Noel Pabalan

Cyclin D1 Pro241Pro (CCND1-G870A) polymorphism is associated with increased cancer risk in human populations: a meta-analysis.

The G870A polymorphism in the CCND1 gene may influence cancer risk. However, data from published studies with individual low statistical power have been controversial. To evaluate whether combined evidence shows an association between this polymorphism and cancer, we considered all available studies in a meta-analysis. Sixty studies were combined representing data for 18,411 cases and 22,209 controls. In our meta-analysis, we investigated overall sample and two ethnic populations (Caucasians and Asians) as well as nine cancer subtypes. Individuals who are homozygous for A allele (AA) were found to be associated with significantly increased cancer risk in overall sample [odds ratio (OR), 1.23; 95% confidence interval (95% CI), 1.13-1.33; P ≤ 0.0001], Caucasians (OR, 1.16; 95% CI, 1.07-1.26; P = 0.0002), and Asians (OR, 1.26; 95% CI, 1.14-1.39; P ≤ 0.001). Among the nine cancer subtypes investigated, modestly significant risk (ORs, 1.08 to 1.51; P = 0.02 to 0.04) was detected in breast, colorectal, head and neck, and other cancers. Highly significant and increased risk was found to be associated with genitourinary (OR, 1.51; 95% CI, 1.20-1.89; P = 0.0004) and blood-related cancers (OR, 1.62; 95% CI, 1.28-2.05; P ≤ 0.0001). Individuals who are heterozygous for AG were found to be at increased risk in overall, ethnic groups, as well as breast and colorectal cancers. Significant dominant effects seem to prevail in the majority of the categories investigated, where some recessive effects were also detected. Overall, the risk effects associated with this polymorphism were small; however, due its common occurrence, it affects a large portion of the human population (AA, 25%; AG, 50%). Although the independent small risk associated with CCND1-A870G polymorphism is not clinically useful, its interaction with other genetic variants and environmental factors has been shown to be associated with further increase in cancer risk (OR, 1.6-7.1). In conclusion, our study strongly supports the increased cancer risk associated with CCND1-A870G polymorphism in the human population. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2773–81)

Menopausal status modifies breast cancer risk associated with the myeloperoxidase (MPO) G463A polymorphism in Caucasian women: a meta-analysis.

Background Breast cancer susceptibility may be modulated partly through polymorphisms in oxidative enzymes, one of which is myeloperoxidase (MPO). Association of the low transcription activity variant allele A in the G463A polymorphism has been investigated for its association with breast cancer risk, considering the modifying effects of menopausal status and antioxidant intake levels of cases and controls. Methodology/Principal Findings To obtain a more precise estimate of association using the odds ratio (OR), we performed a meta-analysis of 2,975 cases and 3,427 controls from three published articles of Caucasian populations living in the United States. Heterogeneity among studies was tested and sensitivity analysis was applied. The lower transcriptional activity AA genotype of MPO in the pre-menopausal population showed significantly reduced risk (OR 0.56–0.57, p = 0.03) in contrast to their post-menopausal counterparts which showed non-significant increased risk (OR 1.14; p = 0.34–0.36). High intake of antioxidants (OR 0.67–0.86, p = 0.04–0.05) and carotenoids (OR 0.68–0.86, p = 0.03–0.05) conferred significant protection in the women. Stratified by menopausal status, this effect was observed in pre-menopausal women especially those whose antioxidant intake was high (OR 0.42–0.69, p = 0.04). In post-menopausal women, effect of low intake elicited susceptibility (OR 1.19–1.67, p = 0.07–0.17) to breast cancer. Conclusions/Significance Based on a homogeneous Caucasian population, the MPO G463A polymorphism places post-menopausal women at risk for breast cancer, where this effect is modified by diet.

Enteroaggregative Escherichia coli and acute diarrhea in children: a meta-analysis of South Asian populations

The purpose of this investigation was to evaluate the association of enteroaggregative Escherichia coli (EAEC) with acute diarrhea in children of South Asian populations. Our meta-analysis included 18 studies published between 1989 and 2011. The odds ratio (OR) was used to evaluate all available observational epidemiology studies. Modifying effects on the overall OR were approached with outlier, subgroup, cumulative, and cumulative recursive analyses. Synthesis of the 18 observational studies revealed an association between EAEC carriage and acute diarrhea, with an overall OR of 1.51, which was significant (p = 0.008), heterogeneous (Pheterogeneity < 0.0001), and unaffected by outlier analysis. This analysis, however, affected the subgroups by eliminating the following: (i) heterogeneity (from Pheterogeneity < 0.0001 to 0.30–0.72) of pooled ORs in the underpowered (OR 1.37, p = 0.15), Indian (OR 1.92, p = 0.09), and hospital-based (OR 1.66, p = 0.06) studies; (ii) non-significance of these three subgroups (OR 1.56–2.01, p < 0.0001–0.003); (iii) significance of the high-powered studies (from OR 1.70, p = 0.02 to OR 1.15, p = 0.28); (iv) heterogeneity (from Pheterogeneity < 0.0001–0.0002 to 0.11–0.15) of pooled ORs in period three (OR 1.85, p = 0.14), population-based (OR 1.36, p = 0.09), and pCVD432 (OR 1.53, p = 0.07) studies. In general, outlier treatment increased precision with the narrowing of confidence intervals, overall, and in the subgroups. Cumulative meta-analysis generally resulted in increases in the frequencies of significant effects and of heterogeneity. This meta-analysis on observational studies suggests that the association between EAEC and acute diarrhea in children is that of increased risk. This effect generally comes from heterogeneous studies of South Asian populations, but is modified with outlier and subgroup treatments.

Meta‐analysis of the human leukocyte antigen‐G (HLA‐G) 14 bp insertion/deletion polymorphism as a risk factor for preeclampsia

The non-classical major histocompatibility complex, human leukocyte antigen (HLA)-G, plays an important role in pregnancy. HLA-G mediates proper interaction between maternal immune cells and fetal trophoblasts invading the uterine wall, to ensure successful placental development and function. Several HLA-G gene variants have been shown to be associated with development of preeclampsia (PE), but the reported associations of the HLA-G 14 base pair (bp) insertion/deletion (I/D) polymorphism (rs66554220) with PE are inconsistent. In this meta-analysis of HLA-G 14 bp I/D in each member of the family triad, we estimated risk (odds ratio [OR], 95% confidence interval) of associations with PE based on nine published offspring, nine mother and three father case-control studies. No significant increased risk associations between PE and HLA-G 14 bp I/D were detected in any of the family triad members (offspring: OR = 1.08-1.21, P = 0.57-0.74; mothers: OR = 1.11-1.28, P = 0.07-0.44; fathers: OR = 1.09-1.65, P = 0.07-0.70). Of the 20 comparisons performed, 14 (70%) were non-heterogeneous and seven of these had zero heterogeneity (I(2) = 0%). Sensitivity treatment confirmed robustness for the overall lack of association for HLA-G 14 bp I/D. In subgroup analysis, significant association between HLA-G 14 bp I/D and PE was shown in offspring from primipara (OR = 1.66-1.95, P = 0.04) and European Caucasian pregnancies (OR = 1.37-2.03, P = 0.02-0.03). However, heterogeneity and sensitivity tests suggest that further investigation is needed to determine if HLA-G 14 bp I/D is involved in trophoblast HLA-G expression and PE development in these subgroups.

Associations between ghrelin and ghrelin receptor polymorphisms and cancer in Caucasian populations: a meta-analysis

BackgroundThere is growing evidence that the ghrelin axis, including ghrelin (GHRL) and its receptor, the growth hormone secretagogue receptor (GHSR), play a role in cancer progression. Ghrelin gene and ghrelin receptor gene polymorphisms have been reported to have a range of effects in cancer, from increased risk, to protection from cancer, or having no association. In this study we aimed to clarify the role of ghrelin and ghrelin receptor polymorphisms in cancer by performing a meta-analysis of published case-control studies.We conducted searches of the literature published up to January 2013 in MEDLINE using the PubMed search engine. Individual data on 8,430 cases and 14,008 controls from six case-control studies of an all Caucasian population were evaluated for three ghrelin gene (GHRL; rs696217, rs4684677, rs2075356) and one ghrelin receptor (GHSR; rs572169) polymorphism in breast cancer, esophageal cancer, colorectal cancer and non-Hodgkins lymphoma.ResultsIn the overall analysis, homozygous and recessive associations indicated that the minor alleles of rs696217 and rs2075356 GHRL polymorphisms conferred reduced cancer risk (odds ratio [OR] 0.61-0.78). The risk was unchanged for breast cancer patients when analysed separately (OR 0.73-0.83). In contrast, the rs4684677 GHRL and the rs572169 GHSR polymorphisms conferred increased breast cancer risk (OR 1.97-1.98, p = 0.08 and OR 1.42-1.43, p = 0.08, respectively). All dominant and co-dominant effects showed null effects (OR 0.96-1.05), except for the rs572169 co-dominant effect, with borderline increased risk (OR 1.08, p = 0.05).ConclusionsThis study suggests that the rs696217 and rs2075356 ghrelin gene (GHRL) polymorphisms may protect carriers against breast cancer, and the rs4684677 GHRL and rs572169 GHSR polymorphisms may increase the risk among carriers. In addition, larger studies are required to confirm these findings.

Association Between the FokI and ApaI Polymorphisms in the Vitamin D Receptor Gene and Intervertebral Disc Degeneration: A Systematic Review and Meta-Analysis

BACKGROUND Evidence supporting an association of intervertebral disc degeneration (DD) with polymorphisms of the vitamin D receptor (VDR) gene has been controversial. We performed a meta-analysis of these studies to determine if there was substantial evidence to support such an association between the VDR polymorphisms and DD. METHODS PubMed, Embase, and Science Direct databases were searched for studies that investigated associations of the FokI (rs2228570, rs10735810), and ApaI (rs7975253) polymorphisms of the VDR gene with DD. From the extracted genotype data from 14 publications, we estimated risk (odds ratio [OR] with 95% confidence intervals). RESULTS Overall associations of FokI with DD were absent (OR 0.96-1.04, p = 0.73-0.95) with heterogeneity in the dominant and codominant models (pheteroegeneity <0.10, I2 = 47-57%). Post-outlier pooled effects yielded dominant significance indicating reduced risk (OR 0.77, p = 0.01) with concomitant zero heterogeneity (I2 = 0%). ApaI effects pointed to reduced risks, with overall dominant significance (OR 0.69, p = 0.04) and Asian subgroup nonsignificance (OR 0.75-0.93, p = 0.17-0.74). In FokI, Non-Hispanic Caucasians (OR 0.77, p = 0.01) and males (OR 0.36-0.66, p = 0.001-0.04) were protected but not Hispanic Caucasians (OR 1.39-1.85, p = 0.006-0.05) and females (OR 1.72, p = 0.05). Tests of interaction between the genders highlighted female susceptibility and male protection (p = 0.001-0.005). Zero heterogeneity (I2 = 0%) is a key strength of these significant effects. CONCLUSION This meta-analysis confirmed the protective role of the ApaI polymorphism, however, susceptibility and protective effects of the FokI polymorphism may be ethnic and gender specific.

A meta-analysis of the C1420T polymorphism in cytosolic serine hydroxymethyltransferase (SHMT1) among Caucasian colorectal cancer populations

PurposeInconsistency of reported associations between the C1420T polymorphism in the cytosolic serine hydroxymethyltransferase (SHMT1) gene and colorectal cancer (CRC) prompted us to undertake a meta-analysis.MethodsWe conducted searches of published literature in MEDLINE through PubMed up to April 2012. Individual data on 5,043 cases and 6,311 controls from 15 published case–control studies were evaluated. Meta-analyses were performed on the compiled dataset.ResultsIn the overall analysis, association was lacking between the C1420T polymorphism and CRC risk (odds ratio [OR] 0.96–1.04, p = 0.47–0.77), materially unchanged when reanalyzed without the Hardy–Weinberg equilibrium-deviating studies (OR 1.03–1.09, p = 0.22–0.55) or subjected to outlier treatment (OR 0.89–0.99, p = 0.10–0.8). In the ethnic subgroups, Europeans were susceptible (OR 1.11–1.17, p = 0.13–0.48) and Americans, slightly protected (OR 0.86–0.87, p = 0.49–0.61). The increased risk effects, however, became null following outlier treatment (OR 0.95–1.06). Test for interaction between decreased risk associations in the low-folate subgroup (OR 0.60–0.85, p = 0.009–0.03) with the susceptible effects in the high-folate category (OR 1.14–1.22, p = 0.19–0.32) was significant (pinteraction = 0.004).ConclusionsOverall summary estimates imply no associations but suggest geography-specific effects of the SHMT1 polymorphism that render Europeans susceptible, but not Americans. Folate status appears to show an inverse association of this polymorphism with CRC.

Association of male circumcision with risk of prostate cancer: a meta-analysis.

Background:Although early reports have suggested an association between circumcision and prostate cancer (PCa) development, results of subsequent epidemiological studies have been conflicting. Here we examine published articles that explore this association.Methods:We searched MEDLINE through PubMed and Embase for articles reporting on the association between PCa and circumcision, and performed a meta-analysis of qualifying studies.Results:On the basis of seven reports of case–control studies published from 1971 to 2014, overall findings showed nonsignificant reduced risk (odds ratio (OR) 0.88, P=0.19) of PCa in circumcised men compared with uncircumcised men, obtained under heterogeneous conditions (I2=65%). Heterogeneity and nonsignificance were erased when the overall effect was subjected to outlier treatment and three studies omitted (OR 0.90, P=0.04, I2=0%). Furthermore, subgroup analysis showed significantly reduced risks in the following subgroups: (i) post-PSA testing publications (OR 0.88, P=0.01), (ii) population-based studies (OR 0.84, P=0.05), (iii) studies that collected data by personal interview (OR 0.83, P=0.03) and (iv) studies in black race (OR 0.59, P=0.02). The strengths of these summary effects lie in the robustness revealed by sensitivity analysis.Conclusions:Stability of the reduced risks observed in key subgroups suggests that the protective feature of circumcision status against PCa is best seen in the context of the post-PSA testing and population-based studies as well as in the black race subgroup.

A review of genetic factors contributing to the etiopathogenesis of anorectal malformations

BackgroundAnorectal malformation (ARM) is a common congenital anomaly with a wide clinical spectrum. Recently, many genetic and molecular studies have been conducted worldwide highlighting the contribution of genetic factors in its etiology. We summarize the current literature on such genetic factors.Materials and methodsLiterature search was done using different combinations of terms related to genetics in anorectal malformations. From 2012 to June 2017, articles published in the English literature and studies conducted on human population were included.Observations and resultsA paradigm shift was observed from the earlier studies concentrating on genetic aberrations in specific pathways to genome wide arrays exploring single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) in ARM patients. Rare CNVs (including 79 genes) and SNPs have been found to genetically contribute to ARM. Out of disrupted 79 genes one such putative gene is DKK4. Down regulation of CDX-1 gene has also been implicated in isolated ARM patients. In syndromic ARM de novo microdeletion at 17q12 and a few others have been identified.ConclusionMajor genetic aberrations proposed in the pathogenesis of ARM affect members of the Wnt, Hox (homebox) genes, Sonic hedgehog (Shh) and Gli2, Bmp4, Fgf and CDX1 signalling pathways; probable targets of future molecular gene therapy.

Association of the intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms with endometriosis: a systematic review and meta-analysis

BackgroundReported associations of the G241R and K469E polymorphisms of the intercellular adhesion molecule-1 gene (ICAM-1) gene with endometriosis have differed in magnitude.Materials and methodsIn a meta-analysis of six published case–control studies (from five articles), we estimated risk [odds ratio (OR) 95 % confidence intervals (CI)] of associations with these polymorphisms using the Review Manager 5.3 software.ResultsBased on 1213 cases and 1103 controls, overall analysis showed significant increased risk in the homozygous (OR 2.83, 95 % CI 0.99–8.10, p = 0.05), dominant (OR 1.86, 95 % CI 1.00–3.46, p = 0.05) and codominant (OR 2.15, 95 % CI 1.06–4.35, p = 0.03) models. Confined to the studies in Hardy–Weinberg Equilibrium erased the significance (OR 1.59–2.59, 95 % CI 0.81–8.22, p = 0.10–0.15). Asian effects were variable (OR 0.93–1.09, p = 0.50–0.57), but Caucasian effects were not (OR 4.09–13.60, p < 0.0001). Independent data for the late stages of endometriosis suggest protection of the ICAM-1 K469E polymorphism among the Asians (OR 0.91–0.95, p = 0.35–0.71). These effects were weak but non-heterogeneous (Pheterogeneity = 0.17–0.57, I2 = 0–40 %).ConclusionIn summary, strengths of the overall effects were consistency, significance and robustness but limited by their high heterogeneity. These strengths and limitations were also observed in the Caucasian subgroup which when tested for interaction against the contrasting Asian effects, highlighted Caucasian susceptibility (p = 0.004–0.01). The findings are an interplay of strengths and limitations, which warrant awareness of their interpretation as susceptibility markers for this disorder.