to evaluate correlations between the population frequencies of 127 HLA Class I and II alleles and the population prevalence of MS in 14 Continental Western European countries to identify an HLA profile for MS. The results of these analyses, which largely corroborated prior findings and revealed several novel and highly robust HLA associations with MS, revealed a larger number of protective HLA alleles than susceptibility alleles, particularly for HLA Class I. Given the role of HLA in pathogen elimination and autoimmunity, these findings point to a contributory role of exposure to pathogens in the absence of protective HLA in underlying the inflammation and autoimmunity associated with MS.

scholarly journals Additive Contribution of HLA Class I Alleles in the Immune Control of HIV-1 Infection

2010 ◽  
Vol 84 (19) ◽  
pp. 9879-9888 ◽  
Author(s):  
Alasdair Leslie ◽  
Philippa C. Matthews ◽  
Jennifer Listgarten ◽  
Jonathan M. Carlson ◽  
Carl Kadie ◽  
...  
Keyword(s):  
Hla Class I ◽  
Cd4 Count ◽  
Class I ◽  
Strong Impact ◽  
Protective Effects ◽  
Hla Alleles ◽  
Individual Level ◽  
Additive Contribution ◽  
The Individual ◽  
Hiv 1

ABSTRACT Previous studies have identified a central role for HLA-B alleles in influencing control of HIV infection. An alternative possibility is that a small number of HLA-B alleles may have a very strong impact on HIV disease outcome, dominating the contribution of other HLA alleles. Here, we find that even following the exclusion of subjects expressing any of the HLA-B class I alleles (B*57, B*58, and B*18) identified to have the strongest influence on control, the dominant impact of HLA-B alleles on virus set point and absolute CD4 count variation remains significant. However, we also find that the influence of HLA on HIV control in this C-clade-infected cohort from South Africa extends beyond HLA-B as HLA-Cw type remains a significant predictor of virus and CD4 count following exclusion of the strongest HLA-B associations. Furthermore, there is evidence of interdependent protective effects of the HLA-Cw*0401-B*8101, HLA-Cw*1203-B*3910, and HLA-A*7401-B*5703 haplotypes that cannot be explained solely by linkage to a protective HLA-B allele. Analysis of individuals expressing both protective and detrimental alleles shows that even the strongest HLA alleles appear to have an additive rather than dominant effect on HIV control at the individual level. Finally, weak but significant frequency-dependent effects in this cohort can be detected only by looking at an individual's combined HLA allele frequencies. Taken together, these data suggest that although individual HLA alleles, particularly HLA-B, can have a strong impact, HIV control overall is likely to be influenced by the additive effect of some or all of the other HLA alleles present.

scholarly journals Association of HLA class I markers with multiple sclerosis in the Italian and UK population: evidence of two independent protective effects

2011 ◽  
Vol 48 (7) ◽  
pp. 485-492 ◽  
Author(s):  
L. Bergamaschi ◽  
M. Ban ◽  
N. Barizzone ◽  
M. Leone ◽  
D. Ferrante ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Hla Class I ◽  
Class I ◽  
Protective Effects

scholarly journals ApoE alleles, depression and positive affect in multiple sclerosis

2009 ◽  
Vol 15 (3) ◽  
pp. 311-315 ◽  
Author(s):  
LJ Julian ◽  
L Vella ◽  
D Frankel ◽  
SL Minden ◽  
JR Oksenberg ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Depressive Symptoms ◽  
Positive Affect ◽  
Depressive Disorders ◽  
Statistical Significance ◽  
Protective Effects ◽  
Apoe Ε4 ◽  
Depression Status ◽  
Apoe Genotypes

Background The role of apolipoprotein E (ApoE) alleles has received recent attention in depressive disorders, the ApoE ε4 conferring greater risk for poorer outcomes, and the ApoE ε2 allele providing some protective effects. Depression is common in multiple sclerosis (MS) and the role of ApoE alleles is unknown. Aims To evaluate ApoE alleles in relation to symptoms of depression in a cohort of patients with MS participating in the Sonya Slifka Longitudinal Multiple Sclerosis Study (Slifka Study). To examine risk and protection, depressed mood and positive affect were each investigated with respect to the ApoE ε4 and ApoE ε2 alleles, respectively. Results Of the total 101 participants, 22.8% were ApoE ε2 carriers and 21.8% were ApoE ε4 carriers. Hierarchical linear regression analyses suggested that after controlling for demographics, disease duration, and disability, ApoE ε2 significantly predicted increased positive affect (R2Δ = 0.05, F(1,94) = 5.44, P = 0.02) and was associated with decreased severity of depressive symptoms, although this did not reach statistical significance (R2Δ = 0.03, F(1,94) = 3.44, P = 0.06). ApoE ε4 did not significantly predict depression status. Conclusion The presence of the ApoE ε2 allele in this study is suggested to be protective against depressive symptoms in our subsample of patients recruited from the Slifka Study. These findings are consistent with reports in psychiatric populations linking ApoE ε2 with decreased incidence of depressive disorders. Further investigation would be warranted to understand the role of ApoE genotypes and risk for depressive symptoms.

scholarly journals Genetic Associations between Delusional Disorder and Paranoid Schizophrenia: A Novel Etiologic Approach

2006 ◽  
Vol 51 (6) ◽  
pp. 342-349 ◽  
Author(s):  
Monojit Debnath ◽  
Sujit K Das ◽  
Nirmal K Bera ◽  
Chitta R Nayak ◽  
Tapas K Chaudhuri
Keyword(s):  
Paranoid Schizophrenia ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Delusional Disorder ◽  
Genetic Associations ◽  
Typing Method ◽  
Leukocyte Antigen ◽  
Hla Genes ◽  
Molecular Typing Method ◽  
Nested Case Control

Objectives: Genetic associations between delusional disorder and paranoid schizophrenia are not well understood, although involvement of biological factors has been suspected. We investigated the incidence of human leukocyte antigen (HLA) class I alleles in patients with delusional disorder and paranoid schizophrenia, first, to explore a possible immunogenetic etiology of these paranoid disorders and, second, to determine whether they share similar etiologic mechanisms. Method: We employed a nested case–control study design. Psychiatric reference data were available for 38500 patients attending a hospital-based psychiatric outpatient department between 1998 and 2005. We enrolled 100 patients with delusional disorder and 50 patients with paranoid schizophrenia as the subject cases, using DSM-IV criteria. We considered equivalent numbers of healthy volunteers matched for age and ethnic background as control subjects. All subjects came from an India-born Bengali population. We applied the polymerase chain reaction–based molecular typing method to all patients and healthy subjects. Results: The HLA-A*03 gene is significantly associated with delusional disorder as well as with paranoid schizophrenia. This HLA gene alone or in linkage disequilibrium with other HLA genes or other closely linked non-HLA genes may influence susceptibility to delusional disorder and paranoid schizophrenia. Conclusions: The study reveals important associations between HLA genes and paranoid disorders. Delusional disorder and paranoid schizophrenia may share similar etiologic mechanisms. This preliminary observation may help our understanding of the genetic basis of these paranoid disorders.

Effects of High Intensity Statin Therapy in the Treatment of Diabetic Dyslipidemia in Patients with Coronary Artery Disease

2018 ◽  
Vol 24 (4) ◽  
pp. 427-441 ◽  
Author(s):  
Marija Vavlukis ◽  
Sasko Kedev
Keyword(s):  
Statin Therapy ◽  
High Intensity ◽  
Statistical Significance ◽  
Incident Diabetes ◽  
Moderate Intensity ◽  
Protective Effects ◽  
Pcsk9 Inhibitors ◽  
Diabetic Dyslipidemia ◽  
Patients With Diabetes

Background: Diabetic dyslipidemia has specifics that differ from dyslipidemia in patients without diabetes, which contributes to accelerated atherosclerosis equally as dysglycemia. The aim of this study was to deduce the interdependence of diabetic dyslipidemia and cardiovascular diseases (CVD), therapeutic strategies and the risk of diabetes development with statin therapy. Method: We conducted a literature review of English articles through PubMed, PubMed Central and Cochrane, on the role of diabetic dyslipidemia in atherosclerosis, the antilipemic treatment with statins, and the role of statin therapy in newly developed diabetes, by using key words: atherosclerosis, diabetes mellitus, diabetic dyslipidemia, CVD, statins, nicotinic acid, fibrates, PCSK9 inhibitors. Results: hyperglycemia and dyslipidemia cannot be treated separately in patients with diabetes. It seems that dyslipidemia plays one of the key roles in the development of atherosclerosis. High levels of TG, decreased levels of HDL-C and increased levels of small dense LDL- C particles in the systemic circulation are the most specific attributes of diabetic dyslipidemia, all of which originate from an inflated flux of free fatty acids occurring due to the preceding resistance to insulin, and exacerbated by elevated levels of inflammatory adipokines. Statins are a fundamental treatment for diabetic dyslipidemia, both for dyslipidemia and for CVD prevention. The use of statin treatment with high intensity is endorsed for all diabetes-and-CVD patients, while a moderate - intensity treatment can be applied to patients with diabetes, having additional risk factors for CVD. Statins alone are thought to possess a small, although of statistical significance, risk of incident diabetes, outweighed by their benefits. Conclusion: As important as hyperglycemia and glycoregulation are in CVD development in patients with diabetes, diabetic dyslipidemia plays an even more important role. Statins remain the cornerstone of antilipemic treatment in diabetic dyslipidemia, and their protective effects in CVD progression overcome the risk of statin- associated incident diabetes.

scholarly journals Family history of early onset acute lymphoblastic leukemia is suggesting genetic associations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xinjun Li ◽  
Kristina Sundquist ◽  
Jan Sundquist ◽  
Asta Försti ◽  
Kari Hemminki
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Age Groups ◽  
Age Group ◽  
Genetic Associations ◽  
Sequencing Data ◽  
Cancer Data ◽  
Group 5 ◽  
Prostate Cancers

AbstractChildhood acute lymphoblastic leukemia (ALL) has an origin in the fetal period which may distinguish it from ALL diagnosed later in life. We wanted to test whether familial risks differ in ALL diagnosed in the very early childhood from ALL diagnosed later. The Swedish nation-wide family-cancer data were used until year 2016 to calculate standardized incidence ratios (SIRs) for familial risks in ALL in three diagnostic age-groups: 0–4, 5–34 and 35 + years. Among 1335 ALL patients diagnosed before age 5, familial risks were increased for esophageal (4.78), breast (1.42), prostate (1.40) and connective tissue (2.97) cancers and leukemia (2.51, ALL 7.81). In age-group 5–34 years, rectal (1.73) and endometrial (2.40) cancer, myeloma (2.25) and leukemia (2.00, ALL 4.60) reached statistical significance. In the oldest age-group, the only association was with Hodgkin lymphoma (3.42). Diagnostic ages of family members of ALL patients were significantly lower compared to these cancers in the population for breast, prostate and rectal cancers. The patterns of increased familial cancers suggest that BRCA2 mutations could contribute to associations of ALL with breast and prostate cancers, and mismatch gene PMS2 mutations with rectal and endometrial cancers. Future DNA sequencing data will be a test for these familial predictions.

Abstract 119: Protective Effects of Chloroquine on Ischemic and Nutrient Depleted Muscle are Mediated by HMGB1 and Caspase-1

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Ulka Sachdev ◽  
Xiangdong Cui ◽  
Qian Sun ◽  
Edith Tzeng ◽  
Alex Chen ◽  
...  
Keyword(s):  
Culture Media ◽  
Statistical Significance ◽  
High Mobility ◽  
Maximal Activity ◽  
Arterial Disease ◽  
Protective Effects ◽  
Artery Ligation ◽  
Beneficial Effects ◽  
Caspase 1 ◽  
Ldh Activity

Introduction: Millions of Americans are at risk for amputation from severe peripheral arterial disease (PAD) when surgery is not possible. Pro-regenerative and angiogenic agents may improve outcome in that setting. Chloroquine (CQ) promotes wound healing in scleroderma but has not been tested in PAD. CQ promotes healing of ischemic muscle, increases muscle high mobility group box 1 (HMGB1), an inflammatory, pro-angiogenic protein, and activates caspase-1 in myoblasts. We hypothesize that HMGB1 mediates protective effects of CQ and is regulated by caspase-1 in muscle. Controlled rather than indiscriminate release of HMGB1 from damaged muscle may be protective during ischemia. Methods: C2C12 myoblasts in low serum were treated with CQ (0-50μM) ± Ac-YVAD-cmk (10 μg/ml), a caspase-1 inhibitor. HMGB1 release in supernatants was measured using ELISA. Cytotoxicity was assessed by comparing spontaneous lactate dehydrogenase (LDH) activity in culture media from control, treated and maximally lysed cells. CQ (50μg/ml) or placebo treated wild-type and inducible HMGB1 knockout (iHMGB1KO) mice underwent unilateral femoral artery ligation (FAL). Laser Doppler perfusion imaging (LDPI) before and 1,7,14 and 21d after FAL was reported as % improvement over time. ANOVA was used to assess statistical significance among groups. Results: CQ (5-10uM) attenuated spontaneous LDH leak after 12h from serum-depleted myoblasts (p <0.01, N=3), and modestly increased HMGB1 release (p <0.001, N=3). Ac-YVAD-cmk reversed the cytoprotective effects of CQ, significantly raising both LDH activity to 55% of maximal activity and HMGB1 in the supernatant. Compared to d1 post FAL, CQ improved perfusion recovery in WT mice by 300-800% over 21 days (p<0.03, N=7/group), but not in iHMGB1KO mice. Conclusion: We present the novel finding that in nutrient-depleted myoblasts, caspase-1 mediates the survival benefits of CQ and regulates HMGB1 release. In turn, HMGB1 is critical for CQ’s beneficial effects on perfusion after FAL, another stress condition. Regulated HMGB1 release may be immunomodulatory, regenerative and modifiable with drugs like CQ. Altering survival and inflammatory pathways through CQ may present a novel therapeutic strategy in PAD.

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