The major histocompatibility complex (MHC) class I chain-related A (
) is the most polymorphic non-classical MHC class I gene in humans. It encodes a ligand for NKG2D (NK group 2, member D), an ...activating natural killer (NK) receptor that is expressed mainly on NK cells and CD8
T cells. The single-nucleotide polymorphism (SNP) rs1051792 causing a valine (Val) to methionine (Met) exchange at position 129 of the MICA protein is of specific interest. It separates MICA into isoforms that bind NKG2D with high (Met) and low affinities (Val). Therefore, this SNP has been investigated for associations with infections, autoimmune diseases, and cancer. Here, we systematically review these studies and analyze them in view of new data on the functional consequences of this polymorphism. It has been shown recently that the MICA-129Met variant elicits a stronger NKG2D signaling, resulting in more degranulation and IFN-γ production in NK cells and in a faster costimulation of CD8
T cells than the MICA-129Val variant. However, the MICA-129Met isoform also downregulates NKG2D more efficiently than the MICA-129Val isoform. This downregulation impairs NKG2D-mediated functions at high expression intensities of the MICA-Met variant. These features of the MICA-129Met/Val dimorphism need to be considered when interpreting disease association studies. Particularly, in the field of hematopoietic stem cell transplantation, they help to explain the associations of the SNP with outcome including graft-versus-host disease and relapse of malignancy. Implications for future disease association studies of the MICA-129Met/Val dimorphism are discussed.
Abstract
Background
ImputAccur
is a software tool to measure genotype-imputation accuracy. Imputation of untyped markers is a standard approach in genome-wide association studies to close the gap ...between directly genotyped and other known DNA variants. However, high accuracy for imputed genotypes is fundamental. Several accuracy measures have been proposed, but unfortunately, they are implemented on different platforms, which is impractical.
Results
With
ImputAccur,
the accuracy measures
info, Iam-hiQ
and
r
2
-based
indices can be derived from standard output files of imputation software. Sample/probe and marker filtering is possible. This allows e.g. accurate marker filtering ahead of data analysis.
Conclusions
The source code (Python version 3.9.4), a standalone executive file, and example data for
ImputAccur
are freely available at
https://gitlab.gwdg.de/kolja.thormann1/imputationquality.git
.
The stress-inducible heat shock protein (HSP) 70 is known to function as an endogenous danger signal that can increase the immunogenicity of tumors and induce CTL responses. We show in this study ...that HSP70 also activates mouse NK cells that recognize stress-inducible NKG2D ligands on tumor cells. Tumor size and the rate of metastases derived from HSP70-overexpressing human melanoma cells were found to be reduced in T and B cell-deficient SCID mice, but not in SCID/beige mice that lack additionally functional NK cells. In the SCID mice with HSP70-overexpressing tumors, NK cells were activated so that they killed ex vivo tumor cells that expressed NKG2D ligands. In the tumors, the MHC class I chain-related (MIC) A and B molecules were found to be expressed. Interestingly, a counter selection was observed against the expression of MICA/B in HSP70-overexpressing tumors compared with control tumors in SCID, but not in SCID/beige mice, suggesting a functional relevance of MICA/B expression. The melanoma cells were found to release exosomes. HSP70-positive exosomes from the HSP70-overexpressing cells, in contrast to HSP70-negative exosomes from the control cells, were able to activate mouse NK cells in vitro to kill YAC-1 cells, which express NKG2D ligands constitutively, or the human melanoma cells, in which MICA/B expression was induced. Thus, HSP70 and inducible NKG2D ligands synergistically promote the activation of mouse NK cells resulting in a reduced tumor growth and suppression of metastatic disease.
Data on genomic susceptibility for adverse outcomes after hematopoietic stem cell transplantation (HSCT) for recipients are scarce.
We performed a genome wide association study (GWAS) to identify ...genes associated with survival/mortality, relapse, and severe graft-versus-host disease (sGvHD), fitting proportional hazard and subdistributional models to data of n=1,392 recipients of European ancestry from three centres.
The single nucleotide polymorphism (SNP) rs17154454, intronic to the neuronal growth guidant semaphorin 3C gene (
, was genome-wide significantly associated with event-free survival (p=7.0x10
) and sGvHD (p=7.5x10
). Further associations were detected for SNPs in the Paxillin gene (
death without prior relapse or sGvHD, as well as for SNPs of the Plasmacytoma Variant Translocation 1 gene
, a long non-coding RNA gene
, the Melanocortin 5 Receptor
and the WW Domain Containing Oxidoreductase gene (
, all associated with the occurrence of sGvHD. Functional considerations support the observed associations.
Thus, new genes were identified, potentially influencing the outcome of HSCT.
Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise ...due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate odds ratio (OR) = 2.78 is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.
Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes ...in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV
: r
= 0.098, p = 2.3 × 10
) and the ratio of FEV
to forced vital capacity (FEV
/FVC: r
= 0.137, p = 2.0 × 10
). Mendelian randomization analyses demonstrate that reduced FEV
increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV
/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.
Abstract Background Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high ...accuracy with which genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately diversely across platforms. In the present paper, we introduce Iam hiQ, an independent pair of accuracy measures that can be applied to dosage files, the output of all imputation software. Iam (imputation accuracy measure) quantifies the average amount of individual-specific versus population-specific genotype information in a linear manner. hiQ (heterogeneity in quantities of dosages) addresses the inter-individual heterogeneity between dosages of a marker across the sample at hand. Results Applying both measures to a large case–control sample of the International Lung Cancer Consortium (ILCCO), comprising 27,065 individuals, we found meaningful thresholds for Iam and hiQ suitable to classify markers of poor accuracy. We demonstrate how Manhattan-like plots and moving averages of Iam and hiQ can be useful to identify regions enriched with less accurate imputed markers, whereas these regions would by missed when applying the accuracy measure info (implemented in IMPUTE2). Conclusion We recommend using Iam hiQ additional to other accuracy scores for variant filtering before stepping into the analysis of imputed GWAS data.
Matrix metalloproteinases (MMP) play a key role in the breakdown of extracellular matrix and in inflammatory processes. MMP1 is the most highly expressed interstitial collagenase degrading fibrillar ...collagens. Overexpression of MMP1 has been shown in tumor tissues and has been suggested to be associated with tumor invasion and metastasis. Nine haplotype tagging and additional two intronic single nucleotide polymorphisms (SNP) of MMP1 were genotyped in a case control sample, consisting of 635 lung cancer cases with onset of disease below 51 years of age and 1,300 age- and sex-matched cancer-free controls. Two regions of linkage disequilibrium (LD) of MMP1 could be observed: a region of low LD comprising the 5' region including the promoter and a region of high LD starting from exon 1 to the end of the gene and including the 3' flanking region. Several SNPs were identified to be individually significantly associated with risk of early-onset lung cancer. The most significant effect was seen for rs1938901 (P = 0.0089), rs193008 (P = 0.0108), and rs996999 (P = 0.0459). For rs996999, significance vanished after correction for multiple testing. For each of these SNPs, the major allele was associated with an increase in risk with an odds ratio between 1.2 and 1.3 (95% confidence interval, 1.0-1.5). The haplotype analysis supported these findings, especially for subgroups with high smoking intensity. In summary, we identified MMP1 to be associated with an increased risk for lung cancer, which was modified by smoking.
Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy with which ...genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately diversely across platforms. In the present paper, we introduce Iam hiQ, an independent pair of accuracy measures that can be applied to dosage files, the output of all imputation software. Iam (imputation accuracy measure) quantifies the average amount of individual-specific versus population-specific genotype information in a linear manner. hiQ (heterogeneity in quantities of dosages) addresses the inter-individual heterogeneity between dosages of a marker across the sample at hand.
Applying both measures to a large case-control sample of the International Lung Cancer Consortium (ILCCO), comprising 27,065 individuals, we found meaningful thresholds for Iam and hiQ suitable to classify markers of poor accuracy. We demonstrate how Manhattan-like plots and moving averages of Iam and hiQ can be useful to identify regions enriched with less accurate imputed markers, whereas these regions would by missed when applying the accuracy measure info (implemented in IMPUTE2).
We recommend using Iam hiQ additional to other accuracy scores for variant filtering before stepping into the analysis of imputed GWAS data.
•We studied a case-control sample and a family sample of young lung cancer patients.•We measured DNA damage and repair after in vitro irradiation of blood cells in 1144 individuals.•After quality ...control we correlated the functional data with 52 SNPs of 9 pre-selected DNA repair genes.•We found associations with SNPs of XRCC1, MSH2, RAD50, XRCC4, MRE11 and ATM.•We demonstrate a measurable impact of gene variation on DNA damage and repair.
Cancer risk and radiation sensitivity are often associated with alterations in DNA repair, cell cycle, or apoptotic pathways. Interindividual variability in mutagen or radiation sensitivity and in cancer susceptibility may also be traced back to polymorphisms of genes affecting e.g. DNA repair capacity. We studied possible associations between 70 polymorphisms of 12 DNA repair genes with basal and initial DNA damage and with repair thereof. We investigated DNA damage induced by ionizing radiation in lymphocytes isolated from 177 young lung cancer patients and 169 cancer-free controls. We also sought replication of our findings in an independent sample of 175 families (in total 798 individuals). DNA damage was assessed by the Olive tail moment (OTM) of the comet assay. DNA repair capacity (DRC) was determined for 10, 30 and, 60min of repair.
Genes involved in the single-strand-repair pathway (SSR; like XRCC1 and MSH2) as well as genes involved in the double-strand-repair pathway (DSR; like RAD50, XRCC4, MRE11 and ATM) were found to be associated with DNA damage. The most significant association was observed for marker rs3213334 (p=0.005) of XRCC1 with basal DNA damage (B), in both cases and controls. A clear additive effect on the logarithm of OTM was identified for the marker rs1001581 of the same LD-block (p=0.039): BCC=−1.06 (95%-CI: −1.16 to −0.96), BCT=−1.02 (95%-CI: −1.11 to −0.93) and BTT=−0.85 (95%-CI: −1.01 to −0.68). In both cases and controls, we observed significantly higher DNA basal damage (p=0.007) for carriers of the genotype AA of marker rs2237060 of RAD50 (involved in DSR). However, this could not be replicated in the sample of families (p=0.781). An alteration to DRC after 30min of repair with respect to cases was observed as borderline significant for marker rs611646 of ATM (involved in DSR; p=0.055), but was the most significant finding in the sample of families (p=0.009).
Our data indicate that gene variation impacts measurably on DNA damage and repair, suggesting at least a partial contribution to radiation sensitivity and lung cancer susceptibility.