Prognosis of Good syndrome : mortality and morbidity of thymoma associated immunodeficiency in perspective

Good syndrome (GS) or thymoma-associated immunodeficiency, is a rare condition that has only been studied in retrospective case series. General consensus was that GS has a worse prognosis than other humoral immunodeficiencies. In this study, physicians of GS patients completed two questionnaires with a two year interval with data on 47 patients, 499 patient years in total. Results on epidemiology, disease characteristics, and outcome are presented. Mean age at diagnosis was 60 years and median follow-up from onset of symptoms was 9 years. There was a high frequency of respiratory tract infections due to encapsulated bacteria. Median survival was 14 years. Survival was reduced compared to age-matched population controls (5-year survival: 82% versus 95%, p = 0.008). In this cohort survival was not associated with gender (HR 0.9, 95% CI 0.3-3.0), autoimmune diseases (HR 2.9, 95% CI 0.8-10.1) or immunosuppressive use (HR 0.3, 95% CI: 0.1-1.2). (C) 2016 The Authors. Published by Elsevier Inc.Peer reviewe

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

HLA-DRB1*15:01 and multiple sclerosis: a female association?

Background: The association between multiple sclerosis (MS) and the HLA-DRB1*15: 01 haplotype has been proven to be strong, but its molecular basis remains unclear. Vitamin D receptor (VDR) gene variants and sex have been proposed to modulate this association. Objectives: 1) Test the association of MS with *15:01 and VDR variants; 2) check whether VDR variants and/or sex modulate the risk conferred by *15:01; 3) study whether *15:01, VDR variants and/or sex affect HLA II gene expression. Methods: Peripheral blood from 364 MS patients and 513 healthy controls was obtained and DNA and total RNA were extracted from leukocytes. HLA-DRB1, DRB5 and DQA1 gene expression measurements and *15:01 genotyping were performed by qPCR. VDR variants were genotyped by PCR-RFLP. Results: Our data confirms that the *15:01 haplotype confers a higher risk of suffering from MS (OR = 1.364; 95% CI = 1.107-1.681). No association was found between VDR variants and MS, but they were shown to moderately modulate the risk conferred by *15:01. Sex confers a much stronger modulation and the *15:01-MS association seems to be female specific. A higher *15:01 frequency has been observed in Basques (45.1%). *15:01 positive samples showed a significant overexpression of DRB1 (p < 0.001), DRB5 (p < 0.001) and DQA1 (p = 0.004) in patients. DRB1 (p = 0.004) and DRB5 (p < 0.001) were also overexpressed in *15:01 controls. Conclusions: We confirm the *15:01-MS association and support that it is female specific. The relevance of ethnic origin on association studies has also been highlighted. HLA-DRB1*15:01 seems to be a haplotype consistently linked to high HLA II gene expression.This work was supported by the Basque Government (grant numbers BFI09.294 to HI and BFI09.206 to MMC), Rio-Hortega (grant number CM09/00129 to TC), the Ilundain Fundazioa, and Fundación 2000 and FIS (grant number PS09/02105)

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele