scholarly journals Neolithic genomes reveal a distinct ancient HLA allele pool and population transformation in Europe

2019 ◽  
Author(s):  
Alexander Immel ◽  
Christoph Rinne ◽  
John Meadows ◽  
Rodrigo Barquera ◽  
András Szolek ◽  
...  
Keyword(s):  
Western Europe ◽  
Viral Infections ◽  
Human Leukocyte ◽  
Neolithic Period ◽  
Late Neolithic ◽  
Leukocyte Antigen ◽  
Cultural Transformations ◽  
Farming Community ◽  
Genome Wide ◽  
A Genome

AbstractThe Wartberg culture (WBC, 3,500-2,800 BCE) dates to the Late Neolithic period, a time of important demographic and cultural transformations in western Europe. We perform a genome-wide analysis of 42 individuals who were interred in a WBC collective burial in Niedertiefenbach, Germany (3,300-3,200 cal. BCE). Our results highlight that the Niedertiefenbach population indeed emerged at the beginning of the WBC. This farming community was genetically heterogeneous and carried a surprisingly large hunter-gatherer ancestry component (40%). We detect considerable differences in the human leukocyte antigen gene pool between contemporary Europeans and the Niedertiefenbach individuals whose immune response was primarily geared towards defending viral infections.

scholarly journals Genome-wide study of a Neolithic Wartberg grave community reveals distinct HLA variation and hunter-gatherer ancestry

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Alexander Immel ◽  
Federica Pierini ◽  
Christoph Rinne ◽  
John Meadows ◽  
Rodrigo Barquera ◽  
...  
Keyword(s):  
Western Europe ◽  
Viral Infections ◽  
Human Leukocyte ◽  
Cultural Transformation ◽  
Neolithic Period ◽  
Late Neolithic ◽  
Leukocyte Antigen ◽  
Cultural Transformations ◽  
Genome Wide ◽  
Genome Wide Study

AbstractThe Wartberg culture (WBC, 3500-2800 BCE) dates to the Late Neolithic period, a time of important demographic and cultural transformations in western Europe. We performed genome-wide analyses of 42 individuals who were interred in a WBC collective burial in Niedertiefenbach, Germany (3300-3200 cal. BCE). The results showed that the farming population of Niedertiefenbach carried a surprisingly large hunter-gatherer ancestry component (34–58%). This component was most likely introduced during the cultural transformation that led to the WBC. In addition, the Niedertiefenbach individuals exhibited a distinct human leukocyte antigen gene pool, possibly reflecting an immune response that was geared towards detecting viral infections.

scholarly journals An updated view of the pathogenesis of steroid-sensitive nephrotic syndrome

2022 ◽  
Author(s):  
Tomoko Horinouchi ◽  
Kandai Nozu ◽  
Kazumoto Iijima
Keyword(s):  
Nephrotic Syndrome ◽  
Genome Wide Association Study ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Genome Wide ◽  
A Genome ◽  
Immunological Mechanisms ◽  
Steroid Sensitive Nephrotic Syndrome ◽  
Steroid Sensitive ◽  
Genetic Techniques

Abstract Idiopathic nephrotic syndrome is the most common childhood glomerular disease. Most forms of this syndrome respond to corticosteroids at standard doses and are, therefore, defined as steroid-sensitive nephrotic syndrome (SSNS). Immunological mechanisms and subsequent podocyte disorders play a pivotal role in SSNS and have been studied for years; however, the precise pathogenesis remains unclear. With recent advances in genetic techniques, an exhaustive hypothesis-free approach called a genome-wide association study (GWAS) has been conducted in various populations. GWASs in pediatric SSNS peaked in the human leukocyte antigen class II region in various populations. Additionally, an association of immune-related CALHM6/FAM26F, PARM1, BTNL2, and TNFSF15 genes, as well as NPHS1, which encodes nephrin expressed in podocytes, has been identified as a locus that achieves genome-wide significance in pediatric SSNS. However, the specific mechanism of SSNS development requires elucidation. This review describes an updated view of SSNS pathogenesis from immunological and genetic aspects, including interactions with infections or allergies, production of circulating factors, and an autoantibody hypothesis.

scholarly journals Protective effects of HLA-DRB1*04 subtypes in Parkinson's and Alzheimer's diseases implicate acetylated Tau PHF6 sequences

2021 ◽  
Author(s):  
Yann Le Guen ◽  
Guo Luo ◽  
Aditya Ambati ◽  
Vincent Damotte ◽  
Iris Jansen ◽  
...  
Keyword(s):  
Adaptive Immune Response ◽  
Human Leukocyte ◽  
Postmortem Brain ◽  
Neuritic Plaque ◽  
Protective Effects ◽  
Hla Association ◽  
Leukocyte Antigen ◽  
Genome Wide ◽  
Association Data ◽  
Lateral Sclerosis

Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's (PD) or Alzheimer's (AD) disease versus controls across ancestry groups. A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10-13; AD: OR=0.91[0.89; 0.93]; p=1.8x10-22), and with a protective HLA association recently reported in amyotrophic lateral sclerosis (ALS). Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03, and absent for HLA-DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brain and was more strongly associated with Tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA-DRB1*04 subtypes strongly bound aggregation-prone Tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. A HLA-DRB1*04-mediated adaptive immune response, potentially against Tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.

scholarly journals Association Between Human Leukocyte Antigen Class I and II Diversity and Non-virus-associated Solid Tumors

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhiwei Liu ◽  
Allan Hildesheim
Keyword(s):  
Human Leukocyte Antigen ◽  
Solid Tumors ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Class I ◽  
European Ancestry ◽  
Leukocyte Antigen ◽  
Genome Wide

Homozygosity at human leukocyte antigen (HLA) loci might lead to reduced immunosurveillance and increased disease risk, including cancers caused by infection or of hematopoietic origin. To investigate the association between HLA zygosity and risk of non-virus-associated solid tumors, we leveraged genome-wide association study (GWAS) data from over 28,000 individuals of European ancestry who participated in studies of 12 cancer sites (bladder, brain, breast, colon, endometrial, kidney, lung, ovary, pancreas, prostate, skin, and testis). Information on HLA zygosity was obtained by imputation; individuals were classified as homozygotes at a given locus when imputed to carry the same four-digit allele at that locus. We observed no evidence for an association between zygosity at six HLA loci and all cancers combined. Increase in number of homozygous at HLA class I loci, class II loci, or class I and II loci was also not associated with cancer overall (Ptrend = 0.28), with adjusted odds ratios (ORs) for risk-per-locus of 1.00 [95% confidence intervals (CIs) = 0.97, 1.03], 1.02 (0.99, 1.04), and 1.01 (0.99, 1.02), respectively. This study does not support a strong role for HLA zygosity on risk of non-virus-associated solid tumors.

scholarly journals Negative trade-off between neoantigen repertoire breadth and the specificity of HLA-I molecules shapes antitumour immunity

2020 ◽  
Author(s):  
Máté Manczinger ◽  
Gergő Balogh ◽  
Benjamin Tamás Papp ◽  
Balázs Koncz ◽  
Leó Asztalos ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Infections ◽  
Peptide Binding ◽  
Human Leukocyte ◽  
Tumour Microenvironment ◽  
Trade Off ◽  
Leukocyte Antigen ◽  
Peptide Binding Specificity ◽  
Worse Prognosis ◽  
Inhibitor Treatment

AbstractThe human leukocyte antigen class I (HLA-I) genes shape our immune response against pathogens and cancer. Certain HLA-I variants can bind a much wider range of peptides than others, a feature that could be favorable against a range of viral diseases. However, the implications of this phenomenon on cancer immune response is unknown. In this paper, we quantified peptide repertoire breadth (or promiscuity) of a representative set of HLA-I alleles, and found that cancer patients that carry HLA-I alleles with high peptide binding promiscuity are characterized by significantly worse prognosis after immune checkpoint inhibitor treatment. This trend can be explained by a reduced capacity of promiscuous HLA-I molecules to discriminate between human self and tumour peptides, yielding a shift in regulation of T-cells in the tumour microenvironment from activation to tolerance. In summary, HLA-I peptide binding specificity shapes neopeptide immunogenicity and the self-immunopeptidome repertoire in an antagonistic manner. It could also underlie a negative trade-off between antitumour immunity and the genetic susceptibility to viral infections.

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