Association Study of a Functional Variant on ABCG2 Gene with Sunitinib-Induced Severe Adverse Drug Reaction

Sunitinib is a tyrosine kinase inhibitor and used as the first-line treatment for advanced renal cell carcinoma (RCC). Nevertheless, inter-individual variability of drug’s toxicity was often observed among patients who received sunitinib treatment. This study is to investigate the association of a functional germline variant on ABCG2 that affects the pharmacokinetics of sunitinib with sunitinib-induced toxicity of RCC patients in the Japanese population. A total of 219 RCC patients were recruited to this pharmacogenetic study. ABCG2 421C>A (Q141K) was genotyped by using PCR-Invader assay. The associations of both clinical and genetic variables were evaluated with logistic regression analysis and subsequently receiver operating characteristic (ROC) curve was plotted. About 43% (92/216) of RCC patients that received sunitinib treatment developed severe grade 3 or grade 4 thrombocytopenia according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 3.0, the most common sunitinib-induced adverse reaction in this study. In the univariate analysis, both age (P = 7.77x10^-3, odds ratio (OR) = 1.04, 95%CI = 1.01–1.07) and ABCG2 421C>A (P = 1.87x10^-2, OR = 1.71, 95%CI = 1.09–2.68) showed association with sunitinib-induced severe thrombocytopenia. Multivariate analysis indicated that the variant ABCG2 421C>A is suggestively associated with severe thrombocytopenia (P = 8.41x10^-3, OR = 1.86, 95% CI = 1.17–2.94) after adjustment of age as a confounding factor. The area under curve (AUC) of the risk prediction model that utilized age and ABCG2 421C>A was 0.648 with sensitivity of 0.859 and specificity of 0.415. Severe thrombocytopenia is the most common adverse reaction of sunitinib treatment in Japanese RCC patients. ABCG2 421C>A could explain part of the inter-individual variability of sunitinib-induced severe thrombocytopenia.     

Association between TNFA Gene Polymorphisms and Helicobacter pylori Infection: A Meta-Analysis

Background

Several host genetic factors are thought to affect susceptibility to Helicobacter pylori infection-related diseases, including tumor necrosis factor (TNF)-α. Previous studies have evaluated the association between TNFA gene polymorphisms and H. pylori infection, but the results were inconclusive. We conducted this meta-analysis to clarify the association between TNFA polymorphisms and H. pylori infection.

Methods

Published literature within PubMed, Embase, and the Cochrane Library were used in our meta-analysis. Data were analyzed with the Stata13.1 software package using pooled odds ratios (ORs) with 95% confidence intervals (CI).

Results

A total of 24 studies were included in our study. The TNFA -308G>A polymorphism was associated with decreasing H. pylori infection (AA vs. AG+GG, OR = 0.64, 95% CI = 0.43–0.97; AA vs. GG, OR = 0.64, 95% CI = 0.43–0.97). A significantly decreased risk was also found for -1031T>C polymorphism (CC vs. CT+TT, OR = 0.61, 95% CI = 0.44–0.84). -863C>A polymorphism was associated with increasing risk of H. pylori infection (AA+AC vs. CC, OR = 1.47, 95% CI = 1.16–1.86; A allele vs. C allele, OR = 1.40, 95% CI = 1.14–1.72). There was no significant association between -857C>T polymorphism and H. pylori infection. When stratified analysis was conducted on H. pylori infection detection methods, -857C>T and -863C>A polymorphisms were associated with H. pylori infection for the non-ELISA subgroup. When stratified for ethnicity or study design, -863C>A significantly increased the risk and -1031T>C decreased the risk for the Asian subgroup and hospital-based subgroup.

Conclusion

Results of our meta-analysis demonstrate that TNFA -308G>A and -1031 T>C polymorphisms may be protective factors against H. pylori infection, and -863C>A may be a risk factor, especially in Asian populations. Further studies with larger sample sizes are required to validate these results.     

Association of IL10 Polymorphisms and Leprosy: A Meta-Analysis

Leprosy is a chronic infectious disease that depends on the interplay of several factors. Single nucleotide polymorphisms (SNPs) in host immune related genes have been consistently suggested as participants in susceptibility towards disease. Interleukin-10 (IL-10) is a crucial immunomodulatory cytokine in mycobacterial pathogenesis and especially the -819C>T SNP (rs1800871) has been tested in several case-control studies indicating association with leprosy risk, although a recent consensus estimate is still missing. In this study, we evaluated the association of the -819C>T SNP and leprosy in two new Brazilian family-based populations. Then, we performed meta-analysis for this polymorphism summarizing published studies including these Brazilian family-based groups. Finally, we also retrieved published studies for other distal and proximal IL10 polymorphisms: -3575 T>A (rs1800890), -2849 G>A (rs6703630), -2763 C>A (rs6693899), -1082 G>A (rs1800896) and -592 C>A (rs1800872). Results from meta-analysis supported a significant susceptibility association for the -819T allele, with pooled Odds Ratio of 1.22 (CI = 1.11–1.34) and P-value = 3x10^–5 confirming previous data. This result remained unaltered after inclusion of the Brazilian family-based groups (OR = 1.2, CI = 1.10–1.31, P-value = 2x10^–5). Also, meta-analysis confirmed association of -592 A allele and leprosy outcome (OR = 1.24, CI = 1.03–1.50, P-value = 0.02). In support of this, linkage disequilibrium analysis in 1000 genomes AFR, EUR, ASN and AMR populations pointed to r² = 1.0 between the -592C>A and -819C>T SNPs. We found no evidence of association for the other IL10 polymorphisms analyzed for leprosy outcome. Our results reinforce the role of the -819C>T as a tag SNP (rs1800871) and its association with leprosy susceptibility.     

The Association between VEGFR Gene Polymorphisms and Stroke: A Meta-Analysis

Several published articles investigated the relationship between VEGF receptor gene polymorphisms and stroke, but they failed to reach the same conclusion. This meta-analysis was performed to identify the relationships between VEGF receptor gene and the risk of stroke. The PubMed, Embase, China National Knowledge Infrastructure (CNKI) database, Wanfang Chinese database, and VIP Chinese database were systemically searched. Data was extracted by two independent reviewers. The pooled odds ratio (OR) with 95% confidence interval (CI) were calculated. 5 case-control studies with a total of 2904 patients with stroke and 2824 control subjects were included, including 2904 cases and 2824 controls for -604T>C, 2733 cases and 2663 controls for +1192C>T, and 2733 cases and 2663 controls for +1719A>T. Under the dominant and recessive models, respectively, the overall ORs and 95% CIs of -604 C were 0.749, 0.493–1.138 (P = 0.176) and 0.819, 0.544–1.234 (P = 0.340); the overall ORs and 95% CIs of +1192 T were 1.148, 0.876–1.504 (P = 0.318) and 1.611, 1.004–2.586 (P = 0.048); the overall ORs and 95% CIs of +1719 T were 1.227, 0.932–1.615 (P = 0.146) and 1.139, 1.015–1.279 (P = 0.027). Our finding indicates that +1192C>T and +1719A>T may be associated with the risk of stroke, but not -604T>C.     

Effects of Nucleotides Supplementation of Infant Formulas on Plasma and Erythrocyte Fatty Acid Composition: A Meta-Analysis

Objective

Nucleotides (NTs) have been added to infant formulas for several years due to their health benefits. However, studies have reported inconsistent findings regarding the association between NTs and fatty acid (FA) composition. A meta-analysis was performed to assess the effects of NTs supplementation of infant formula on erythrocyte and plasma FA composition.

Methods

Randomized controlled trials that evaluated the association between NTs supplementation and FA composition and were published before October 2014 were included. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. Heterogeneity was assessed using Q and I ² tests.

Results

Eight studies (364 infants) were included in the meta-analysis. NTs supplementation did not affect the concentrations of total saturated FAs (SMD= 0.05; 95% CI= -0.23–0.32; P = 0.75) or total monounsaturated FAs (SMD= -0.01; 95% CI= -0.28–0.27; P = 0.95) in erythrocyte membranes. Erythrocyte total n-3 (SMD= 0.15; 95% CI= -0.11–0.41; P = 0.27) and n-6 PUFA (SMD= -0.16; 95% CI= -0.42–0.10, P = 0.22) concentrations did not increase with NTs supplementation. The concentrations of erythrocyte n-3 PUFA (18:3, 20:5, 22:5, and 22:6) and n-6 PUFA (18:2, 20:3, 20:4, and 22:4) were not affected by NTs supplementation. NTs significantly increased plasma concentrations of 18:2 n-6 (SMD= 0.90; 95% CI= 0.47–1.33; P < 0.0001), 20:3 n-6 (SMD= 0.56; 95% CI= 0.14–0.97; P = 0.009), and 20:4 n-6 PUFA (SMD= 0.92; 95% CI= 0.50–1.35; P < 0.0001), and significantly decreased the concentration of plasma 18:3 n-3 PUFA (SMD= -0.60; 95% CI -1.12 to -0.09; P = 0.02). No effect was obtained on plasma 20:2 n-6 PUFA concentrations (SMD= 0.06; 95 % CI, -1.03 to -0.2; P = 0.93).

Conclusions

Our meta-analysis revealed that NTs supplementation significantly increased plasma 18:2 n-6, 20:3 n-6, and 20:4 n-6 PUFA concentrations in infants, but did not affect erythrocyte FA composition.     

Parenting interventions to promote early child development in the first three years of life: A global systematic review and meta-analysis

BackgroundParents are the primary caregivers of young children. Responsive parent–child relationships and parental support for learning during the earliest years of life are crucial for promoting early child development (ECD). We conducted a global systematic review and meta-analysis to evaluate the effectiveness of parenting interventions on ECD and parenting outcomes.Methods and findingsWe searched MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and Global Health Library for peer-reviewed, published articles from database inception until November 15, 2020. We included randomized controlled trials (RCTs) of parenting interventions delivered during the first 3 years of life that evaluated at least 1 ECD outcome. At least 2 reviewers independently screened, extracted data, and assessed study quality from eligible studies. ECD outcomes included cognitive, language, motor, and socioemotional development, behavior problems, and attachment. Parenting outcomes included parenting knowledge, parenting practices, parent–child interactions, and parental depressive symptoms. We calculated intervention effect sizes as the standardized mean difference (SMD) and estimated pooled effect sizes for each outcome separately using robust variance estimation meta-analytic approaches. We used random-effects meta-regression models to assess potential effect modification by country-income level, child age, intervention content, duration, delivery, setting, and study quality. This review was registered with PROSPERO (CRD42018092458 and CRD42018092461). Of the 11,920 articles identified, we included 111 articles representing 102 unique RCTs. Pooled effect sizes indicated positive benefits of parenting interventions on child cognitive development (SMD = 0.32, 95% CI [confidence interval]: 0.23, 0.40, P < 0.001), language development (SMD = 0.28, 95% CI: 0.18 to 0.37, P < 0.001), motor development (SMD = 0.24, 95% CI: 0.15 to 0.32, P < 0.001), socioemotional development (SMD = 0.19, 95% CI: 0.10 to 0.28, P < 0.001), and attachment (SMD = 0.29, 95% CI: 0.18 to 0.40, P < 0.001) and reductions in behavior problems (SMD = −0.13, 95% CI: −0.18 to −0.08, P < 0.001). Positive benefits were also found on parenting knowledge (SMD = 0.56, 95% CI: 0.33 to 0.79, P < 0.001), parenting practices (SMD = 0.33, 95% CI: 0.22 to 0.44, P < 0.001), and parent–child interactions (SMD = 0.39, 95% CI: 0.24 to 0.53, P < 0.001). However, there was no significant reduction in parental depressive symptoms (SMD = −0.07, 95% CI: −0.16 to 0.02, P = 0.08). Subgroup analyses revealed significantly greater effects on child cognitive, language, and motor development, and parenting practices in low- and middle-income countries compared to high-income countries; and significantly greater effects on child cognitive development, parenting knowledge, parenting practices, and parent–child interactions for programs that focused on responsive caregiving compared to those that did not. On the other hand, there was no clear evidence of effect modification by child age, intervention duration, delivery, setting, or study risk of bias. Study limitations include considerable unexplained heterogeneity, inadequate reporting of intervention content and implementation, and varying quality of evidence in terms of the conduct of trials and robustness of outcome measures used across studies.ConclusionsParenting interventions for children during the first 3 years of life are effective for improving ECD outcomes and enhancing parenting outcomes across low-, middle-, and high-income countries. Increasing implementation of effective and high-quality parenting interventions is needed globally and at scale in order to support parents and enable young children to achieve their full developmental potential.

In a systematic review and meta-analysis, Joshua Jeong and colleagues study the effectiveness of parenting interventions in children 3 years and younger in promoting early childhood development and parenting outcomes.     

The rs738409 (I148M) variant of the PNPLA3 gene and cirrhosis: a meta-analysis

The human patatin-like phospholipase domain-containing-3 (PNPLA3) gene rs738409 C>G polymorphism is associated with several types of liver disease. The aim of this meta-analysis was to assess the risk of cirrhosis on the basis of rs738409 allele frequency and genotype. Medline, the Cochrane Library, EMBASE, and Google Scholar were searched for prospective and retrospective studies assessing the effect of the rs738409 polymorphism on liver cirrhosis. Seven studies, involving 2,023 patients with cirrhosis, were included. The G allele was associated with a significantly increased risk of cirrhosis versus the C allele [pooled odds ratio (OR) = 1.86, 95% confidence interval (CI) = 1.64–2.12, Z = 9.55, P < 0.001]. Both the GC and GG genotypes were associated with a significantly increased risk of cirrhosis versus the CC genotype (GC vs. CC: pooled OR = 1.73, 95% CI = 1.51–1.98, Z = 7.86, P < 0.001; GG vs. CC: pooled OR = 3.41, 95% CI = 2.77–4.18, Z = 11.65, P < 0.001). There was no evidence of publication bias. Our findings suggest that patients at risk for liver cirrhosis may benefit from PNPLA3 genotyping and thus more intensive monitoring if the rs738409 C>G polymorphism is identified.     

Polymorphisms in ERCC1 and XPF Genes and Risk of Gastric Cancer in an Eastern Chinese Population

Background

Inherited functional single nucleotide polymorphisms (SNPs) in DNA repair genes may alter DNA repair capacity and thus contribute to cancer risk.

Methods

Three ERCC1 functional SNPs (rs2298881C>A, rs3212986C>A and rs11615G>A) and two XPF/ERCC4 functional SNPs (rs2276466C>G and rs6498486A>C) were genotyped for 1125 gastric adenocarcinoma cases and 1196 cancer-free controls by Taqman assays. Odds ratios (OR) and 95% confidence intervals (CI) were used to estimate risk associations, and false-positive report probabilities (FPRP) were calculated for assessing significant findings.

Results

ERCC1 rs2298881C and rs11615A variant genotypes were associated with increased gastric cancer risk (adjusted OR = 1.33, 95% CI = 1.05–1.67 for rs2298881 AC/CC and adjusted OR = 1.23, 95% CI = 1.05–1.46 for rs11615 AG/AA, compared with their common genotype AA and GG, respectively). Patients with 2–3 ERCC1 risk genotypes had significant increased risk (adjusted OR = 1.56, 95% CI = 1.27–1.93), compared with those with 0–1 ERCC1 risk genotypes, and this risk was more significantly in subgroups of never drinkers, non-gastric cardia adenocarcinoma (NGCA) and clinical stage I+II. All these risks were not observed for XPF SNPs.

Conclusions

These findings suggest that functional ERCC1 SNPs may contribute to risk of gastric cancer. Larger and well-designed studies with different ethnic populations are needed to validate our findings.     

PUNISHER rs12318065 C>A transversion: a putative somatic driver mutation for poor prognosis in colon cancer

Objective: Colon cancer (CC) remains one of the leading causes of cancer death worldwide. Several mutations/polymorphisms have been implicated in CC development and/or progression. The role of the recently identified variants related to the long non-coding RNAs (lncRNAs) family has not yet been fully uncovered. In this sense, we aimed to explore the association between the lncRNA PUNISHER rs12318065 variant and the CC risk and/or prognosis. Methods: A total of 408 CC (paired 204 cancer/non-cancer) tissues were genotyped using the TaqMan allelic discrimination assay. Results: “A” variant was associated with higher susceptibility to develop CC under heterozygote (A/C vs. C/C: OR = 1.39, 95%CI = 1.09–2.17, P=0.002), homozygote (A/A vs. C/C: OR = 2.63, 95%CI = 1.51–4.58, P=0.001), dominant (A/C-A/A vs. C/C: OR = 1.72, 95%CI = 1.15–02.57, P=0.008), and recessive (A/A vs. C/C-A/C: OR = 2.23, 95%CI = 1.34–3.72, P=0.001) models. Patients with metastasis were more likely to harbor A/A and A/C genotypes (16.7% and 14.1%) than 11% with the C/C genotype (P=0.027). Patients harboring C>A somatic mutation were more likely to develop relapse (52.6% vs. 26.5%, P=0.003), have poor survival (57.9% vs. 27.7%, P=0.001), and have shorter disease-free survival (43.2 ± 2.6 months vs. 56.8 ± 1.29 months, P<0.001) and overall survival (49.6 ± 2.4 months vs. 56.6 ± 0.99 months, P<0.001). Multivariate Cox regression analysis showed that patients with distal metastasis and C>A somatic mutation were three times more likely to die. Conclusions: To our knowledge, the present study is the first to identify that the PUNISHER rs12318065 variant could be a novel putative driver of colon cancer and is associated with poor prognosis.     

The Interleukin-10 Promoter Polymorphism rs1800872 (-592C>A), Contributes to Cancer Susceptibility: Meta-Analysis of 16 785 Cases and 19 713 Controls

Interleukin-10 (IL-10) is a multifunctional cytokine which participates in the development and progression of various malignant tumors. To date, a number of case–control studies were conducted to detect the association between IL-10-592C>A polymorphism and cancer risk in humans. However, the results of these studies on the association remain conflicting. In an effort to solve this controversy, we performed a meta-analysis based on 70 case–control studies from 65 articles, including 16 785 cancer cases and 19 713 controls. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. The overall results suggested that the variant homozygote genotype AA of the IL-10-592C>A polymorphism was associated with a moderately decreased risk of all cancer types (OR = 0.90, 95% CI = 0.83–0.98 for homozygote comparison, OR = 0.92, 95% CI = 0.86–0.98 for recessive model). In the stratified analyses, the risk remained for studies of smoking-related cancer, Asian populations and hospital-based studies. These results suggested that the IL-10-592C>A polymorphism might contribute to the cancer susceptibility, especially in smoking-related cancer, Asians and hospital-based studies. Further studies are needed to confirm the relationship.     

Association Study of Single Nucleotide Polymorphisms in XRCC1 Gene with the Risk of Gastric Cancer in Chinese Population

Gastric cancer is one of highly cancer-related deaths in the world. Previous evidence suggests that the X-ray repair cross-complementing group 1 gene (XRCC1) is one of the most important candidate genes for influencing gastric cancer risk. The objective of this study was to detect the potential association of genetic variants in XRCC1 gene with gastric cancer risk in Chinese Han population. In total, we enrolled 395 gastric cancer patients and 398 cancer-free controls in this study. The genotyping of c.910A>G and c.1804C>A genetic variants in XRCC1 gene were investigate by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and created restriction site-PCR (CRS-PCR) methods, respectively. We found the genotypes/alleles from these two genetic variants were statistically associated with the increased risk of gastric cancer (for c.910A>G, GG versus (vs.) AA: OR = 2.00, 95% CI 1.21-3.31; AG vs. AA: OR = 1.50, 95% CI 1.12-2.02; GG/AG vs. AA: OR = 1.59, 95% CI 1.20-2.10; GG vs. AG/AA: OR = 1.68, 95% CI 1.03-2.73; G vs. A: OR = 1.47, 95% CI 1.18-1.83; for c.1804C>A, AA vs. CC: OR = 2.68, 95% CI 1.46-4.94; AA vs. CA/CC: OR = 2.62, 95% CI 1.44-4.76; A vs. C: OR = 1.33, 95% CI 1.06-1.66). The allele-G of c.910A>G and allele-A of c.1804C>A genetic variants may contribute to gastric cancer susceptibility. These preliminary results indicate that these XRCC1 genetic variants are potentially related to gastric cancer susceptibility in Chinese Han population, and might be used as molecular markers.     

Tumor Necrosis Factor (TNF) –308G>A,Nitric Oxide Synthase 3 (NOS3) +894G>T Polymorphisms and Migraine Risk: A Meta-Analysis

Background and Objective

Conflicting data have been reported on the association between tumor necrosis factor (TNF) –308G>A and nitric oxide synthase 3 (NOS3) +894G>T polymorphisms and migraine. We performed a meta-analysis of case-control studies to evaluate whether the TNF –308G>A and NOS3 +894G>T polymorphisms confer genetic susceptibility to migraine.

Method

We performed an updated meta-analysis for TNF –308G>A and a meta-analysis for NOS3 +894G>T based on studies published up to July 2014. We calculated study specific odds ratios (OR) and 95% confidence intervals (95% CI) assuming allele contrast, dominant model, recessive model, and co-dominant model as pooled effect estimates.

Results

Eleven studies in 6682 migraineurs and 22591 controls for TNF –308G>A and six studies in 1055 migraineurs and 877 controls for NOS3 +894G>T were included in the analysis. Neither indicated overall associations between gene polymorphisms and migraine risk. Subgroup analyses suggested that the “A” allele of the TNF –308G>A variant increases the risk of migraine among non-Caucasians (dominant model: pooled OR = 1.82; 95% CI 1.15 – 2.87). The risk of migraine with aura (MA) was increased among both Caucasians and non-Caucasians. Subgroup analyses suggested that the “T” allele of the NOS3 +894G>T variant increases the risk of migraine among non-Caucasians (co-dominant model: pooled OR = 2.10; 95% CI 1.14 – 3.88).

Conclusions

Our findings appear to support the hypothesis that the TNF –308G>A polymorphism may act as a genetic susceptibility factor for migraine among non-Caucasians and that the NOS3 +894G>T polymorphism may modulate the risk of migraine among non-Caucasians.     

Associations of Genetic Variants in the PSCA,MUC1 and PLCE1 Genes with Stomach Cancer Susceptibility in a Chinese Population

BackgroundSeveral genetic variants including PSCA rs2294008 C>T and rs2976392 G>A, MUC1 rs4072037 T>C, and PLCE1 rs2274223 A>G have shown significant association with stomach cancer risk in the previous genome-wide association studies (GWASs).MethodsTo evaluate associations of these SNPs in the Han Chinese, an independent hospital based case-control study was performed by genotyping these four polymorphisms in a total of 692 stomach cancer cases and 774 healthy controls acquired by using frequency matching for age and gender. False-positive report probability (FPRP) analysis was also performed to validate all statistically significant findings.ResultsIn the current study, significant association with stomach cancer susceptibility was observed for all the four polymorphisms of interest. Specifically, a significant increased stomach cancer risk was associated with PSCA rs2294008 (CT vs. CC: adjusted OR = 1.37, 95% CI = 1.07–1.74, and CT/TT vs.CC: adjusted OR = 1.30, 95% CI = 1.03–1.63), PSCA rs2976392 (AG vs. GG: adjusted OR = 1.30, 95% CI = 1.02–1.65, and AG/AA vs. GG: adjusted OR = 1.26, 95% CI = 1.00–1.59), or PLCE1 rs2274223 (AG vs. AA: adjusted OR = 1.48, 95% CI = 1.15–1.90, and AG/GG vs. AA: adjusted OR = 1.45, 95% CI = 1.14–1.84), respectively. In contrast, MUC1 rs4072037 was shown to decrease the cancer risk (CT vs. TT: adjusted OR = 0.77, 95% CI = 0.60–0.98). Patients with more than one risk genotypes had significant increased risk to develop stomach cancer (adjusted OR = 1.30, 95% CI = 1.03–1.64), when compared with those having 0–1 risk genotypes. Stratified analysis indicated that the increased risk was more pronounced in younger subjects, men, ever smokers, smokers with pack years ≤ 27, patients with high BMI, or non-cardia stomach cancer.ConclusionsThis study substantiated the associations between four previous reported genetic variants and stomach cancer susceptibility in an independent Han Chinese population. Further studies with larger sample size and different ethnicities are warranted to validate our findings.     

Association between CXCL10 and DPP4 Gene Polymorphisms and a Complementary Role for Unfavorable IL28B Genotype in Prediction of Treatment Response in Thai Patients with Chronic Hepatitis C Virus Infection

Pretreatment serum levels of interferon-γ-inducible protein-10 (IP-10, CXCL10) and dipeptidyl peptidase-4 (DPP IV) predict treatment response in chronic hepatitis C (CHC). The association between functional genetic polymorphisms of CXCL10 and DPP4 and treatment outcome has not previously been studied. This study aimed to determine the association between genetic variations of CXCL10 and DPP4 and the outcome of treatment with pegylated interferon-α (PEG-IFN-α) based therapy in Thai patients with CHC. 602 Thai patients with CHC treated using a PEG-IFN-α based regimen were genotyped for CXCL10 rs56061981 G>A and IL28B rs12979860 C>T. In addition, in patients infected with CHC genotype 1, DPP4 (rs13015258 A>C, rs17848916 T>C, rs41268649 G>A, and rs 17574 T>C) were genotyped. Correlations between single nucleotide polymorphisms, genotype, and treatment response were analyzed. The rate of sustained virologic response (SVR) was higher for the CC genotype of IL28B rs12979860 polymorphisms than for non-CC in both genotype 1 (60.6% vs. 29.4%, P < 0.001) and non-genotype 1 (69.4% vs. 49.1%, P < 0.05) CHC. SVR was not associated with the CXCL10 gene variant in all viral genotypes or DPP4 gene polymorphisms in viral genotype1. Multivariate analysis revealed IL28B rs12979860 CC genotype (OR = 3.12; 95% CI, 1.72–5.67; P < 0.001), hepatitis C virus RNA < 400,000 IU/ml (OR = 2.21; 95% CI, 1.22–3.99, P < 0.05), age < 45 years (OR = 2.03; 95% CI, 1.11–3.68; P < 0.05), and liver fibrosis stage 0–1 (OR = 1.64; 95% CI, 1.01–2.65, P < 0.05) were independent factors for SVR. Unfavorable IL28B rs12979860 CT or TT genotypes with the CXCL10 rs56061981 non-GG genotype were associated with a higher SVR than GG genotype (66.7% vs. 33.0%, P = 0.004) in viral genotype 1. In Thai CHC genotype 1 infected patients with an unfavorable IL28B rs12979860 CT/TT genotype, the complementary CXCL10 polymorphism strongly enhances prediction of treatment response.     

Polymorphisms in CYP1B1, CYP3A5, GSTT1, and SULT1A1 Are Associated with Early Age Acute Leukemia

Based on observational studies, early age leukemia (EAL) was associated with maternal hormone exposure during pregnancy. We studied the association between genetic polymorphisms of estrogen metabolism and EAL. Using data from the Brazilian Collaborative Study Group of Infant Acute Leukemia (2000–2012), 350 cases and 404 age-matched controls and 134 mothers of cases and controls were genotyped to explore polymorphisms in genes of the estrogen metabolism pathway: CYP1B1 (c.1294C>G, rs1056836), CYP3A4 (c.-392A>G, rs2740574), CYP3A5 (c.219-237G>A, rs776746), GSTM1/GSTT1 deletions, and SULT1A1 (c.638G>A, rs9282861; and c.667A>G, rs1801030). Logistic regression was used to calculate the odds ratios (OR) with 95% confidence intervals (CIs), and unconditional logistic regression was used to estimate adjusted odds ratios (aORs) by ethnicity. Because of multiple testing, p values < 0.01 were significant after Bonferroni correction. SULT1A1 (c.638G>A) was associated to infant acute lymphoblastic leukemia and acute myeloid leukemia (AML) risk in males (additive model: aOR = 0.52; 95% CI: 0.29–0.95, p = 0.03; dominant model: aOR = 2.18; 95% CI: 1.17–4.05, p = 0.01, respectively). CYP1B1 polymorphism was associated with a decreased risk of AML either for non-white or female children (additive model: OR = 0.24; 95% CI: 0.08–0.76, p < 0.01; additive model: aOR = 0.27; 95% CI: 0.08–0.89, p = 0.03, respectively). Since polymorphisms of Cytochrome P450 genes presented gender-specific risk associations, we also investigated their expression. CYP1B1 was not expressed in 57.1% of EAL cases, and its expression varied by genotype, gender, and leukemia subtype. Maternal-fetal GSTT1 null genotype was associated with risk of EAL. This study shows that polymorphisms in genes of estrogen metabolism confer genetic susceptibility to EAL, mainly in males, and maternal susceptibility genes modify the risk for developing EAL in newborns.     

Association of SNP Rs9943582 in APLNR with Left Ventricle Systolic Dysfunction in Patients with Coronary Artery Disease in a Chinese Han GeneID Population

Heart failure affects 1–2% of the adult population worldwide and coronary artery disease (CAD) is the underlying etiology of heart failure in 70% of the patients. The pathway of apelin and its apelin receptor (APJ) was implicated in the pathogenesis of heart failure in animal models, but a similar role in humans is unknown. We studied a functional variant, rs9943582 (-154G/A), at the 5’-untranslated region, that was associated with decreased expression of the APJ receptor gene (APLNR) in a population consisting of 1,751 CAD cases and 1,022 controls. Variant rs9943582 was not associated with CAD, but among CAD patients, it showed significant association with left ventricular systolic dysfunction (431 CAD patients with left ventricular systolic dysfunction (LV ejection fraction or LVEF< 40%) versus 1,046 CAD patients without LV systolic dysfunction (LVEF>50%) (P-adj = 6.71×10^-5, OR = 1.43, 95% CI, 1.20–1.70). Moreover, rs9943582 also showed significant association with quantitative echocardiographic parameters, including left ventricular end-diastolic diameter (effect size: increased 1.67±0.43 mm per risk allele A, P = 1.15×10^-4), left atrial size (effect size: increased 2.12±0.61 mm per risk allele A, P = 9.56×10^-4) and LVEF (effect size: decreased 2.59±0.32 percent per risk allele A, P = 7.50×10^-15). Our findings demonstrate that allele A of rs9943582 was significantly associated with left ventricular systolic dysfunction, left ventricular end-diastolic diameter, the left atrial diameter and LVEF in the CAD population, which suggests an important role of the apelin/APJ system in the pathology of heart failure associated with ischemic heart disease.     

A Meta-Analysis of the Association between ESR1 Genetic Variants and the Risk of Breast Cancer

BackgroundSingle nucleotide polymorphisms (SNPs) in the estrogen receptor gene (ESR1) play critical roles in breast cancer (BC) susceptibility. Genome-wide association studies have reported that SNPs in ESR1 are associated with BC susceptibility; however, the results of recent studies have been inconsistent. Therefore, we performed this meta-analysis to obtain more accurate and credible results.MethodsWe pooled published literature from PubMed, EMBASE, and Web of Science and calculated odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of associations using fixed effects models and random effects models. Twenty relevant case-control and cohort studies of the 3 related SNPs were identified.ResultsThree SNPs of the ESR1 gene, rs2077647:T>C, rs2228480:G>A and rs3798577:T>C, were not associated with increased BC risk in our overall meta-analysis. Stratified analysis by ethnicity showed that in Caucasians, the rs2228480 AA genotype was associated with a 26% decreased risk of BC compared with the GG genotype (OR = 0.740, 95% CI: 0.555–0.987). The C allele of the rs3798577:T>C variant was associated with decreased BC risk in Asians (OR = 0.828, 95% CI: 0.730–0.939), while Caucasians with this allele were found to experience significantly increased BC risk (OR = 1.551, 95% CI: 1.037–2.321). A non-significant association between rs2077647 and BC risk was identified in all of the evaluated ethnic populations.ConclusionRs3798577 was associated with an increased risk of BC in Caucasian populations but a decreased risk in Asians. Rs2228480 had a large protective effect in Caucasians, while rs2077647 was not associated with BC risk.     

Association of PDE4B Polymorphisms with Susceptibility to Schizophrenia: A Meta-Analysis of Case-Control Studies

Background

The PDE4B single nucleotide polymorphisms (SNPs) have been reported to be associated with schizophrenia risk. However, current findings are ambiguous or even conflicting. To better facilitate the understanding the genetic role played by PDE4B in susceptibility to schizophrenia, we collected currently available data and conducted this meta-analysis.

Methods

A comprehensive electronic literature searching of PubMed, Embase, Web of Science and Cochrane Library was performed. The association between PDE4B SNPs and schizophrenia was evaluated by odds ratios (ORs) and 95% confidence intervals (CIs) under allelic, dominant and recessive genetic models. The random effects model was utilized when high between-study heterogeneity (I² > 50%) existed, otherwise the fixed effects model was used.

Results

Five studies comprising 2376 schizophrenia patients and 3093 controls were finally included for meta-analysis. The rs1040716 was statistically significantly associated with schizophrenia risk in Asian and Caucasian populations under dominant model (OR = 0.87, 95% CI: 0.76–0.99, P = 0.04). The rs2180335 was significantly related with schizophrenia risk in Asian populations under allelic (OR = 0.82, 95% CI: 0.72–0.93, P = 0.003) and dominant (OR = 0.75, 95% CI: 0.64–0.88, P < 0.001) models. A significant association was also observed between rs4320761 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.75–1.00, P = 0.048). In addition, a strong association tendency was found between rs6588190 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.76–1.00, P = 0.055).

Conclusion

This meta-analysis suggests that PDE4B SNPs are genetically associated with susceptibility to schizophrenia. However, due to limited sample size, more large-scale, multi-racial association studies are needed to further clarify the genetic association between various PDE4B variants and schizophrenia.     

Molecular Determination of Vascular Endothelial Growth Factor,miRNA-423 Gene Abnormalities by Utilizing ARMS-PCR and Their Association with Fetal Hemoglobin Expression in the Patients with Sickle Cell Disease

Recent studies have indicated that microRNA and VEGF are considered to be genetic modifiers and are associated with elevated levels of fetal haemoglobin HbF, and thus they reduce the clinical impact of sickle haemoglobin (HbS) patients. This cross-sectional study was performed on clinical confirmed subjects of SCD cases. miR-423-rs6505162 C>T and VEGF-2578 C>A genotyping was conducted by ARMS-PCR in SCD and healthy controls. A strong clinical significance was reported while comparing the association of miR-423 C>T genotypes between SCD patients and controls (p = 0.031). The microRNA-423 AA genotype was associated with an increased severity of SCD in codominant model with odd ratio (OR = 2.36, 95% CI, (1.15–4.84), p = 0.018) and similarly a significant association was observed in recessive inheritance model for microRNA-423 AA vs (CC+CA) genotypes (OR = 2.19, 95% CI, (1.32–3.62), p < 0.002). The A allele was associated with SCD severity (OR = 1.57, 95% CI, (1.13–2.19), p < 0.007). The distribution of VEGF-2578 C>A genotypes between SCD patients and healthy controls was significant (p < 0.013). Our results indicated that in the codominant model, the VEGF-2578-CA genotype was strongly associated with increased SCD severity with OR = 2.56, 95% CI, (1.36–4.82), p < 0.003. The higher expression of HbA1 (65.9%), HbA2 (4.40%), was reported in SCD patients carrying miR-423-AA genotype than miR-423 CA genotype in SCD patients carrying miR-423 CA genotype HbA1 (59.98%), HbA2 (3.74%) whereas SCD patients carrying miR-423 CA genotype has higher expression of HbF (0.98%) and HbS (38.1%) than in the patients carrying AA genotype HbF (0.60%), HbS (36.1%). ARMS-PCR has been proven to be rapid, inexpensive and is highly applicable to gene mutation screening in laboratories and clinical practices. This research highlights the significance of elucidating genetic determinants that play roles in the amelioration of the HbF levels that is used as an indicator of severity of clinical complications of the monogenic disease. Further well-designed studies with larger sample sizes are necessary to confirm our findings.     

The Influence of Diabetes,Glycemic Control,and Diabetes-Related Comorbidities on Pulmonary Tuberculosis

Background

To assess the influence of diabetes mellitus (DM), glycemic control, and diabetes-related comorbidities on manifestations and outcome of treatment of pulmonary tuberculosis (TB).

Methodology/Principal Findings

Culture positive pulmonary TB patients notified to health authorities in three hospitals in Taiwan from 2005–2010 were investigated. Glycemic control was assessed by glycated haemoglobin A1C (HbA1C) and diabetic patients were categorized into 3 groups: HbA1C<7%, HbA1C 7–9%, HbA1C>9%. 1,473 (705 with DM and 768 without DM) patients were enrolled. Of the 705 diabetic patients, 82 (11.6%) had pretreatment HbA1C<7%, 152 (21.6%) 7%–9%, 276 (39.2%) >9%, and 195 (27.7%) had no information of HbA1C. The proportions of patients with any symptom, cough, hemoptysis, tiredness and weight loss were all highest in diabetic patients with HbA1C>9%. In multivariate analysis adjusted for age, sex, smoking, and drug resistance, diabetic patients with HbA1C>9% (adjOR 3.55, 95% CI 2.40–5.25) and HbA1C 7–9% (adjOR 1.62, 95% CI 1.07–2.44) were significantly more likely to be smear positive as compared with non-diabetic patients, but not those with HbA1C<7% (adjOR 1.16, 95% CI 0.70–1.92). The influence of DM on outcome of TB treatment was not proportionately related to HbA1C, but mainly mediated through diabetes-related comorbidities. Patients with diabetes-related comorbidities had an increased risk of unfavorable outcome (adjOR 3.38, 95% CI 2.19–5.22, p<0.001) and one year mortality (adjOR 2.80, 95% CI 1.89–4.16). However, diabetes was not associated with amplification of resistance to isoniazid (p = 0.363) or to rifampicin (p = 0.344).

Conclusions/Significance

Poor glycemic control is associated with poor TB treatment outcome and improved glycemic control may reduce the influence of diabetes on TB.