Bonferroni Multiple Correction Research Articles

Associations between gut microbiota and chronic sinusitis: A bidirectional Mendelian randomization study.

Studies have indicated a close association between dysbiosis of the gut microbiota and chronic sinusitis. However, the causal relationship between the gut microbiota and the risk of chronic sinusitis remains unclear. Using genome-wide association study (GWAS) data for the gut microbiota and chronic sinusitis, we conducted a two-sample Mendelian randomization (MR) study to determine the potential causal relationship between the microbiota and chronic sinusitis. We employed the inverse variance-weighted (IVW) method as the primary analytical approach to estimate the effect. Additionally, sensitivity, heterogeneity, and pleiotropy analyses were conducted to evaluate the robustness of the results. Reverse MR analysis was also applied to investigate potential reverse causality. Through MR analysis, we identified 17 gut microbiota classifications that are closely associated with chronic sinusitis. However, after Bonferroni multiple correction, only class Bacilli (odds ratio: 0.785, 95%confidence interval: 0.677-0.911, p = .001, false discovery rate = 0.023) maintained a significant causal negative relationship with chronic sinusitis. Sensitivity analysis did not reveal any evidence of heterogeneity or horizontal pleiotropy. Reverse MR analysis found five gut microbiota classifications that are significantly associated with chronic sinusitis, but they were no longer significant after Bonferroni multiple correction. There was no evidence to suggest a reverse causal relationship between chronic sinusitis and class Bacilli. Specific gut microbiota predicted by genetics exhibit a potential causal relationship with chronic sinusitis, and class Bacilli may have a protective effect on chronic sinusitis.

Genetic susceptibility to high myopia in Han Chinese population.

High myopia is a common ocular genetic disease in the world. The study sought to investigate the effect of the Insulin-like growth factor-1 (IGF-1) and Matrix metalloproteinase-9 (MMP-9) genes polymorphisms on high myopia in a Han population of China. This study recruited 216 unrelated Han Chinese subjects, including 103 cases with high myopia and 113 controls. Four tagging single nucleotide polymorphisms (SNPs) of IGF-1 and MMP-9 genes were genotyped using the Sequenom MassARRAY method. The chi-square test showed that the family history was significantly correlated with myopia. The SNP genotypes were all in Hardy–Weinberg equilibrium (P > 0.05). Among the four SNPs, there were statistically significant differences in the genotype and allele frequencies of rs2236416 between the groups (P = 0.024). The significant associations of rs2236416 between cases and controls also appeared after Bonferroni multiple correction (P = 0.024). Then, there were significant differences in the genotypes dominant model and codominant model of rs2236416 between groups (P = 0.007 and P = 0.004, respectively). rs5742632 showed a significant difference between the cases and the controls in the recessive model (P = 0.037). Our findings indicated that rs2236416 of MMP-9 was associated with myopia in the population. The result suggested MMP-9 gene locus may play a role in myopia.

Evaluation of genome-wide association signals for nonsyndromic cleft lip with or without cleft palate in a multiethnic Brazilian population

ObjectiveTo evaluate previous nonsyndromic cleft lip with or without cleft palate (NSCL±P) associated signals in 4p16.2, 8p11.23, 12q13.13, 12q13.2 and 17q21.32 in a multiethnic Brazilian cohort. DesignThe single nucleotide polymorphisms (SNPs) rs34246903 in 4p16.2, rs13317 in 8p11.23 (FGFR1, fibroblast growth factor receptor 1), rs3741442 in 12q13.13, rs705704 in 12q13.2 and rs4968247 in 17q21.32 were genotyped with TaqMan allelic discrimination assays in a case-control sample including 801 NSCL±P patients [233 nonsyndromic cleft lip (NSCLO) and 568 nonsyndromic cleft lip and palate (NSCLP)] and 881 healthy controls. Multiple logistic regression analyses, considering sex and genomic ancestry as covariates, were conducted, and the p value was adjusted with Bonferroni multiple correction testing (p ≤ 0.01). ResultsAlthough several associations were identified, those that resisted the multiple correction testing involved the alleles and genotypes of rs34246903 and rs13317. The NSCLO group had a lower frequency of the minor C allele of rs34246903 compared to controls, giving an odds ratio (OR) of 0.74 [95% confidence interval (CI): 0.59–0.93, p = 0.01]. The rs34246903 CC genotype (homozygous) and the recessive model revealed significant protective associations with NSCLO, yielding ORs of 0.50 (95% CI: 0.29–0.85, p = 0.005) and 0.55 (95% CI: 0.33–0.93, p = 0.01) respectively. The presence of C variant allele of rs13317 (OR: 0.81, 95% CI: 0.69–0.96, p = 0.01) as well the TC genotype (OR: 0.77, 95% CI: 0.62–0.94, p = 0.01) and the dominant model (OR: 0.77, 95% CI: 0.63–0.94, p = 0.009) showed significant associations with reduced risk of NSCL±P. ConclusionOur study is the first to support the association of rs34246903 (4p16.2) with NSCLO and rs13317 within FGFR1 with NSCL±P in the highly admixed Brazilian population. Further studies are needed to determine the functionality of those SNPs or to identify the causal markers in linkage disequilibrium with those susceptibility markers.

Occlusal tactile acuity in temporomandibular disorder pain patients: A case-control study.

To compare the smallest thickness that can be perceived between occluding teeth (occlusal tactile acuity, OTA) of temporomandibular disorder pain (TMD-P) patients with that of control (CTR) individuals. Twenty TMD-P patients (17 women and 3 men, mean age: 31.3±10.4years) diagnosed according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) protocol and 20 age- and gender-matched controls (17 women and 3 men, mean age: 31.4±10.5years) were enrolled. The OTA was tested with 10 different thicknesses: 9 aluminium foils (8µm-72µm with a constant increment of 8µm) and 1 sham test (without foil), each thickness being tested 10 times in random order (100 tests in total). The participants were instructed to close their mouth once and to report whether they felt the foil between their molar teeth. A between-group comparison (TMD-P vs CTR) was performed for each testing thickness (analysis of variance for repeated measurements, with Bonferroni multiple correction) (P<.005). Significantly increased OTA was observed in the TMD-P group for the thicknesses between 8µm and 40µm, while no significant differences were found for the sham test and for the larger thicknesses tested (from 48µm to 72µm). TMD-pain subjects presented an increased OTA as compared to controls.

Do age-related macular degeneration genes show association with keratoconus?

BackgroundKeratoconus (KC) is a common corneal condition with an unknown gender predominance. Although numerous studies have investigated the genetic component of KC, no specific genes have yet been attributed to the condition. We recently reported posterior segment changes occurring in the eyes of KC patients. However, it is not clear whether these changes are part of KC pathogenesis or reflect changes in anatomical features of the eye manifested by changes at the cornea. Given retinal changes represent the main characteristics observed in age-related macular degeneration (AMD) and that pleiotropy has been demonstrated between different eye diseases, we wished to assess if known AMD associated genes were also associated with KC.MethodsA total of 248 KC subjects and 366 non-KC (control) subjects were recruited from public and private clinics in Melbourne for this analysis. Nineteen single nucleotide polymorphisms (SNPs) previously associated with AMD, including rs10490924 (ARMS2/HTRA1), rs10737680 (CFH), rs13278062 (TNFRSF10A), rs1864163 (CETP), rs2230199 (C3), rs3130783 (IER3/DDR1), rs334353 (TGFBR1), rs3812111 (COL10A1), rs429608 (C2/CFB), rs4420638 (APOE), rs4698775 (CFI), rs5749482 (TIMP3), rs6795735 (ADAMTS9), rs8017304 (RAD51B), rs8135665 (SLC16A8), rs920915 (LIPC), rs943080 (VEGFA), rs9542236 (B3GALTL) and rs13081855 (COL8A1/FILIP1L), were genotyped in this cohort. Logistic regression was applied to evaluate the association between these SNPs and KC on both genders together, as well as each gender separately. Linear regression was also applied to assess the association between SNPs and corneal curvature. Bonferroni correction was applied to adjust for multiple testing.ResultsGenotyping data were available for 18 SNPs. The SNP, rs6795735 (ADAMTS9) was significantly associated with KC (p = 3.5 × 10− 4) when both genders were assessed, whereas rs5749482 (TIMP3) was only associated in males (p = 7.7 × 10− 4) following Bonferroni multiple correction. However, when the covariates of age and gender were included, the associations became non-significant. In addition, none of the SNPs appeared significant for corneal curvature.ConclusionsOur study suggested a potential association of rs6795735 in the ADAMTS9 gene and rs5749482 in the TIMP3 gene in KC and that different associations may be gender specific. Overall, SNPs initially identified as associated with AMD following multiple correction may be further impacted by other factors such as age or gender and further studies are needed to resolve this issue.

Evaluation of FGF10 as a candidate gene for high myopia in a Han Chinese population

BackgroundFibroblast growth factor 10 (FGF10) is implicated in the growth and development of the eye. Four singles nucleotide polymorphisms (SNPs) in the FGF10 gene (including rs1384449, rs339501, rs12517396 and rs10462070) were found to be associated with extreme myopia (EM, refractive error ≤ − 10.0 diopters) in Japanese and Chinese Taiwan population. This case-control association study was conducted to explore the relationship between these four SNPs and high myopia in a western Chinese population.MethodsA total of 869 high myopia patients (HM, including 485 EM patients) and 899 healthy controls were recruited. These four SNPs were genotyped using the ABI SNaPshot method. Five genetic models (allelic, homozygous, heterozygous, dominant, and recessive) were applied to further evaluate the possible correlation between the SNPs and high myopia. The linkage-disequilibrium block (LD) structure was tested by Haploview Software.ResultsIn our study, no statistically significant differences were found between HM/EM patients and controls after Bonferroni multiple-correction (P > 0.05) in the allele frequencies of these four SNPs in the FGF10 gene. We further found that rs12517396AA and rs10462070GG carriers showed a decreased risk of HM/EM compared with rs12517396AC + CC and rs10462070GA + AA carriers (P = 0.045, OR = 0.366; P = 0.021, OR = 0.131; P = 0.03, OR = 0.341; P = 0.015, OR = 0.122; respectively). Additionally, rs12517396AA and rs10462070GG carriers showed the same decreased risk of HM/EM compared with rs12517396CC and rs10462070AA carriers (P = 0.048, OR = 0.370; P = 0.023, OR = 0.133; P = 0.032, OR = 0.346; P = 0.017, OR = 0.126). However, these significant associations between rs12517396/rs10462070 and HM/EM disappeared after Bonferroni multiple-correction (P > 0.05).ConclusionOur findings indicate that rs12517396 and rs10462070 had marginal association with HM and EM. The other two common polymorphisms in FGF10 unlikely have significant effects in the genetic predisposition to HM/EM in western Chinese population. Further replication studies are needed to validate our findings in both animal models and human genetic epidemiologic studies.

Inflammation-Related Gene Polymorphisms Associated With Primary Immune Thrombocytopenia.

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by a reduced platelet count and an increased risk of bleeding. Although immense research has improved our understanding of ITP, the pathogenesis remains unclear. Here, we investigated the involvement of 25 single-nucleotide polymorphisms (SNPs) of the inflammation-related genes, including CD24, CD226, FCRL3, IL2, IRF5, ITGAM, NLRP3, CARD8, PTPN22, SH2B2, STAT4, TNFAIP3, and TRAF1, in the pathogenesis and treatment response of ITP. We recruited 312 ITP inpatients and 154 healthy participants in this case–control study. Inflammation-related SNP genotyping was performed on the Sequenom MassARRAY iPLEX platform. The expression of TNFAIP3 mRNA was determined by quantitative real-time RT-PCR. All SNPs in healthy controls were consistent with Hardy–Weinberg equilibrium. Statistical analysis revealed that rs10499194 in TNFAIP3 was significantly associated with a decreased risk of ITP after Bonferroni multiple correction (codominant, CT vs. CC, OR = 0.431, 95% CI = 0.262–0.711, p = 0.001; dominant, TT/CT vs. CC, OR = 0.249, 95% CI = 0.141–0.440, p = 0.000). Besides, TNFAIP3 expression was significantly higher in patients with CT and pooled CT/TT genotypes compared with CC genotype (p = 0.001; p = 0.001). Interestingly, rs10499194 was also associated with corticosteroid-sensitivity (codominant, CT vs. CC, OR = 0.092, 95% CI = 0.021–0.398, p = 0.001; dominant, TT/CT vs. CC, OR = 0.086, 95% CI = 0.020–0.369, p = 0.001; allelic, T vs. C, OR = 0.088, 95% CI = 0.021–0.372, p = 0.001). Furthermore, no significant association was found between inflammation-related SNPs and the severity or refractoriness of ITP after Bonferroni multiple correction. Our findings suggest that rs10499194 may be a protective factor for susceptibility and corticosteroid sensitivity in ITP patients.

A novel Markov Blanket-based repeated-fishing strategy for capturing phenotype-related biomarkers in big omics data.

BackgroundWe propose a novel Markov Blanket-based repeated-fishing strategy (MBRFS) in attempt to increase the power of existing Markov Blanket method (DASSO-MB) and maintain its advantages in omic data analysis.ResultsBoth simulation and real data analysis were conducted to assess its performances by comparing with other methods including χ2 test with Bonferroni and B-H adjustment, least absolute shrinkage and selection operator (LASSO) and DASSO-MB. A serious of simulation studies showed that the true discovery rate (TDR) of proposed MBRFS was always close to zero under null hypothesis (odds ratio = 1 for each SNPs) with excellent stability in all three scenarios of independent phenotype-related SNPs without linkage disequilibrium (LD) around them, correlated phenotype-related SNPs without LD around them, and phenotype-related SNPs with strong LD around them. As expected, under different odds ratio and minor allel frequency (MAFs), MBRFS always had the best performances in capturing the true phenotype-related biomarkers with higher matthews correlation coefficience (MCC) for all three scenarios above. More importantly, since proposed MBRFS using the repeated fishing strategy, it still captures more phenotype-related SNPs with minor effects when non-significant phenotype-related SNPs emerged under χ2 test after Bonferroni multiple correction. The various real omics data analysis, including GWAS data, DNA methylation data, gene expression data and metabolites data, indicated that the proposed MBRFS always detected relatively reasonable biomarkers.ConclusionsOur proposed MBRFS can exactly capture the true phenotype-related biomarkers with the reduction of false negative rate when the phenotype-related biomarkers are independent or correlated, as well as the circumstance that phenotype-related biomarkers are associated with non-phenotype-related ones.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0358-5) contains supplementary material, which is available to authorized users.

Abstract B66: Chronic myeloid leukemic cells trigger poly(ADP-ribose) polymerase-dependent cell death in natural killer cells.

Abstract Background and Purpose: Natural killer (NK) cells are commonly dysfunctional in chronic myeloid leukemia (CML) and their status may determine the course of disease. We aimed to define the molecular mechanisms of leukemia-induced NK cell inhibition with focus on the role of CML cell-derived reactive oxygen species (ROS) and the poly(ADP-ribose) polymerase-1 (PARP-1) pathway of cell death (parthanatos). Methods: Malignant granulocytes from patients with BCR-ABL+ CML were analyzed using flow cytometry for cell surface expression of the oxygen radical-producing NADPH/NOX-2 oxidase (determined by expression of the NADPH oxidase subunit gp91phox). ROS production by CML cells was assessed by chemiluminescence. In co-culture experiments, purified NK cells from healthy donors were exposed to malignant CML cells followed by analysis of NK cell viability. In these experiments, inhibitors of PARP-1 (PJ34 and EB-47) and the caspase cascade (Z-VAD.fmk) were added to determine the mechanisms of cell death in NK cells exposed to CML cells. Translocation of apoptosis-inducing factor (AIF) from mitochondria to nucleus was determined in sorted NK cells by immunoblot technique. Results: All BCR-ABL+ CML cells showed high cell surface expression of gp91phox, indicating the presence of a NADPH/NOX-2 oxidase. CML cells produced high amounts of ROS upon stimulation with the protein kinase C activator PMA or by the bacterial tripeptide fMLF suggestive of a functional ROS-forming oxidase. Unstimulated CML cells triggered extensive apoptosis-like cell death in co-cultured NK cells, which was prevented by the ROS-degrading enzyme catalase and by the NADPH oxidase/NOX-2 inhibitor diphenylene iodonium. The PARP-1 inhibitor PJ34 (0.5 microM) prevented CML-induced NK cell death at CML/NK cell ratios of 0.125: p&amp;lt;0.05 (using cells from five CML patients); 0.25: p&amp;lt;0.0001 (n=8), 0.5: p&amp;lt;0.0001 (n=6), and 1: p&amp;lt;0.0001 (n=8; analyzed by two-way Anova followed by Bonferroni's multiple correction test). A structurally unrelated PARP-1 inhibitor, EB-47, shared the NK cell-protective properties of PJ34 and EB-47 whereas the pan-caspase inhibitor Z-VAD.fmk failed to rescue NK cells from CML cell-induced death. After CML cell exposure, NK cells expressed JC-1 monomers suggestive of a disrupted mitochondrial membrane potential. AIF, a mitochondrial protein involved in PARP-1 dependent cell death, accumulated in NK cell nuclei after interaction with CML cells. Conclusions: Our results imply (1) that paracrine ROS production by CML cells followed by NK cell death may constitute a mechanism by which CML cells evade destruction by cytotoxic lymphocytes, and (2) that CML cells trigger NK cell death by inducing PARP-1 dependent parthanatos. These findings may have implications for the design of more efficient immunotherapeutic protocols in CML. Citation Format: Johan Aurelius, Anna Martner, Rebecca E. Riise, Ana I. Romero, Lars Palmqvist, Mats Brune, Kristoffer Hellstrand, Fredrik B. Thorén. Chronic myeloid leukemic cells trigger poly(ADP-ribose) polymerase-dependent cell death in natural killer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B66.

No Association Found between the Type 1 Sigma Receptor Gene Polymorphisms and Methamphetamine Abuse in the Japanese Population: A Collaborative Study by the Japanese Genetics Initiative for Drug Abuse

It has been suggested that individual genetic factors are involved in susceptibility to drug dependence and the manifestation of drug-induced psychosis. The aim of this study was to examine the relation between methamphetamine abusers/psychosis and the type 1 sigma receptor gene polymorphisms. Subjects comprised 143 MAP abusers and 181 healthy controls. Two polymorphisms in the type 1 sigma receptor gene, GC-241-240TT and A61C (Gln2Pro), were examined in the present study. No significant differences were observed in either polymorphism between healthy controls and MAP abusers/psychosis. In the subgroup analyses, the rate of CC genotype of A61C tended to be higher in MAP patients who had experienced spontaneous relapse without MAP use than in those who had not (P = .06, OR = 3.02 95%CI = 0.92-9.92). However, the level of this significant trend did not remain after the Bonferroni's multiple correction. This study suggests that type 1 sigma receptor gene is unlikely to play a major role in substance abuse liability and/or the development of MAP psychosis.