Thiopurine pharmacogenomics: association of SNPs with clinical response and functional validation of candidate genes

Aim: We investigated candidate genes associated with thiopurine metabolism and clinical response in childhood acute lymphoblastic leukemia. Materials & methods: We performed genome-wide SNP association studies of 6-thioguanine and 6-mercaptopurine cytotoxicity using lymphoblastoid cell lines. We then genotyped the top SNPs associated with lymphoblastoid cell line cytotoxicity, together with tagSNPs for genes in the ‘thiopurine pathway’ (686 total SNPs), in DNA from 589 Caucasian UK ALL97 patients. Functional validation studies were performed by siRNA knockdown in cancer cell lines. Results: SNPs in the thiopurine pathway genes ABCC4, ABCC5, IMPDH1, ITPA, SLC28A3 and XDH, and SNPs located within or near ATP6AP2, FRMD4B, GNG2, KCNMA1 and NME1, were associated with clinical response and measures of thiopurine metabolism. Functional validation showed shifts in cytotoxicity for these genes. Conclusion: The clinical response to thiopurines may be regulated by variation in known thiopurine pathway genes and additional novel genes outside of the thiopurine pathway

Cancer incidence in type 2 diabetes patients - first results from a feasibility study of the D2C cohort

<p>Abstract</p> <p>Background</p> <p>A large prospective study in patients with type 2 diabetes (T2D), the German D2C cohort, is presently being enumerated to investigate risk factors of incident cancer in diabetic patients.</p> <p>Study setting</p> <p>A disease management program was offered, on a voluntary basis, to all T2D patients who were members of a statutory health insurance fund in Germany. This first feasibility report uses data from 26.742 T2D patients, who were 40 to 79 years old, resided in the Muenster District, and who were enrolled between June 2003 and July 2008. Cancer cases were identified through the regional Cancer Registry.</p> <p>Methods</p> <p>Invasive cancer cases were identified using probabilistic record linkage procedures and pseudonymised personal identifiers. Censoring date was December 31, 2008. We included only first cancers, leaving 12.650 male and 14.092 female T2D with a total of 88.778 person-years (py). We computed standardised incidence ratios (SIR) for external comparisons and we employed Cox regression models and hazard ratios (HR) within the cohort.</p> <p>Results</p> <p>We identified 759 first cancers among male T2D patients (18.7 per 1,000 py) and 605 among females (12.7 per 1,000 py). The risk of any incident cancer in T2D was raised (SIR = 1.14; 95% confidence interval [1.10 - 1.21]), in particular for cancer of the liver (SIR = 1.94 [1.15 - 2.94]) and pancreas (SIR = 1.45 [1.07-1.92]). SIRs decreased markedly with time after T2D diagnosis. In Cox models, adjusting for diabetes duration, body mass index and sex, insulin therapy was related to higher cancer risk (HR = 1.25 [1.17 - 1.33]). No effect was seen for metformin.</p> <p>Discussion</p> <p>Our study demonstrates feasibility of record linkage between DMP and cancer registries. These first cohort results confirm previous reports. It is envisaged to enhance this cohort by inclusion of further regions of the state, expansion of the follow-up times, and collection of a more detailed medication history.</p

Long-term outcome and patterns of failure in patients with advanced head and neck cancer

<p>Abstract</p> <p>Purpose</p> <p>To access the long-time outcome and patterns of failure in patients with advanced head and neck squamous cell carcinoma (HNSCC).</p> <p>Methods and materials</p> <p>Between 1992 and 2005 127 patients (median age 55 years, UICC stage III n = 6, stage IV n = 121) with primarily inoperable, advanced HNSCC were treated with definite platinum-based radiochemotherapy (median dose 66.4 Gy). Analysed end-points were overall survival (OS), disease-free survival (DFS), loco-regional progression-free survival (LPFS), development of distant metastases (DM), prognostic factors and causes of death.</p> <p>Results</p> <p>The mean follow-up time was 34 months (range, 3-156 months), the 3-, 5- and 10-year OS rates were 39%, 28% and 14%, respectively. The median OS was 23 months. Forty-seven patients achieved a complete remission and 78 patients a partial remission. The median LPFS was 17 months, the 3-, 5- and 10-year LPFS rates were 41%, 33% and 30%, respectively. The LPFS was dependent on the nodal stage (p = 0.029). The median DFS was 11 months (range, 2-156 months), the 3-, 5- and 10-year DFS rates were 30%, 24% and 22%, respectively. Prognostic factors in univariate analyses were alcohol abuse (n = 102, p = 0.015), complete remission (n = 47, p < 0.001), local recurrence (n = 71, p < 0.001), development of DM (n = 45, p < 0.001; median OS 16 months) and borderline significance in nodal stage N2 versus N3 (p = 0.06). Median OS was 26 months with lung metastases (n = 17). Nodal stage was a predictive factor for the development of DM (p = 0.025). Cause of death was most commonly tumor progression.</p> <p>Conclusions</p> <p>In stage IV HNSCC long-term survival is rare and DM is a significant predictor for mortality. If patients developed DM, lung metastases had the most favourable prognosis, so intensified palliative treatment might be justified in DM limited to the lungs.</p

Genetic Association Studies of Copy-Number Variation: Should Assignment of Copy Number States Precede Testing?

Recently, structural variation in the genome has been implicated in many complex diseases. Using genomewide single nucleotide polymorphism (SNP) arrays, researchers are able to investigate the impact not only of SNP variation, but also of copy-number variants (CNVs) on the phenotype. The most common analytic approach involves estimating, at the level of the individual genome, the underlying number of copies present at each location. Once this is completed, tests are performed to determine the association between copy number state and phenotype. An alternative approach is to carry out association testing first, between phenotype and raw intensities from the SNP array at the level of the individual marker, and then aggregate neighboring test results to identify CNVs associated with the phenotype. Here, we explore the strengths and weaknesses of these two approaches using both simulations and real data from a pharmacogenomic study of the chemotherapeutic agent gemcitabine. Our results indicate that pooled marker-level testing is capable of offering a dramatic increase in power (-fold) over CNV-level testing, particularly for small CNVs. However, CNV-level testing is superior when CNVs are large and rare; understanding these tradeoffs is an important consideration in conducting association studies of structural variation

Association of the polygenic scores for personality traits and response to selective serotonin reuptake inhibitors in patients with major depressive disorder

Studies reported a strong genetic correlation between the Big Five personality traits and major depressive disorder (MDD). Moreover, personality traits are thought to be associated with response to antidepressants treatment that might partly be mediated by genetic factors. In this study, we examined whether polygenic scores (PGSs) derived from the Big Five personality traits predict treatment response and remission in patients with MDD who were prescribed selective serotonin reuptake inhibitors (SSRIs). In addition, we performed meta-analyses of genome-wide association studies (GWASs) on these traits to identify genetic variants underpinning the cross-trait polygenic association. The PGS analysis was performed using data from two cohorts: the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS, n = 529) and the International SSRI Pharmacogenomics Consortium (ISPC, n = 865). The cross-trait GWAS meta-analyses were conducted by combining GWAS summary statistics on SSRIs treatment outcome and on the personality traits. The results showed that the PGS for openness and neuroticism were associated with SSRIs treatment outcomes at p < 0.05 across PT thresholds in both cohorts. A significant association was also found between the PGS for conscientiousness and SSRIs treatment response in the PGRN-AMPS sample. In the cross-trait GWAS meta-analyses, we identified eight loci associated with (a) SSRIs response and conscientiousness near YEATS4 gene and (b) SSRI remission and neuroticism eight loci near PRAG1, MSRA, XKR6, ELAVL2, PLXNC1, PLEKHM1, and BRUNOL4 genes. An assessment of a polygenic load for personality traits may assist in conjunction with clinical data to predict whether MDD patients might respond favorably to SSRIs.Azmeraw T. Amare, Klaus Oliver Schubert, Fasil Tekola-Ayele, Yi-Hsiang Hsu, Katrin Sangkuhl … Bernhard T. Baune … et al

Multi-ancestry meta-analysis of tobacco use disorder prioritizes novel candidate risk genes and reveals associations with numerous health outcomes

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviors, and although strides have been made using genome-wide association studies (GWAS) to identify risk variants, the majority of variants identified have been for nicotine consumption, rather than TUD. We leveraged five biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records, EHR) in 898,680 individuals (739,895 European, 114,420 African American, 44,365 Latin American). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviors in children, and hundreds of medical outcomes, including HIV infection, heart disease, and pain. This work furthers our biological understanding of TUD and establishes EHR as a source of phenotypic information for studying the genetics of TUD

The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response

Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P=5.03E-08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P=1.20E-06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.JM Biernacka … BT Baune et. al

New Constraint on the Local Relic Neutrino Background Overdensity with the First KATRIN Data Runs

We report on the direct search for cosmic relic neutrinos using data acquired during the first two science campaigns of the KATRIN experiment in 2019. Beta-decay electrons from a high-purity molecular tritium gas source are analyzed by a high-resolution MAC-E filter around the end point at 18.57 keV. The analysis is sensitive to a local relic neutrino overdensity ratio of η < 9.7 × 10$^{10}$/α (1.1 × 10$^{11}$/α) at a 90% (95%) confidence level with α = 1 (0.5) for Majorana (Dirac) neutrinos. A fit of the integrated electron spectrum over a narrow interval around the end point accounting for relic neutrino captures in the tritium source reveals no significant overdensity. This work improves the results obtained by the previous neutrino mass experiments at Los Alamos and Troitsk. We furthermore update the projected final sensitivity of the KATRIN experiment to η < 1×10$^{10}$/α at 90% confidence level, by relying on updated operational conditions

Improved eV-scale sterile-neutrino constraints from the second KATRIN measurement campaign

We present the results of the light sterile neutrino search from the second Karlsruhe Tritium Neutrino (KATRIN) measurement campaign in 2019. Approaching nominal activity, 3.76×106 tritium β-electrons are analyzed in an energy window extending down to 40 eV below the tritium end point at E0=18.57  keV. We consider the 3ν+1 framework with three active and one sterile neutrino flavors. The analysis is sensitive to a fourth mass eigenstate m24≲1600  eV2 and active-to-sterile mixing |Ue4|2≳6×10−3. As no sterile-neutrino signal was observed, we provide improved exclusion contours on m24 and |Ue4|2 at 95% C.L. Our results supersede the limits from the Mainz and Troitsk experiments. Furthermore, we are able to exclude the large Δm241 solutions of the reactor antineutrino and gallium anomalies to a great extent. The latter has recently been reaffirmed by the BEST Collaboration and could be explained by a sterile neutrino with large mixing. While the remaining solutions at small Δm241 are mostly excluded by short-baseline reactor experiments, KATRIN is the only ongoing laboratory experiment to be sensitive to relevant solutions at large Δm241 through a robust spectral shape analysis

New Constraint on the Local Relic Neutrino Background Overdensity with the First KATRIN Data Runs

We report on the direct cosmic relic neutrino background search from the first two science runs of the KATRIN experiment in 2019. Beta-decay electrons from a high-purity molecular tritium gas source are analyzed by a high-resolution MAC-E filter around the kinematic endpoint at 18.57 keV. The analysis is sensitive to a local relic neutrino overdensity of 9.7e10 (1.1e11) at a 90% (95%) confidence level. A fit of the integrated electron spectrum over a narrow interval around the kinematic endpoint accounting for relic neutrino captures in the Tritium source reveals no significant overdensity. This work improves the results obtained by the previous kinematic neutrino mass experiments at Los Alamos and Troitsk. We furthermore update the projected final sensitivity of the KATRIN experiment to <1e10 at 90% confidence level, by relying on updated operational conditions.Comment: 7 pages, 7 figure