Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium.

The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.

Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

Taste receptor polymorphisms and male infertility.

STUDY QUESTION: Are polymorphisms of taste receptor genes associated with male infertility? SUMMARY ANSWER: This study has showed the associations between three single nucleotide polymorphisms (SNPs) in taste receptors genes (TASR) and male infertility. WHAT IS KNOWN ALREADY: Recent studies showed the expression of taste receptors in the testis and in spermatozoa, suggesting their possible role in infertility. The vast genetic variability in taste genes results in a large degree of diversity in various human phenotypes. STUDY DESIGN, SIZE, DURATION: In this study, we genotyped 19 SNPs in 12 taste related genes in a total of 494 Caucasian male patients undergoing semen evaluation at the Centre of Couple Sterility of the Siena University Hospital. Consecutive patients were enrolled during infertility investigations from October 2014 to February 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Median age of the patients was 36 years (18-58) and 141 were smokers. Genotyping was performed using the allele-specific PCR. The statistical analysis was carried out using generalized linear model (GLM) to explore the association between age, smoking, the genetic polymorphisms and sperm parameters. MAIN RESULTS AND THE ROLE OF CHANCE: We observed that the homozygous carriers of the (G) allele of the TAS2R14-rs3741843 polymorphism showed a decreased sperm progressive motility compared to heterozygotes and (A) homozygotes (P = 0.003). Moreover, the homozygous carriers of the (T) allele of the TAS2R3-rs11763979 SNP showed fewer normal acrosome compared with the heterozygous and the homozygous carriers of the (G) allele (P = 0.002). Multiple comparisons correction was applied and the Bonferroni-corrected critical P-value was = 0.003. LIMITATIONS, REASONS FOR CAUTION: The analysis is restricted to SNPs within genes and to men of Caucasian ancestry. WIDER IMPLICATIONS OF THE FINDINGS: In silico analyses strongly point towards a functional effect of the two SNPs: TAS2R14-rs3741843 regulates TAS2R43 expression, a gene that is involved in cilia motility and therefore could influences sperm mobility; the (T) allele of TAS2R3-rs11763979 increases the expression of the WEE2 antisense RNA one gene (WEE2-AS1). According to Genotype-Tissue Expression (GTEx) project the WEE2 gene is expressed in the testes where presumably it has the role of down regulating meiotic cell division. It is plausible to hypothesize that the WEE2-AS1 increased expression may down regulate WEE2 which in turn can alter the natural timing of sperm maturation increasing the number of abnormal sperm cells. STUDY FUNDING/COMPETING INTEREST(S): None.

Factors associated with oxidative stress and cancer risk in the Breast and Prostate Cancer Cohort Consortium.

Both endogenous factors (genomic variations) and exogenous factors (environmental exposures, lifestyle) impact the balance of reactive oxygen species (ROS). Variants of the ND3 (rs2853826; G10398A) gene of the mitochondrial genome, manganese superoxide dismutase (MnSOD; rs4880 Val16Ala) and glutathione peroxidase (GPX-1; rs1050450 Pro198Leu), are purported to have functional effects on regulation of ROS balance. In this study, we examined associations of breast and prostate cancer risks and survival with these variants, and interactions between rs4880-rs1050450, and alcohol consumption-rs2853826. Nested case-control studies were conducted in the Breast and Prostate Cancer Cohort Consortium (BPC3), consisting of nine cohorts. The analyses included over 10726 post-menopausal breast and 7532 prostate cancer cases with matched controls. Logistic regression models were used to evaluate associations with risk, and proportional hazard models were used for survival outcomes. We did not observe significant interactions between polymorphisms in MnSOD and GPX-1, or between mitochondrial polymorphisms and alcohol intake and risk of either breast (p-interaction of 0.34 and 0.98, respectively) or prostate cancer (p-interaction of 0.49 and 0.50, respectively). We observed a weak inverse association between prostate cancer risk and GPX-1 Leu198Leu carriers (OR 0.87, 95% CI 0.79-0.97, p = 0.01). Overall survival among women with breast cancer was inversely associated with G10398 carriers who consumed alcohol (HR 0.66 95% CI 0.49-0.88). Given the high power in our study, it is unlikely that interactions tested have more than moderate effects on breast or prostate cancer risk. Observed associations need both further epidemiological and biological confirmation.

Single nucleotide polymorphism detection by optical DNA-based sensing coupled with whole genomic amplification.

The work presented here deals with the optimization of a strategy for detection of single nucleotide polymorphisms based on surface plasmon resonance imaging. First, a sandwich-like assay was designed, and oligonucleotide sequences were computationally selected in order to study optimized conditions for the detection of the rs1045642 single nucleotide polymorphism in the gene ABCB1. Then the strategy was optimized on a surface plasmon resonance imaging biosensor using synthetic DNA sequences in order to evaluate the best conditions for the detection of a single mismatching base. Finally, the assay was tested on DNA extracted from human blood which was subsequently amplified using a whole genome amplification kit. The direct detection of the polymorphism was successfully achieved. The biochip was highly regenerable and reusable for up to 20 measurements. Furthermore, coupling these promising results with the multiarray assay, we can foresee applying this biosensor in clinical research extended to concurrent analysis of different polymorphisms.

Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief.

The pharmacokinetics and pharmacodynamics of morphine are under the control of several polymorphic genes, which can account for part of the observed interindividual variation in pain relief. We focused on two such genes: ABCB1/MDR1, a major determinant of morphine bioavailability, and OPRM1, which encodes for the mu-opioid receptor, the primary site of action for morphine. One hundred and forty-five patients of Italian origin undergoing morphine therapy were genotyped for the single-nucleotide polymorphism (SNP) C3435T of ABCB1/MDR1 and for the A80G SNP of OPRM1. Pain relief variability was significantly (P<0.0001) associated with both polymorphisms. Combining the extreme genotypes of both genes, the association between patient polymorphism and pain relief improved (P<0.00001), allowing the detection of three groups: strong responders, responders, and non-responders, with sensitivity close to 100% and specificity more than 70%. This study provides a good example of the possible clinical use of pharmacogenetics.

Elective cervical discectomy in California: postoperative in-hospital complications and their risk factors.

STUDY DESIGN: A retrospective cohort study of short-term outcomes after elective cervical discectomy in California hospitals. OBJECTIVES: To compare the frequency of elective cervical discectomy across population strata, to determine the frequency of adverse outcomes in the early postoperative period, and to identify risk factors for such outcomes. SUMMARY OF BACKGROUND DATA: Previous cervical discectomy series have been too small to analyze risk factors for early complications, and have originated from centers that may not adequately represent the population. METHODS: Computerized hospital discharge abstracts were obtained from the California Office of Statewide Health Planning and Development. Inclusion and exclusion criteria were applied to identify 10,416 routine discectomies at 257 hospitals in 1990-1991. Several categories of postoperative complications were identified, along with inpatient deaths, early reoperations, and nursing home transfers. Logistic regression was used to estimate the independent effects of patient characteristics on short-term outcomes. RESULTS: After adjustment for age and gender, blacks were 51% and Hispanics were 24% as likely as whites to undergo elective cervical discectomy. Overall, 6.7% of patients had one or more reported postoperative complications: 1.8% had noninfectious surgical complications, 1.8% had infectious complications, 4.0% had other medical complications, and 0.35% had unplanned reoperations before discharge. Fourteen inpatient deaths were reported (0.13%). Congestive heart failure, alcohol/drug abuse, chronic lung disease, previous spine surgery, psychological disorders, and chronic musculoskeletal disorders were independently associated with postoperative complications. Even after adjustment, risk was higher with advancing age, higher among women than among men, and higher after posterior fusion than after discectomy without fusion. CONCLUSIONS: The ethnic disparity in cervical discectomy rates suggests overuse among whites or underuse among minority populations. The complication rates reported here are similar to those synthesized from previous literature, except that the lower incidence of neurologic complications reflects our inability to distinguish preoperative from postoperative deficits. Important comorbidities should be identified and treated, if appropriate, before cervical spine surgery.

The California Hospital Outcomes Project: using administrative data to compare hospital performance.

BACKGROUND: The California Hospital Outcomes Project was created by an act of the state legislature in 1991. The California Office of Statewide Health Planning and Development (OSHPD) publishes annual reports on risk-adjusted hospital outcomes for medical, surgical, and obstetric patients. These outcomes indicators were chosen: in-hospital mortality within 30 days (acute myocardial infarction [AMI]), reported post-operative complications (diskectomy, delivery), post-operative length of stay (diskectomy), and readmission within 6 weeks (delivery). Project reports are based on discharge abstracts submitted by hospitals and edited by OSHPD. For each outcome, two risk adjustment models were used to estimate expected and risk-adjusted hospital outcome rates, along with p values representing the likelihood that the observed number of adverse outcomes occurred by chance. RESULTS: The first hospital outcomes report was distributed to hospitals in June 1993 and released to the public in December 1993. The total number of hospitals labeled as "better than expected" was 14 for AMI, 5 for cervical diskectomy, and 25 for lumbar diskectomy. The second hospital outcomes report was distributed to hospitals in June 1995. RESPONSE AND CONCLUSIONS: Letters submitted for 168 hospitals in response to the 1993 report demonstrated that hospitals had studied and used project results to evaluate their coding practices and quality of care. Media coverage of the 1993 report was balanced but sometimes critical of OSHPD's failure to identify "worse" hospitals. In response to providers' concerns, OSHPD has undertaken a validation study to explore whether differences in coding, unmeasured risk factors, or processes of care explain the reported differences in risk-adjusted outcome rates.