Association of HADHA expression with the risk of breast cancer: targeted subset analysis and meta-analysis of microarray data

<p>Abstract</p> <p>Background</p> <p>The role of n-3 fatty acids in prevention of breast cancer is well recognized, but the underlying molecular mechanisms are still unclear. In view of the growing need for early detection of breast cancer, Graham et al. (2010) studied the microarray gene expression in histologically normal epithelium of subjects with or without breast cancer. We conducted a secondary analysis of this dataset with a focus on the genes (n = 47) involved in fat and lipid metabolism. We used stepwise multivariate logistic regression analyses, volcano plots and false discovery rates for association analyses. We also conducted meta-analyses of other microarray studies using random effects models for three outcomes--risk of breast cancer (380 breast cancer patients and 240 normal subjects), risk of metastasis (430 metastatic compared to 1104 non-metastatic breast cancers) and risk of recurrence (484 recurring versus 890 non-recurring breast cancers).</p> <p>Results</p> <p>The <it>HADHA </it>gene [hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit] was significantly under-expressed in breast cancer; more so in those with estrogen receptor-negative status. Our meta-analysis showed an 18.4%-26% reduction in <it>HADHA </it>expression in breast cancer. Also, there was an inconclusive but consistent under-expression of <it>HADHA </it>in subjects with metastatic and recurring breast cancers.</p> <p>Conclusions</p> <p>Involvement of mitochondria and the mitochondrial trifunctional protein (encoded by <it>HADHA </it>gene) in breast carcinogenesis is known. Our results lend additional support to the possibility of this involvement. Further, our results suggest that targeted subset analysis of large genome-based datasets can provide interesting association signals.</p

Association of Urinary Phthalates with Self-Reported Eye Affliction/Retinopathy in Individuals with Diabetes: National Health and Nutrition Examination Survey, 2001-2010

Background. An epidemiological association between exposure to phthalates and type 2 diabetes (T2D) is known. However, the potential role of environmental phthalates in the complications of T2D is unknown. Methods. Using data from the National Health and Nutrition Examination Survey (NHANES) 2001-2010, we studied the association of 12 urinary phthalate metabolites with self-reported eye affliction/retinopathy in 1,004 participants with diabetes. Data from retinal imaging was used to validate this outcome. Independence of the phthalates→T2D association was studied by adjusting for age, sex, race, marital status, educational attainment, poverty income ratio, physical activity, glycated hemoglobin levels, total serum cholesterol, serum high-density lipoprotein cholesterol, serum triglycerides, blood pressure, duration of diabetes, total calorie intake, and obesity. Results. Self-reported eye affliction/retinopathy had 82% accuracy with Cohen\u27s kappa of 0.31 (p \u3c 0.001). Urinary mono-n-octyl phthalate (MOP) was independently associated with the likelihood of self-reported eye affliction/retinopathy in subjects with T2D after accounting for all the confounders. This significance of this association was robust to the potential misclassification in cases and controls of retinopathy. Further, a significant dose-response relationship between MOP and self-reported eye affliction/retinopathy was demonstrable. Conclusions. We show a novel epidemiological link between the environment and diabetic complications in NHANES 2001-2010 participants

Association of Urinary Phthalates with Self-Reported Eye Affliction/Retinopathy in Individuals with Diabetes: National Health and Nutrition Examination Survey, 2001-2010

Background. An epidemiological association between exposure to phthalates and type 2 diabetes (T2D) is known. However, the potential role of environmental phthalates in the complications of T2D is unknown. Methods. Using data from the National Health and Nutrition Examination Survey (NHANES) 2001-2010, we studied the association of 12 urinary phthalate metabolites with self-reported eye affliction/retinopathy in 1,004 participants with diabetes. Data from retinal imaging was used to validate this outcome. Independence of the phthalates→T2D association was studied by adjusting for age, sex, race, marital status, educational attainment, poverty income ratio, physical activity, glycated hemoglobin levels, total serum cholesterol, serum high-density lipoprotein cholesterol, serum triglycerides, blood pressure, duration of diabetes, total calorie intake, and obesity. Results. Self-reported eye affliction/retinopathy had 82% accuracy with Cohen\u27s kappa of 0.31 (p \u3c 0.001). Urinary mono-n-octyl phthalate (MOP) was independently associated with the likelihood of self-reported eye affliction/retinopathy in subjects with T2D after accounting for all the confounders. This significance of this association was robust to the potential misclassification in cases and controls of retinopathy. Further, a significant dose-response relationship between MOP and self-reported eye affliction/retinopathy was demonstrable. Conclusions. We show a novel epidemiological link between the environment and diabetic complications in NHANES 2001-2010 participants

Association of umbilical cord blood lead with neonatal behavior at varying levels of exposure

BACKGROUND: In the light of the ongoing debate about lowering the cut-off for acceptable blood lead level to <5 μg/dL from the currently recommended level of <10 μg/dL, we considered whether prenatal exposure to varying levels of lead is associated with similar or disparate effects on neonatal behavior. METHODS: Using Brazelton's Neonatal Behavioral Assessment Scale (NBAS), an epidemiological approach and robust statistical techniques like multivariate linear regression, logistic regression, Poisson regression and structural equations modeling analyses we estimated the simultaneous indirect effects of umbilical cord blood lead (CBL) levels and other neonatal covariates on the NBAS clusters. RESULTS: We observed that when analyzed in all study subjects, the CBL levels independently and strongly influenced autonomic stability and abnormal reflexes clusters. However, when the analysis was restricted to neonates with CBL <10 μg/dL, CBL levels strongly influenced the range of state, motor and autonomic stability clusters. Abnormal walking reflex was consistently associated with an increased CBL level irrespective of the cut-off for CBL, however, only at the lower cut-offs were the predominantly behavioral effects of CBL discernible. CONCLUSION: Our results further endorse the need to be cognizant of the detrimental effects of blood lead on neonates even at a low-dose prenatal exposure

Influence of Zinc Supplementation in Acute Diarrhea Differs by the Isolated Organism

Zinc supplementation is recommended in all acute diarrheas in children from developing countries. We aimed to assess whether zinc supplementation would be equally effective against all the common organisms associated with acute diarrheas. We used data on 801 children with acute diarrhea recruited in a randomized, double blind controlled trial (ISRCTN85071383) of zinc and copper supplementation. Using prespecified subgroup analyses, multidimensionality reduction analyses, tests of heterogeneity, and stepwise logistic regression for tests of interactions, we found that the influence of zinc on the risk of diarrhea for more than 3 days depended on the isolated organism—beneficial in Klebsiella, neutral in Esherichia coli and parasitic infections, and detrimental in rotavirus coinfections. Although we found similar results for the outcome of high stool volume, the results did not reach statistical significance. Our findings suggest that the current strategy of zinc supplementation in all cases of acute diarrheas in children may need appropriate fine tuning to optimize the therapeutic benefit based on the causative organism, but further studies need to confirm and extend our findings

Therapeutic Value of Zinc Supplementation in Acute and Persistent Diarrhea: A Systematic Review

BACKGROUND: For over a decade, the importance of zinc in the treatment of acute and persistent diarrhea has been recognized. In spite of recently published reviews, there remain several unanswered questions about the role of zinc supplementation in childhood diarrhea in the developing countries. Our study aimed to assess the therapeutic benefits of zinc supplementation in the treatment of acute or persistent diarrhea in children, and to examine the causes of any heterogeneity of response to zinc supplementation. METHODS AND FINDINGS: EMBASE, MEDLINE and CINAHL databases were searched for published reviews and meta-analyses on the use of zinc supplementation for the prevention and treatment of childhood diarrhea. Additional RCTs published following the meta-analyses were also sought. The reviews and published RCTs were qualitatively mapped followed by updated random-effects meta-analyses, subgroup meta-analyses and meta-regression to quantify and characterize the role of zinc supplementation with diarrhea-related outcomes. We found that although there was evidence to support the use of zinc to treat diarrhea in children, there was significant unexplained heterogeneity across the studies for the effect of zinc supplementation in reducing important diarrhea outcomes. Zinc supplementation reduced the mean duration of diarrhea by 19.7% but had no effect on stool frequency or stool output, and increased the risk of vomiting. Our subgroup meta-analyses and meta-regression showed that age, stunting, breast-feeding and baseline zinc levels could not explain the heterogeneity associated with differential reduction in the mean diarrheal duration. However, the baseline zinc levels may not be representative of the existing zinc deficiency state. CONCLUSIONS: Understanding the predictors of zinc efficacy including the role of diarrheal disease etiology on the response to zinc would help to identify the populations most likely to benefit from supplementation. To improve the programmatic use of zinc, further evaluations of the zinc salts used, the dose, the frequency and duration of supplementation, and its acceptability are required. The significant heterogeneity of responses to zinc suggests the need to revisit the strategy of universal zinc supplementation in the treatment children with acute diarrhea in developing countries

Clinical Study Influence of Zinc Supplementation in Acute Diarrhea Differs by the Isolated Organism

Zinc supplementation is recommended in all acute diarrheas in children from developing countries. We aimed to assess whether zinc supplementation would be equally effective against all the common organisms associated with acute diarrheas. We used data on 801 children with acute diarrhea recruited in a randomized, double blind controlled trial (ISRCTN85071383) of zinc and copper supplementation. Using prespecified subgroup analyses, multidimensionality reduction analyses, tests of heterogeneity, and stepwise logistic regression for tests of interactions, we found that the influence of zinc on the risk of diarrhea for more than 3 days depended on the isolated organism-beneficial in Klebsiella, neutral in Esherichia coli and parasitic infections, and detrimental in rotavirus coinfections. Although we found similar results for the outcome of high stool volume, the results did not reach statistical significance. Our findings suggest that the current strategy of zinc supplementation in all cases of acute diarrheas in children may need appropriate fine tuning to optimize the therapeutic benefit based on the causative organism, but further studies need to confirm and extend our findings

A simple method to combine multiple molecular biomarkers for dichotomous diagnostic classification

BACKGROUND: In spite of the recognized diagnostic potential of biomarkers, the quest for squelching noise and wringing in information from a given set of biomarkers continues. Here, we suggest a statistical algorithm that – assuming each molecular biomarker to be a diagnostic test – enriches the diagnostic performance of an optimized set of independent biomarkers employing established statistical techniques. We validated the proposed algorithm using several simulation datasets in addition to four publicly available real datasets that compared i) subjects having cancer with those without; ii) subjects with two different cancers; iii) subjects with two different types of one cancer; and iv) subjects with same cancer resulting in differential time to metastasis. RESULTS: Our algorithm comprises of three steps: estimating the area under the receiver operating characteristic curve for each biomarker, identifying a subset of biomarkers using linear regression and combining the chosen biomarkers using linear discriminant function analysis. Combining these established statistical methods that are available in most statistical packages, we observed that the diagnostic accuracy of our approach was 100%, 99.94%, 96.67% and 93.92% for the real datasets used in the study. These estimates were comparable to or better than the ones previously reported using alternative methods. In a synthetic dataset, we also observed that all the biomarkers chosen by our algorithm were indeed truly differentially expressed. CONCLUSION: The proposed algorithm can be used for accurate diagnosis in the setting of dichotomous classification of disease states

Lack of Association between SLC30A8 Variants and Type 2 Diabetes in Mexican American Families

SLC30A8 encodes zinc transporter 8 which is involved in packaging and release of insulin. Evidence for the association of SLC30A8 variants with type 2 diabetes (T2D) is inconclusive. We interrogated single nucleotide polymorphisms (SNPs) around SLC30A8 for association with T2D in high-risk, pedigreed individuals from extended Mexican American families. This study of 118 SNPs within 50 kb of the SLC30A8 locus tested the association with eight T2D-related traits at four levels: (i) each SNP using measured genotype approach (MGA); (ii) interaction of SNPs with age and sex; (iii) combinations of SNPs using Bayesian Quantitative Trait Nucleotide (BQTN) analyses; and (iv) entire gene locus using the gene burden test. Only one SNP (rs7817754) was significantly associated with incident T2D but a summary statistic based on all T2D-related traits identified 11 novel SNPs.Three SNPs and one SNP were weakly but interactively associated with age and sex, respectively. BQTN analyses could not demonstrate any informative combination of SNPs over MGA. Lastly, gene burden test results showed that at best the SLC30A8 locus could account for only 1-2% of the variability in T2D-related traits. Our results indicate a lack of association of the SLC30A8 SNPs with T2D in Mexican American families