20‐year follow‐up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20)

Antipsychotics are effective in preventing relapses of schizophrenia, but it is generally believed that their long‐term use is harmful for patients’ physical well‐being. However, there are no long‐term studies which have verified this view. This nationwide, register‐based cohort study aimed to assess the risk of hospitalization due to physical health problems, as a marker for severe physical morbidity, and the risk of all‐cause mortality, as well as of cardiovascular and suicidal death, associated with antipsychotic use in all patients treated for schizophrenia in inpatient care between 1972 and 2014 in Finland (N=62,250), with up to 20 years of follow‐up (median: 14.1 years). The use of antipsychotic drugs (i.e., use of any antipsychotic compared with non‐use) and the use of specific antipsychotics were investigated, and outcomes were somatic and cardiovascular hospitalization, and all‐cause, cardiovascular and suicide death. Hospitalization‐based outcomes were analyzed by a within‐individual design to eliminate selection bias, comparing use and non‐use periods in the same individual by stratified Cox model. Mortality outcomes were assessed by traditional between‐individual Cox multivariate models. The adjusted hazard ratios (aHRs) for any somatic hospitalization and cardiovascular hospitalization were 1.00 (95% CI: 0.98‐1.03) and 1.00 (95% CI: 0.92‐1.07) during use of any antipsychotic compared to non‐exposure periods within the same individual. The aHRs were 0.48 (95% CI: 0.46‐0.51) for all‐cause mortality, 0.62 (95% CI: 0.57‐0.67) for cardiovascular mortality, and 0.52 (95% CI: 0.43‐0.62) for suicide mortality during use vs. non‐use of any antipsychotic. The most beneficial mortality outcome was associated with use of clozapine in terms of all‐cause (aHR=0.39, 95% CI: 0.36‐0.43), cardiovascular (aHR=0.55, 95% CI: 0.47‐0.64) and suicide mortality (aHR=0.21, 95% CI: 0.15‐0.29). The cumulative mortality rates during maximum follow‐up of 20 years were 46.2% for no antipsychotic use, 25.7% for any antipsychotic use, and 15.6% for clozapine use. These data suggest that long‐term antipsychotic use does not increase severe physical morbidity leading to hospitalization, and is associated with substantially decreased mortality, especially among patients treated with clozapine.     

Bupropion Use and Risk of Open-Angle Glaucoma among Enrollees in a Large U.S. Managed Care Network

Objective

Tumor Necrosis Factor (TNF) mediates retinal ganglion cell death in glaucoma. Anti-TNF drugs are neuroprotective in an animal model of glaucoma. It is unclear whether medications with anti-TNF properties such as bupropion have an impact on the risk of developing open-angle glaucoma (OAG) in humans. The purpose of this study is to determine whether bupropion use alters the risk of developing OAG.

Methods

Claims data for beneficiaries age ≥35 years with no pre-existing OAG enrolled in a large nationwide U.S. managed care network continuously for ≥4 years between 2001-2011 was analyzed to identify patients who had been newly-diagnosed with OAG. The amount of bupropion use as captured from outpatient pharmacy claims over a four-year period was also quantified for each beneficiary. Multivariable Cox regression modeling assessed the impact of bupropion and other antidepressant medications on the risk of developing OAG with adjustment for sociodemographic characteristics of the enrollees along with medical and ocular comorbidities.

Results

Of 638,481 eligible enrollees, 15,292 (2.4%) developed OAG. After adjustment for confounding factors including use of other antidepressant medication classes, each additional month of bupropion use was associated with a 0.6% reduced risk of OAG (HR = 0.994, (95% CI: 0.989-0.998), p = 0.007). Compared to nonusers, those with 24-48 months of bupropion use had a 21% reduced hazard (HR=0.79, (CI: 0.65-0.94), p = 0.0099) of OAG. This association did not differ among persons taking bupropion for depression or for other reasons (p-interaction = 0.82). There was no significant association between use of tricyclic antidepressants (HR = 1.000, (CI: 0.997-1.004), p = 0.95) or selective serotonin reuptake inhibitors (HR = 0.999, (CI: 0.997-1.001), p = 0.39) and development of OAG.

Conclusion

These findings suggest bupropion use may be beneficial in reducing the risk of OAG. If prospective studies confirm the findings of this analysis, this may identify a novel therapeutic target for OAG.     

Quantitative assessment of the association between TAP2 rs241447 polymorphism and cancer risk

The findings regarding the relation of transporter associated with antigen processing (TAP) to cancer risk have been inconsistent. The aim of this study was to comprehensively evaluate the association between TAP2 rs241447 polymorphism and cancer susceptibility. A meta-analysis of nine investigations with 2800 cases and 1620 controls was conducted to gain a better understanding of the effect of TAP2 rs241447 polymorphism on cancer risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the correlation between TAP2 gene polymorphism and cancer susceptibility. The pooled results from TAP2 rs241447 polymorphism showed a decreased risk of cancer in two dominant genetic models (GG + AG vs AA: OR = 0.86, 95% CI, 0.75-0.99; AG vs AA: OR = 0.85, 95% CI, 0.73-0.99). From the subgroup analysis, decreased cancer susceptibility was found in Caucasians (GG + AG vs AA: OR = 0.82, 95% CI, 0.68-0.99), especially among the subgroup of cervical carcinoma (GG + AG vs AA: OR = 0.82, 95% CI, 0.69-0.96; AG vs AA: OR = 0.83, 95% CI, 0.70-0.99). Overall, the results suggest that TAP2 rs241447 polymorphism contributes to decreased cancer susceptibility.     

Use of low‐dose quetiapine increases the risk of major adverse cardiovascular events: results from a nationwide active comparator‐controlled cohort study

At standard doses used for schizophrenia or bipolar disorder, quetiapine has been associated with weight gain and increased levels of triglycerides, to­tal cholesterol and low‐density lipoprotein (LDL) cholesterol, which are risk factors for cardiovascular morbidity and mortality. However, this drug is also commonly used off‐label at low doses for anxiolytic or hypnotic purposes, and its cardiovascular safety at these doses is unknown. We aimed to assess the risk of major adverse cardiovascular events with use of low‐dose quetiapine compared to use of Z‐drug hypnotics in a nationwide, active comparator‐controlled cohort study. The cohort included new users of either drugs in Denmark from 2003 to 2017, aged 18‐85 years, without history of ischemic stroke, myocardial infarction, cancer, and severe mental illness. The main outcome was the occurrence of major adverse cardiovascular events, defined as non‐fatal myocardial infarction or ischemic stroke, or death from cardiovascular causes. Selective serotonin reuptake inhibitors (SSRIs) were used as an alternative comparator in sensitivity analyses. Altogether, we compared 60,566 low‐dose quetiapine users with 454,567 Z‐drug users, followed for 890,198 person‐years in intent‐to‐treat analysis, and 330,334 person‐years in as‐treated analysis. In intention‐to‐treat analysis, low‐dose quetiapine was associated with an increased risk of major adverse cardiovascular events (adjusted hazard ratio, aHR=1.13, 95% CI: 1.02‐1.24, p=0.014) and cardiovascular death (aHR=1.26, 95% CI: 1.11‐1.43, p<0.001). In as‐treated analysis, continuous low‐dose quetiapine use was associated with increased risk of major adverse cardiovascular events (aHR=1.52, 95% CI: 1.35‐1.70, p<0.001), non‐fatal ischemic stroke (aHR=1.37, 95% CI: 1.13‐1.68, p=0.002) and cardiovascular death (aHR=1.90, 95% CI: 1.64‐2.19, p<0.001). The risk of major adverse cardiovascular events was greater in women (aHR=1.28, p=0.02) and those aged ≥65 years at initiation (aHR=1.24, p<0.001). Compared to SSRIs, low‐dose quetiapine use was associated with an increased risk of major adverse cardiovascular events (aHR=1.42, p<0.001), non‐fatal ischemic stroke (aHR=1.27, p=0.0028) and cardiovascular death (aHR=1.72, p<0.001). So, we conclude that the use of low‐dose quetiapine is associated with an increased risk of major adverse cardiovascular events, especially in women and the elderly. On the basis of these findings, we suggest that use of off‐label low‐dose quetiapine for sedative or hypnotic purposes should be discouraged.     

miR-196a2 C allele is a low-penetrant risk factor for cancer development

Published data on the association between miR-196a2 T/C polymorphism and cancer susceptibility are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 21 studies including 10,441 cases and 12,353 controls were involved in this meta-analysis. Overall, significantly elevated cancer risk was associated with miR-196a2 C allele when all studies were pooled into the meta-analysis (TC vs. TT: OR=1.23, 95% CI=1.11-1.36; CC vs. TT: OR=1.30, 95% CI=1.14-1.48; dominant model: OR=1.25, 95% CI=1.13-1.38). In the subgroup analysis by ethnicity, significantly increased risks were found in Asains (TC vs. TT: OR=1.24, 95% CI=1.10-1.40; CC vs. TT: OR=1.31, 95% CI=1.13-1.52; dominant model: OR=1.26, 95% CI=1.12-1.41) but with bordline statistical significance in Caucasians (TC vs. TT: OR=1.15, 95% CI=1.00-1.31). In the subgroup analysis by cancer type, statistically significantly increased risks were found for breast cancer (TC vs. TT: OR=1.15, 95% CI=1.01-1.31; CC vs. TT: OR=1.30, 95% CI=1.01-1.68; dominant model: OR=1.22, 95% CI=1.00-1.50; and recessive model: OR=1.11, 95% CI=1.01-1.23) and lung cancer (CC vs. TT: OR=1.30, 95% CI=1.10-1.54; and recessive model: OR=1.18, 95% CI=1.02-1.36). When stratified by study design, statistically significantly elevated risk was found in hospital-based studies (TC vs. TT: OR=1.30, 95% CI=1.13-1.49; CC vs. TT: OR=1.37, 95% CI=1.14-1.66; dominant model: OR=1.32, 95% CI=1.15-1.53) and population-based studies (CC vs. TT: OR=1.19, 95% CI=1.06-1.35; dominant model: OR=1.13, 95% CI=1.01-1.25). Despite some limitations, this meta-analysis suggests that the miR-196a2 C allele is a low-penetrant risk factor for cancer development.     

Tardive dyskinesia risk with first‐ and second‐generation antipsychotics in comparative randomized controlled trials: a meta‐analysis

Tardive dyskinesia (TD) risk with D2/serotonin receptor antagonists or D2 receptor partial agonists (second‐generation antipsychotics, SGAs) is considered significantly lower than with D2 antagonists (first‐generation antipsychotics, FGAs). As some reports questioned this notion, we meta‐analyzed randomized controlled studies (RCTs) to estimate the risk ratio (RR) and annualized rate ratio (RaR) of TD comparing SGAs vs. FGAs and SGAs vs. SGAs. Additionally, we calculated raw and annualized pooled TD rates for each antipsychotic. Data from 57 head‐to‐head RCTs, including 32 FGA and 86 SGA arms, were meta‐analyzed, yielding 32 FGA‐SGA pairs and 35 SGA‐SGA pairs. The annualized TD incidence across FGA arms was 6.5% (95% CI: 5.3‐7.8%) vs. 2.6% (95% CI: 2.0‐3.1%) across SGA arms. TD risk and annualized rates were lower with SGAs vs. FGAs (RR=0.47, 95% CI: 0.39‐0.57, p<0.0001, k=28; RaR=0.35, 95% CI: 0.28‐0.45, p<0.0001, number‐needed‐to‐treat, NNT=20). Meta‐regression showed no FGA dose effect on FGA‐SGA comparisons (Z=?1.03, p=0.30). FGA‐SGA TD RaRs differed by SGA comparator (Q=21.8, df=7, p=0.003), with a significant advantage of olanzapine and aripiprazole over other non‐clozapine SGAs in exploratory pairwise comparisons. SGA‐SGA comparisons confirmed the olanzapine advantage vs. non‐clozapine SGAs (RaR=0.66, 95% CI: 0.49‐0.88, p=0.006, k=17, NNT=100). This meta‐analysis confirms a clinically meaningfully lower TD risk with SGAs vs. FGAs, which is not driven by high dose FGA comparators, and documents significant differences with respect to this risk between individual SGAs.     

Association between single-nucleotide polymorphisms in pre-miRNAs and the risk of asthma in a Chinese population

Single-nucleotide polymorphisms (SNPs) in pre-miRNAs may alter microRNA (miRNA) expression levels or processing and contribute to susceptibility to a wide range of diseases. We investigated the correlation between four SNPs (rs11614913, rs3746444, rs2910164, and rs229283) in pre-miRNAs and the risk of asthma in 220 asthma patients and 540 controls using polymerase chain reaction-restriction fragment length polymorphism methodology and DNA-sequencing. There were significant differences in the genotype and allelic distribution of rs2910164G/C and rs2292832C/T polymorphisms among cases and controls. The CC genotype and C allele of rs2910164G/C were significantly associated with a decreased risk of asthma (CC vs. GG, odds ratio [OR]?= 0.51, 95% confidence interval [CI]: 0.31-0.82; C vs. G, OR = 0.74, 95% CI: 0.59-0.93). Similarly, the TT genotype and T allele of rs2292832C/T were significantly associated with a decreased risk of asthma (TT vs. CC, OR = 0.56, 95% CI: 0.33-0.95; T vs. C, OR = 0.71, 95% CI: 0.53-0.95). However, no significant association between the other two polymorphisms (i.e., rs11614913C/T and rs3746444C/T) and the risk of asthma was observed. Our data indicate that rs2910164G/C and rs2292832C/T may play a role in the development of asthma.     

Association of excision repair cross-complimentary group 1 gene polymorphisms with breast and ovarian cancer susceptibility

The role of excision repair cross-complimentary group 1 (ERCC1) gene polymorphisms in breast and ovarian cancer development has long been controversial and existing data were inconsistent. Here, we conducted a comprehensive meta-analysis to better clarify the association. Case-control studies published from December 2008 to November 2018 were assessed. The statistical analyses of the pooled odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated. Fifteen articles with 24 case-control studies and 3 ERCC1 polymorphisms were enrolled. A total of 20 923 participants including 9896 cases and 11 027 controls were analyzed. The results showed that C to T variation in the ERCC1 rs11615 (C/T) polymorphisms was correlated with breast cancer susceptibility (T vs C: OR = 1.19, 95% CI = 1.02-1.38; TT + CT vs CC: OR = 1.24, 95% CI = 1.12-1.36). ERCC1 rs3212986 (C/A) polymorphisms posed an increased risk for breast and ovarian cancer as whole (A vs C: OR = 1.12, 95% CI = 1.01-1.25; AA + CA vs CC: OR = 1.11, 95% CI = 1.02-1.22), and presented especially higher risk for ovarian cancer (A vs C: OR = 1.31, 95% CI = 1.05-1.63; AA vs CA + CC: OR = 1.66, 95% CI = 1.12-2.47; AA vs CC: OR = 1.72, 95% CI = 1.12-2.64). Meanwhile, neither overall group analyses nor stratified analyses displayed any association of ERCC1 rs2298881 (A/C) polymorphisms in breast and ovarian cancer susceptibility. This meta-analysis suggested that ERCC1 rs11615 (C/T) polymorphisms were associated with breast cancer susceptibility and rs3212986 (C/A) polymorphisms were especially correlated with ovarian cancer risk. More case-control studies with well-adjusted data and diverse populations are essential for validation of our conclusion.     

Interactions between <Emphasis Type="Italic">CYP1A1</Emphasis> polymorphisms and cigarette smoking are associated with the risk of hepatocellular carcinoma: evidence from epidemiological studies

The Cytochrome P-450 1A1 (CYP1A1) gene has been implicated in the etiology of hepatocellular carcinoma (HCC). However, the results have been inconsistent. In this study, a meta-analysis was performed to clarify the associations of polymorphisms in CYP1A1 gene with HCC risk. Published literature from PubMed, Embase, CNKI and Wanfang Data were retrieved. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Eight studies (1,752 cases and 2,279 controls) for Ile-Val polymorphism and eight studies (933 cases and 1,449 controls) for MspI polymorphism were identified. The results showed that there was no statistically significant association between the Ile-Val polymorphism and HCC risk under all genetic models (co-dominant model: Val/Val vs. Ile/Ile: OR = 1.62, 95% CI 0.96-2.72 and Ile/Val vs. Ile/Ile: OR = 1.15, 95% CI 0.87-1.52; dominant model: OR = 1.25, 95% CI 0.92-1.70; recessive model: OR = 1.48, 95% CI 0.99-2.21). The MspI polymorphism was also not associated with HCC risk (co-dominant model: m2m2 vs. m1m1: OR = 1.09, 95% CI 0.83-1.42 and m1m2 vs. m1m1: OR = 1.30, 95% CI 1.05-1.61; dominant model: OR = 1.20, 95% CI 0.99–1.45; recessive model: OR = 0.94, 95% CI 0.74-1.18). However, the significant associations were found between both the Ile–Val and MspI polymorphisms and HCC risk among the cigarette smoking subjects (Ile-Val: OR = 1.40, 95% CI 1.06-1.85; MspI: OR = 2.65, 95% CI 1.47-4.77). The present meta-analysis indicated that the MspI and Ile-Val polymorphisms of CYP1A1 may play important roles in increasing susceptibility to smoking-related HCC.     

Incidence and Predictors of First Line Antiretroviral Regimen Modification in Western Kenya

Background

Limited antiretroviral treatment regimens in resource-limited settings require long-term sustainability of patients on the few available options. We evaluated the incidence and predictors of combined antiretroviral treatment (cART) modifications, in an outpatient cohort of 955 patients who initiated cART between January 2009 and January 2011 in western Kenya.

Methods

cART modification was defined as either first time single drug substitution or switch. Incidence rates were determined by Poisson regression and risk factor analysis assessed using multivariate Cox regression modeling.

Results

Over a median follow-up period of 10.7 months, 178 (18.7%) patients modified regimens (incidence rate (IR); 18.6 per 100 person years [95% CI: 16.2–21.8]). Toxicity was the most common cited reason (66.3%). In adjusted multivariate Cox piecewise regression model, WHO disease stage III/IV (aHR; 1.82, 95%CI: 1.25–2.66), stavudine (d4T) use (aHR; 2.21 95%CI: 1.49–3.30) and increase in age (aHR; 1.02, 95%CI: 1.0–1.04) were associated with increased risk of treatment modification within the first year post-cART. Zidovudine (AZT) and tenofovir (TDF) use had a reduced risk for modification (aHR; 0.60 95%CI: 0.38–0.96 and aHR; 0.51 95%CI: 0.29–0.91 respectively). Beyond one year of treatment, d4T use (aHR; 2.75, 95% CI: 1.25–6.05), baseline CD4 counts ≤350 cells/mm³ (aHR; 2.45, 95%CI: 1.14–5.26), increase in age (aHR; 1.05 95%CI: 1.02–1.07) and high baseline weight >60kg aHR; 2.69 95% CI: 1.58–4.59) were associated with risk of cART modification.

Conclusions

Early treatment initiation at higher CD4 counts and avoiding d4T use may reduce treatment modification and subsequently improve sustainability of patients on the available limited options.     

Is Time to Reach EDSS 6.0 Faster in Patients with Late-Onset versus Young-Onset Multiple Sclerosis?

MethodsThis cross-sectional cohort study was conducted to identify LOMS and YOMS patients’ with relapsing remitting course at MS diagnosis. Time (years) to reach sustained EDSS 6.0 was compared between LOMS and AOMS patients. Cox proportional hazards model was used to evaluate the demographic and clinical predictors of time to EDSS 6.0 in these cohorts.ResultsLOMS and YOMS cohorts comprised 99 (10.7%) and 804 (89.3%) patients respectively. Spinal cord presentation at MS onset was more common among LOMS patients (46.5% vs. 32.3%). The proportions of LOMS and YOMS patients reaching EDSS 6.0 during the follow-up period were 19.2% and 15.7% respectively. In multivariable Cox proportional hazards model, older age at MS onset (adjusted hazard ratio (aHR) = 3.96; 95% CI: 2.14–7.32; p < 0.001), male gender (aHR = 1.85; 95% CI: 1.22–2.81; p = 0.004) and spinal cord presentation at onset (aHR = 1.47; 95% CI: 0.98–2.21; p = 0.062) were significantly associated with shorter time to EDSS 6.0.ConclusionsLOMS patients attained EDSS 6.0 in a significantly shorter period that was influenced by male gender and spinal cord presentation at MS onset.     

Interleukin-10 Promoter Gene Polymorphisms and Susceptibility to Tuberculosis: A Meta-Analysis

Objective

As an update to other recent meta-analyses, the purpose of this study was to explore whether interleukin-10 (IL-10) polymorphisms and their haplotypes contribute to tuberculosis (TB) susceptibility.

Methods

We searched for published case-control studies examining IL-10 polymorphisms and TB in PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Wanfang databases and the Chinese National Knowledge Infrastructure (CNKI). Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strengths of the associations.

Results

A total of 28 studies comprising 8,242 TB patients and 9,666 controls were included in the present study. There were no significant associations between the -1082G/A, -819C/T, and -592A/C polymorphisms and TB in the pooled samples. Subgroup analyses revealed that the -819T allele was associated with an increased TB risk in Asians in all genetic models (T vs. C: OR=1.17, 95% CI=1.05-1.29, P=0.003; TT vs. CC: OR=1.37, 95% CI=1.09-1.72, P=0.006; CT+TT vs. CC: OR=1.33, 95% CI=1.09-1.63, P=0.006; TT vs. CT+CC: OR=1.17, 95% CI=1.02-1.35, P=0.03) and that the -592A/C polymorphism was significantly associated with TB in Europeans under two genetic models (A vs. C: OR=0.77, 95% CI=0.60-0.98, P=0.03; AA vs. CC: OR=0.53, 95% CI=0.30-0.95, P=0.03). Furthermore, the GCC IL-10 promoter haplotype was associated with an increased risk of TB (GCC vs. others: P=1.42, 95% CI=1.02-1.97, P=0.04). Subgroup analyses based on ethnicity revealed that the GCC haplotype was associated with a higher risk of TB in Europeans, whereas the ACC haplotype was associated with a lower TB risk in both Asians and Europeans.

Conclusions

This meta-analysis suggests that the IL-10-819T/C polymorphism is associated with the risk of TB in Asians and that the IL-10-592A/C polymorphism may be a risk factor for TB in Europeans. Furthermore, these data indicate that IL-10 promoter haplotypes play a vital role in the susceptibility to or protection against the development of TB.     

Association of Erythropoietin-Stimulating Agent Responsiveness with Mortality in Hemodialysis and Peritoneal Dialysis Patients

Erythropoiesis-stimulating agent (ESA) responsiveness has been reported to be associated with increased mortality in hemodialysis (HD) patients. ESA requirement to obtain the same hemoglobin (Hb) level is different between HD and peritoneal dialysis (PD) patients. In this study, we investigated the impact of ESA responsiveness on mortality between both HD and PD patients. Prevalent HD and PD patients were selected from the Clinical Research Center registry for end-stage renal disease, a prospective cohort study in Korea. ESA responsiveness was estimated using an erythropoietin resistant index (ERI) (U/kg/week/g/dL). Patients were divided into three groups by tertiles of ERI. ESA responsiveness was also assessed based on a combination of ESA dosage and hemoglobin (Hb) levels. The primary outcome was all-cause mortality. A total of 1,594 HD and 876 PD patients were included. The median ESA dose and ERI were lower in PD patients compared with HD patients (ESA dose: 4000 U/week vs 6000 U/week, respectively. P<0.001, ERI: 7.0 vs 10.4 U/kg/week/g/dl, respectively. P<0.001). The median follow-up period was 40 months. In HD patients, the highest ERI tertile was significantly associated with higher risk for all-cause mortality (HR 1.96, 95% CI, 1.07 to 3.59, P = 0.029). HD patients with high-dose ESA and low Hb levels (ESA hypo-responsiveness) had a significantly higher risk of all-cause mortality (HR 2.24, 95% CI, 1.16 to 4.31, P = 0.016). In PD patients, there was no significant difference in all-cause mortality among the ERI groups (P = 0.247, log-rank test). ESA hypo-responsiveness was not associated with all-cause mortality (HR = 1.75, 95% CI, 0.58 to 5.28, P = 0.319). Our data showed that ESA hypo-responsiveness was associated with an increased risk of all-cause mortality in HD patients. However, in PD patients, ESA hypo-responsiveness was not related to all-cause mortality. These finding suggest the different prognostic value of ESA responsiveness between HD and PD patients.     

Interleukin-4 rs2243250 polymorphism is associated with asthma among Caucasians and related to atopic asthma

Published data on the association between interleukin-4 (IL-4) rs2243250 (C-589T) polymorphism and asthma susceptibility are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 17 studies with 3037 asthma patients and 3032 healthy controls were included. Overall, significantly elevated asthma risk was associated with IL-4 T allele when all studies were pooled into the meta-analysis (CT vs. CC: OR=1.187, 95% CI=1.016-1.387; dominant model: OR=1.213, 95% CI=1.046-1.405). In the subgroup analysis by ethnicity, significantly increased risk was only found for Caucasians (TT vs. CC: OR=1.591, 95% CI=1.032-2.452; dominant model: OR=1.292, 95% CI=1.028-1.624). When stratified by asthma type, statistically significantly elevated risk was only found in atopic asthma group (dominant model: OR=1.313, 95% CI=1.033-1.667). Despite some limitations, this meta-analysis suggests that T allele at position -589 of the IL-4 gene promoter region is a low-penetrant risk factor for asthma development especially for Caucasians and atopic type.     

Association of the CYP1B1 Leu432Val polymorphism with the risk of prostate cancer: a meta-analysis

Cytochrome P450 1B1 (CYP1B1) is a key P450 enzyme involved in the metabolism of exogenous and endogenous substrates in endocrine-mediated tumors such as prostate cancer. The potential significance of nonsynonymous SNP Leu432Val (rs1056836) as a risk factor in prostate cancer has been extensively studied. The objective of this meta-analysis was to quantitatively summarize the association between CYP1B1 Leu432Val polymorphism and prostate cancer. All eligible studies were searched and acquired from the PubMed and ISI databases. Statistical analysis was performed by using the software STATA 11.0. Ten case-controlled studies from nine eligible publications were identified, which includes 6,668 subjects with 3,221 cases and 3,447 controls. Overall, no significant association was found between the CYP1B1 Leu432Val polymorphism and prostate cancer susceptibility for Val/Val vs Leu/Leu (OR = 1.07; 95% CI: 0.79-1.44; P = 0.67), Leu/Val vs Leu/Leu (OR = 1.05; 95% CI: 0.94-1.17; P = 0.42), Leu/Val + Val/Val vs Leu/Leu (OR = 1.07; 95% CI: 0.91-1.26; P = 0.40) and Val/Val vs Leu/Val + Leu/Leu (OR = 1.11; 95% CI: 0.86-1.44; P = 0.43). However, a higher risk was found among Asians in all genetic models (Val/Val vs Leu/Leu :OR = 2.48, 95% CI: 1.14-5.39, P = 0.02; Leu/Val vs Leu/Leu: OR = 1.40, 95% CI: 1.03-1.89, P = 0.03; Leu/Val + Val/Val vs Leu/Leu: OR = 1.51, 95% CI = 1.14-2.01, P = 0.004; Val/Val vs Leu/Val + Leu/Leu: OR = 2.50, 95% CI = 1.35-4.56, P = 0.004). We were not able to detect any association in the subgroup analysis by source of controls and genotyping method in all genetic models. In conclusion, this meta-analysis provides evidence that CYP1B1 Leu432Val polymorphism is not associated with prostate cancer risk overall with the exception in Asians.     

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.     

Association between ATM polymorphisms and cancer risk: a meta-analysis

To date, epidemiological studies have assessed the association between Ataxia-telangiectasia mutated (ATM) gene polymorphisms and cancer risk, including lung cancer, breast cancer, glioma and pancreatic cancer. However, the results of these studies remain controversial. We aimed to examine the associations between two SNPs (rs664143 and rs664677) and cancer risk by conducting a meta-analysis of case–control studies. A total of 12 publications were included in this meta-analysis, 8 for rs664143 and 7 for rs664677. Overall, rs664143 heterozygote carriers turned out to be associated with cancer risk (OR = 1.18, 95% CI 1.02–1.36). In the subgroup analysis by cancer type, we observed that the ATM rs664143 polymorphism was significantly associated with lung cancer risk (GA vs. GG: OR = 1.48, 95% CI 1.18–1.85, AA vs. GG: OR = 1.51, 95% CI 1.18–1.93) and rs664677 polymorphism was associated with decreased lung cancr risk and increased breast cancer risk (for lung cancer: TC vs. TT: OR = 0.76, 95% CI 0.62–0.92, CC vs. TT: OR = 0.80, 95% CI 0.64–0.99 and for breast cancer: TC vs. TT: OR = 1.42, 95% CI 1.17–1.73, CC vs. TT: OR = 1.51, 95% CI 1.21–1.87). In the subgroup analysis by region, we also observed that individuals with ATM rs664143 GA or AA genotype had an obvious increased cancer risk among Asian people (GA vs. GG: OR = 1.40, 95% CI 1.20–1.63, AA vs. GG: OR = 1.37, 95% CI 1.16–1.62). In conclusion, ATM rs664143 polymorphism was associated with cancer susceptibility. ATM rs664143 polymorphism was significantly associated with lung cancer risk. ATM rs664677 polymorphism was associated with decreased lung cancer risk as well as increased breast cancer risk.     

Polymorphisms in the cytotoxic T-lymphocyte antigen 4 gene and acute rejection risk in transplant recipients

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene polymorphisms have been reported to influence the risk for acute rejection (AR) in transplant recipients. However, the results still remain controversial and ambiguous. The objective of the current study was to conduct a meta-analysis investigating the association between polymorphisms in the CTLA-4 gene and the risk of AR in transplant recipients. Electronic searches for all publications were conducted on associations between this variant and acute rejection in Medline and Embase databases through November 2011. Crude odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated to estimate the strength of the association. Three polymorphisms (+49 adenine/guanine [+49A/G], -318 cytosine/thymine [-318C/T], and the +6230G/A polymorphism [CT60]) in 18 case-control studies from ten articles were analyzed. This meta-analysis included 2,081 cases of transplant recipients in which 813 cases developed AR and 1,268 cases did not develop AR. The results indicated that there was no statistically significant association between the risk of AR and the +49A/G polymorphism or the -318C/T polymorphism (+49A/G: OR = 0.876, 95 % CI = 0.650-1.180 for GG vs. AA; OR = 1.121, 95 % CI = 0.911-1.379 for AG + GG vs. AA; -318C/T: OR = 0.397, 95 % CI = 0.138-1.143 for TT vs. CC; OR = 0.987, 95 %CI = 0.553-1.760 for CT + TT vs. CC). However, individuals who carried CT60 A allele might have a decreased risk of AR (AA vs. GG OR = 0.535, 95 % CI = 0.340-0.841, A vs. G OR = 0.759, 95 % CI = 0.612-0.914) in liver transplant recipients among Europeans, but because only two studies were included, so the result should be caution. In further stratified analyses for the +49A/G and the -318C/T polymorphisms, no obvious significant associations were found in subgroups of renal transplant recipients and Europeans, a reduced incidence of acute rejection was observed in liver transplant recipients that are homogenous for +49G (OR = 0.638, 95 % CI = 0.427-0.954 for GG vs. AA/AG), while this has not been observed in renal transplant recipients. Overall this meta-analysis suggests that +49A/G and the -318C/T polymorphisms in CTLA-4 may be not associated with the risk of rejection after organ transplantation, but CTLA +49A/G and +6230G/A polymorphisms may be associated with acute rejection after liver transplantation, not after renal transplantation. In future, more studies should be included to evaluate the association between +6230G/A polymorphism and AR risk.     

Genetic variation in α1-antichymotrypsin and its association with Alzheimer's disease

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by extracellular neuritic plaques and intracellular neurofibrillary tangles in brain parenchyma. Alpha-1-antichymotrypsin (ACT) is a component of plaque cores, can bind to Abeta, and has been proposed as a possible candidate gene for AD susceptibility. The genetic association between the ACT codon -17*A allele of the signal peptide polymorphism and AD has been shown in some, but not in all studies. One hypothesis is that the ACT codon -17*A allele is in linkage disequilibrium with unknown functional mutation(s) in the ACT gene. This study was undertaken to identify new mutation(s) in the ACT gene by PCR-SSCP-sequencing and, in conjunction with known mutations, to assess their role in affecting the risk of AD. A total of seven new point mutations were observed: 5'UTR(A-->G), Asp128Asn(G-->A), Ser250Ser(C-->T), Leu301Pro(T-->C), Thr324Thr(A-->G), G-->A in intron 4, and 3'UTR C-->A. Of these, mutations at codon 250, codon 324, intron 4 and 3'UTR showed a frequency of 1% or more. Of the known mutations, Thr-17Ala(A-->G), Lys76Lys(A-->G) and Leu241Leu(G-->A) occur at a polymorphic level. The ACT codon -17*A allele was associated with increased risk of AD (OR for AA vs TT: 1.71; 95% CI: 1.16-2.53; P=0.007), especially in the presence of the APOE*4 allele (OR for AA vs TT: 2.35; 95% CI: 1.13-4.85; P=0.02). The codon 241*A allele and the codon 250*T allele were associated with protective effects against AD (OR: 0.36; 95% CI: 0.13-0.86; P=0.02) (OR:0.39; 95% CI: 0.18-0.85; P=0.02). irrespective of the APOE*4 status. The codon 324*G allele was associated with a marginal protective effect (OR:0.57; 95% CI: 0.26-1.26; P=0.17). While the codon 241*A allele was in linkage disequilibrium with the codon -17*A allele, the codon 250*T and codon 324*G alleles were non-randomly associated with the codon -17*T allele. In contrast, the codon 76*G (OR:1.34; 95% CI: 0.92-1.95; P=0.13), codon 227*G (OR:3.96; 95% CI: 0.83-18.8; P=0.08) and intron 4*G (OR:1.47; 95% CI: 0.88-2.29; P=0.15) alleles were associated with a modest risk of AD, and all were in linkage disequilibrium with the codon -17*A allele. EH-based haplotype analysis showed that certain haplotypes are associated with either higher or lower risk of AD. Our data indicate that the ACT gene harbors several potentially important variable sites, which are associated with either an increased or decreased risk of AD. The non-random combination of risk and protective alleles may explain, in part, why the association studies regarding the ACT codon -17*A have been inconsistent, especially if the frequency of other ACT mutations varies between populations.