Survivin ?31G>C Polymorphism and Gastrointestinal Tract Cancer Risk: A Meta-Analysis

Background

Emerging evidence showed that common functional −31G>C polymorphism (rs9904341 G>C) in the promoter region of the survivin gene is involved in the regulation of survivin expression, thus increasing an individual’s susceptibility to gastrointestinal tract (GIT) cancer; but individually published results are inconclusive. The aim of this systematic review and meta-analysis was to derive a more precise estimation of the association between survivin −31G>C polymorphism and GIT cancer risk.

Methods

A literature search of PubMed, Embase, Web of Science and CBM databases was conducted from inception through July 1st, 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association.

Results

Nine case-control studies were included with a total of 2,231 GIT cancer cases and 2,287 healthy controls. The results indicated that survivin −31G>C polymorphism was associated with increased risk of GIT cancer. In the stratified analysis by cancer types, significant associations were observed between survivin −31G>C polymorphism and increased risk of colorectal and gastric cancers. However, the lack of association of survivin −31G>C polymorphism with esophageal cancer risk may be due to a lack of a sufficient number of eligible studies and the influence of different genetic and environmental factors.

Conclusion

Results from the current meta-analysis suggests that survivin −31G>C polymorphism might increase the risk of GIT cancer, especially among gastric and colorectal cancers.     

Single Nucleotide Polymorphisms of PIN1 Promoter Region and Cancer Risk: Evidence from a Meta-Analysis

Background

Peptidylprolyl cis/trans isomerase NIMA-interacting 1 (PIN1) is involved in the process of tumorigenesis. The two single nucleotide polymorphisms (−677T>C, −842G>C) in the PIN1 promoter region have been suspected of being associated with cancer risk for years, but the conclusion is still inconclusive.

Methods

Eligible case-control studies were retrieved by searching databases and references of related reviews and studies. Genotype distribution data, adjusted odds ratios (ORs) and 95% confidence (CIs) intervals were extracted to calculate pooled ORs.

Results

A total of 4619 cancer cases and 4661 controls were included in this meta-analysis. Overall, the PIN1 −667T>C polymorphism was not associated with cancer risk, while the −842C allele was significantly associated with reduced cancer risk (CC+GC vs. GG, OR = 0.725, 95% CI: 0.607–0.865; P_{heterogeneity} = 0.012 and GC vs. GG: OR = 0.721, 95% CI: 0.591–0.880; P_{heterogeneity} = 0.003). Results from genotype distribution data were in agreement with those calculated with adjusted ORs and 95% CIs. No publication bias was detected.

Conclusions

Results of this meta-analysis suggest that the PIN1 −842G>C polymorphism is associated with decreased cancer risk, but that the −667T>C polymorphism is not.     

Selected ABCB1, ABCB4 and ABCC2 Polymorphisms Do Not Enhance the Risk of Drug-Induced Hepatotoxicity in a Spanish Cohort

Background and Aims

Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort.

Methods

A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (−1774G>del, −1549A>G, −24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5′ allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed.

Results

None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 −1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 −1774G/−1549A/−24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI.

Conclusions

Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 −1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility.     

Meta-Analysis of the Association between COX-2 Polymorphisms and Risk of Colorectal Cancer Based on Case–Control Studies

Objective

Cyclooxygenase-2 (COX-2) is an inducible enzyme converting arachidonic acid to prostaglandins and playing important roles in inflammatory diseases as well as tumor development. Previous studies investigating the association between COX-2 polymorphisms and colorectal cancer (CRC) risk reported conflicting results. We performed a meta-analysis of all available studies to explore this association.

Methods

All studies published up to October 2013 on the association between COX-2 polymorphisms and CRC risk were identified by searching electronic databases PubMed, EMBASE, and Cochrane library. The association between COX-2 polymorphisms and CRC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).

Results

Ten studies with 6,774 cases and 9,772 controls were included for −1195A>G polymorphism, 13 studies including 6,807 cases and 10,052 controls were available for −765G>C polymorphism, and 8 studies containing 5,121 cases and 7,487 controls were included for 8473T>C polymorphism. With respect to −765G>C polymorphism, we did not find a significant association with CRC risk when all eligible studies were pooled into the meta-analysis. However, in subgroup analyses by ethnicity and cancer location, with a Bonferroni corrected alpha of 0.05/2, statistical significant increased CRC risk was found in the Asian populations (dominant model CC+CG vs. GG: OR = 1.399, 95%CI: 1.113–1.760, P = 0.004) and rectum cancer patients (CC vs. GG: OR = 2.270, 95%CI: 1.295–3.980, P = 0.004; Recessive model CC vs. CG+GG: OR = 2.269, 95%CI: 1.297–3.970, P = 0.004). In subgroup analysis according to source of control, no significant association was detected. With respect to −1195A>G and 8473T>C polymorphisms, no significant association with CRC risk was demonstrated in the overall and subgroup analyses.

Conclusions

The present meta-analysis suggests that the COX-2 −765G>C polymorphism may be a risk factor for CRC in Asians and rectum cancer patients. Further large and well-designed studies are needed to confirm this association.     

The rs2233678 Polymorphism in PIN1 Promoter Region Reduced Cancer Risk: A Meta-Analysis

Background

Published evidence suggests that the rs2233678 (−842 G>C) polymorphism in the PIN1 (peptidyl-prolyl cis/trans somerase NIMA-interacting 1) promoter region may be associated with cancer risk; however, the conclusion is still inconclusive.

Methods

We conducted a meta-analysis to determine whether −842 G>C polymorphism was associated with cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association. Genotype distribution data and adjusted ORs were collected to calculate the pooled ORs. Meta-regression was conducted to detect the source of heterogeneity. Publication bias was evaluated by Egger’s test and Begg’s test.

Results

A total of 11 eligible studies, including 9280 participants, were identified and analyzed. Overall, we found that carriers of the −842 C allele were associated with significantly decreased cancer risk (C vs. G, OR = 0.750, 95% CI: 0.639–0.880, P_{heterogeneity} = 0.014, estimated by genotype distribution data; CC+GC vs. GG, OR = 0.668, 95% CI: 0.594–0.751, P_{heterogeneity} = 0.638, estimated by adjusted ORs). No evidence of publication bias was observed. Meta-regression revealed that ethnicities (p = 0.021) and sample size (p = 0.02) but not sources of control (p = 0.069) were the source of heterogeneity.

Conclusion

These results suggest that the PIN1 rs2233678 (−842 G>C) polymorphism significantly reduces cancer risk.     

A Meta-Analysis of the Association between TNF-α ?308G>A Polymorphism and Type 2 Diabetes Mellitus in Han Chinese Population

Objective

A meta-analysis was applied to evaluate the associations between tumor necrosis factor-α (TNF-α) −308G>A (rs1800629) polymorphism and type 2 diabetes mellitus (T2DM).

Methods

Hardy-Weinberg equilibrium (HWE) was employed to test genetic equilibrium among the genotypes of the selected literature. Power analysis was performed with the Power and Sample Size Calculation (PS) program. A fixed or random effect model was used on the basis of heterogeneity. Publication bias was quantified and examined with the Begg''s funnel plot test and Egger''s linear regression test. The meta-analysis was performed with Review Manager 5.1 and Stata 11.0.

Results

There were 10 studies including 1425 T2DM patients and 1116 healthy control subjects involved in this meta-analysis. No significant publication bias was found in the studies. The pooled ORs (95% CIs) for TNF-α −308G>A of A vs. G allele and GA+AA vs. GG genotype were 1.63 (1.17–2.25) and 1.47 (1.17–1.85), respectively.

Conclusion

This meta-analysis result suggested that TNF-α −308G>A polymorphism was strongly associated with T2DM risk, and A allele at this locus might be a susceptibility allele for the development of T2DM in Han Chinese population.     

Mitochondrial Genomic Analysis of Late Onset Alzheimer’s Disease Reveals Protective Haplogroups H6A1A/H6A1B: The Cache County Study on Memory in Aging

Background

Alzheimer’s disease (AD) is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA) variants and haplogroups in AD risk is uncertain.

Methodology/Principal Findings

We determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p = 0.017, corrected for multiple comparisons). The protective haplotypes were defined by three variants: m.3915G>A, m.4727A>G, and m.9380G>A. These three variants characterize two different major haplogroups. Together m.4727A>G and m.9380G>A define H6A1, and it has been suggested m.3915G>A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status.

Conclusions/Significance

Our findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary.     

Associations between Individual and Combined Polymorphisms of the TNF and VEGF Genes and the Embryo Implantation Rate in Patients Undergoing In Vitro Fertilization (IVF) Programs

Background

A multiple pregnancy is now considered to be the most common adverse outcome associated with in vitro fertilization (IVF). As a consequence, the identification of women with the best chances of embryo implantation is a challenge in IVF program, in which the objective is to offer elective single-embryo transfer (eSET) without decreasing the pregnancy rate. To date, a range of hormonal and clinical parameters have been used to optimize eSET but none have significant predictive value. This variability could be due to genetic predispositions related to single-nucleotide polymorphisms (SNPs). Here, we assessed the individual and combined impacts of thirteen SNPs that reportedly influence the outcome of in vitro fertilisation (IVF) on the embryo implantation rate for patients undergoing intracytoplasmic sperm injection program (ICSI).

Materials and Methods

A 13 gene polymorphisms: FSHR(Asn680Ser), p53(Arg72Pro), AMH(Ile49Ser), ESR2(+1730G>A), ESR1(−397T>C), BMP15(−9C>G), MTHFR1(677C>T), MTHFR2(1298A>C), HLA-G(−725C>G), VEGF(+405G>C), TNFα(−308A>G), AMHR(−482A>G), PAI-1(4G/5G), multiplex PCR assay was designed to genotype women undergoing ICSI program. We analyzed the total patients population (n = 428) and a subgroup with homogeneous characteristics (n = 112).

Results

Only the VEGF(+405G>C) and TNFα(−308A>G) polymorphisms impacted fertilization, embryo implantation and pregnancy rates. Moreover, the combined VEGF+405.GG and TNFα-308.AG or AA genotype occurred significantly more frequently in women with high implantation potential. In contrast, the VEGF+405.CC and TNFα-308.GG combination was associated with a low implantation rate.

Conclusion

We identified associations between VEGF(+405G>C) and TNFα(−308A>G) polymorphisms (when considered singly or as combinations) and the embryo implantation rate. These associations may be predictive of embryo implantation and could help to define populations in which elective single-embryo transfer should be recommended (or, conversely, ruled out). However, the mechanism underlying the function of these polymorphisms in embryo implantation remains to be determined and the associations observed here must be confirmed in a larger, more heterogeneous cohort.     

The Cannabinoid 1 Receptor (CNR1) 1359 G/A Polymorphism Modulates Susceptibility to Ulcerative Colitis and the Phenotype in Crohn's Disease

Background

Recent evidence suggests a crucial role of the endocannabinoid system, including the cannabinoid 1 receptor (CNR1), in intestinal inflammation. We therefore investigated the influence of the CNR1 1359 G/A (p.Thr453Thr; rs1049353) single nucleotide polymorphism (SNP) on disease susceptibility and phenotype in patients with ulcerative colitis (UC) and Crohn''s disease (CD).

Methods

Genomic DNA from 579 phenotypically well-characterized individuals was analyzed for the CNR1 1359 G/A SNP. Amongst these were 166 patients with UC, 216 patients with CD, and 197 healthy controls.

Results

Compared to healthy controls, subjects A/A homozygous for the CNR1 1359 G/A SNP had a reduced risk to develop UC (p = 0.01, OR 0.30, 95% CI 0.12–0.78). The polymorphism did not modulate CD susceptibility, but carriers of the minor A allele had a lower body mass index than G/G wildtype carriers (p = 0.0005). In addition, homozygous carriers of the G allele were more likely to develop CD before 40 years of age (p = 5.9×10⁻⁷) than carriers of the A allele.

Conclusion

The CNR1 p.Thr453Thr polymorphism appears to modulate UC susceptibility and the CD phenotype. The endocannabinoid system may influence the manifestation of inflammatory bowel diseases, suggesting endocannabinoids as potential target for future therapies.     

Gastric Bypass Surgery Is Followed by Lowered Blood Pressure and Increased Diuresis - Long Term Results from the Swedish Obese Subjects (SOS) Study

Objective

To compare two bariatric surgical principles with regard to effects on blood pressure and salt intake.

Background

In most patients bariatric surgery induces a sustained weight loss and a reduced cardiovascular risk profile but the long-term effect on blood pressure is uncertain.

Methods

Cohort study with data from the prospective, controlled Swedish Obese Subjects (SOS) study involving 480 primary health care centres and 25 surgical departments in Sweden. Obese patients treated with non-surgical methods (Controls, n = 1636 and n = 1132 at 2 y and 10 y follow up, respectively) were compared to patients treated with gastric bypass (GBP, n = 245 and n = 277, respectively) or purely restrictive procedures (vertical banded gastroplasty or gastric banding; VBG/B, n = 1534 and n = 1064, respectively).

Results

At long-term follow-up (median 10 y) GBP was associated with lowered systolic (mean: −5.1 mm Hg) and diastolic pressure (−5.6 mmHg) differing significantly from both VBG/B (−1.5 and −2.1 mmHg, respectively; p<0.001) and Controls (+1.2 and −3.8 mmHg, respectively; p<0.01). Diurnal urinary output was +100 ml (P<0.05) and +170 ml (P<0.001) higher in GBP subjects than in weight-loss matched VBG/B subjects at the 2 y and 10 y follow-ups, respectively. Urinary output was linearly associated with blood pressure only after GBP and these patients consumed approximately 1 g salt per day more at the follow-ups than did VBG/B (P<0.01).

Conclusions

The purely restrictive techniques VBG/B exerted a transient blood pressure lowering effect, whereas gastric bypass was associated with a sustained blood pressure reduction and an increased diuresis. The daily salt consumption was higher after gastric bypass than after restrictive bariatric surgery.     

Low Birthweight (LBW) and Neonatal Hyperbilirubinemia (NNH) in an Indian Cohort: Association of Homocysteine,Its Metabolic Pathway Genes and Micronutrients as Risk Factors

Background & Aims

Indian subcontinent has the highest child mortality rates along with a very high frequency of low birthweight (LBW). Folate and vitamin B12 (Vit-B12) are necessary during foetal development and their deficiency prevalence in Indians is very high. The objective of the present paper is to assess whether foetal homocysteine (Hcy)/folate metabolic pathway genes, their cofactors and homocysteine level independently (or collectively) predispose children to Low birth weight.

Methods

Cord blood was collected for the study. Frequency of 5 SNPs in 4-Hcy-pathway genes, and levels of Hcy, Vit-B12 and folate were evaluated.

Results

Of the 421 newborns recruited for the study, 38% showed low birth weight (<2.5kg) and 16% were preterm babies. 101 neonates developed neonatal hyperbilirubinemia (NNH). High prevalence of Vit-B12 (65%) and folate (27%) deficiency was observed in newborns along with hyperhomocystinemia (hypHcy-25%). Preterm delivery, micronutrient deficiency, hypHcy and MTHFR 677T SNP are associated as risk factor while G allele of TCN2 C776G is protective against LBW. MTHFR 677T allele and folate deficiency are also independent risk factors for NNH.

Conclusion

We record the highest incidence of Vit-B12, folate deficiency and elevated Hcy levels, of all the studies so far reported on neonates. These together with MTHFR 677T are potential risk factors for LBW. Association of impaired folate/Hcy metabolism with NNH is reported for the first time and the possible way of interaction is discussed. It appears that proper nutritional management during pregnancy would reduce the risk of complex clinical outcomes.     

Passive Smoking Exposure from Partners as a Risk Factor for ER+/PR+ Double Positive Breast Cancer in Never-Smoking Chinese Urban Women: A Hospital-Based Matched Case Control Study

Background

The relationship between passive smoking exposure (PSE) and breast cancer risk is of major interest.

Objective

To evaluate the relationship between PSE from partners and breast cancer risk stratified by hormone-receptor (HR) status in Chinese urban women population.

Design

Hospital-based matched case control study.

Setting

Chinese urban breast cancer patients without current or previous active smoking history in China Medical University 1st Hospital, Liaoning Province, China between Jan 2009 and Nov 2009.

Patients

Each breast cancer patient was matched 1∶1 with healthy controls by gender and age (±2 years) from the same hospital.

Measurements

The authors used unconditional logistic regression analyses to estimate odds ratio for women with PSE from partners and breast cancer risk.

Results

312 pairs were included in the study. Women who endured PSE had significantly increased risk of breast cancer (adjusted OR: 1.46; 95% CI: 1.05–2.03; P = 0.027), comparing with unexposed women. Women who exposed to >5 cigarettes/day also had significant increased risk (adjusted OR: 1.99; 95% CI: 1.28–3.10; P = 0.002), as were women exposed to passive smoke for 16–25 years (adjusted OR: 1.87 95% CI: 1.22–2.86; P = 0.004), and those exposed to > 4 pack-years (adjusted OR: 1.71 95% CI: 1.17–2.50; P = 0.004). Similar trends were significant for estrogen receptor (ER)/progesterone receptor (PR) double positive subgroup(adjusted OR: 1.71; 2.20; 1.99; 1.92, respectively), but not for ER+/PR−, ER−/PR+, or ER−/PR− subgroups.

Limitations

limitations of the hospital-based retrospective study, lack of information on entire lifetime PSE and low statistical power.

Conclusions

Our findings provide further evidence that PSE from partners contributes to increased risk of breast cancer, especially for ER/PR double positive breast cancer, in Chinese urban women.     

Association between MLH1 -93G>A Polymorphism and Risk of Colorectal Cancer

Background

The -93G>A (rs1800734) polymorphism located in the promoter of mismatch repair gene, MLH1, has been identified as a low-penetrance variant for cancer risk. Many published studies have evaluated the association between the MLH1 -93G>A polymorphism and colorectal cancer (CRC) risk. However, the results remain conflicting rather than conclusive.

Objective

The aim of this study was to assess the association between the MLH1 -93G>A polymorphism and the risk of CRC.

Methods

To derive a more precise estimation of the association, a meta-analysis of six studies (17,791 cases and 13,782 controls) was performed. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the association. Four of these published studies were performed on subjects of known microsatellite instability (MSI) status. An additional analysis including 742 cases and 10,895 controls was used to assess the association between the MLH1 -93G>A polymorphism and the risk of MSI-CRC.

Results

The overall results indicated that the variant genotypes were associated with a significantly increased risk of CRC (AG versus GG: OR = 1.06, 95% CI = 1.01–1.11; AA/AG versus GG: OR = 1.06, 95% CI = 1.01–1.11). This increased risk was also found during stratified analysis of MSI status (AA versus GG: OR = 2.52, 95% CI = 1.94–3.28; AG versus GG: OR = 1.29, 95% CI = 1.10–1.52; AA/AG versus GG: OR = 1.45, 95% CI = 1.24–1.68; AA versus AG/GG: OR = 2.29, 95% CI = 1.78–2.96). Egger’s test did not show any evidence of publication bias.

Conclusion

Our results suggest that the MLH1 -93G>A polymorphism may contribute to individual susceptibility to CRC and act as a risk factor for MSI-CRC.     

Moxibustion Treatment for Knee Osteoarthritis: A Multi-Centre,Non-Blinded,Randomised Controlled Trial on the Effectiveness and Safety of the Moxibustion Treatment versus Usual Care in Knee Osteoarthritis Patients

Introduction

This study tested the effectiveness of moxibustion on pain and function in chronic knee osteoarthritis (KOA) and evaluated safety.

Methods

A multi-centre, non-blinded, parallel-group, randomised controlled trial compared moxibustion with usual care (UC) in KOA. 212 South Korean patients aged 40–70 were recruited from 2011–12, stratified by mild (Kellgren/Lawrence scale grades 0/1) and moderate-severe KOA (grades 2/3/4), and randomly allocated to moxibustion or UC for four weeks. Moxibustion involved burning mugwort devices over acupuncture and Ashi points in affected knee(s). UC was allowed. Korean Western Ontario and McMaster Universities Questionnaire (K-WOMAC), Short Form 36 Health Survey (SF-36v2), Beck Depression Inventory (BDI), physical performance test, pain numeric rating scale (NRS) and adverse events were evaluated at 5 and 13 weeks. K-WOMAC global score at 5 weeks was the primary outcome.

Results

102 patients (73 mild, 29 moderate-severe) were allocated to moxibustion, 110 (77 mild, 33 moderate-severe) to UC. K-WOMAC global score (moxibustion 25.42+/−SD 19.26, UC 33.60+/−17.91, p<0.01, effect size  = 0.0477), NRS (moxibustion 44.77+/−22.73, UC 56.23+/−17.71, p<0.01, effect size  = 0.0073) and timed-stand test (moxibustion 24.79+/−9.76, UC 25.24+/−8.84, p = 0.0486, effect size  = 0.0021) were improved by moxibustion at 5 weeks. The primary outcome improved for mild but not moderate-severe KOA. At 13 weeks, moxibustion significantly improved the K-WOMAC global score and NRS. Moxibustion improved SF-36 physical component summary (p = 0.0299), bodily pain (p = 0.0003), physical functioning (p = 0.0025) and social functioning (p = 0.0418) at 5 weeks, with no difference in mental component summary at 5 and 13 weeks. BDI showed no difference (p = 0.34) at 5 weeks. After 1158 moxibustion treatments, 121 adverse events included first (n = 6) and second degree (n = 113) burns, pruritus and fatigue (n = 2).

Conclusions

Moxibustion may improve pain, function and quality of life in KOA patients, but adverse events are common. Limitations included no sham control or blinding.

Trial Registration

Clinical Research Information Service (CRIS) KCT0000130     

HIF-1α Polymorphism in the Susceptibility of Cervical Spondylotic Myelopathy and Its Outcome after Anterior Cervical Corpectomy and Fusion Treatment

Background

To investigate the association between the single nucleotide polymorphism (SNP) of hypoxia-inducible factor1 α (HIF-1α) and the susceptibility to cervical spondylotic myelopathy (CSM) and its outcome after surgical treatment.

Method

A total of 230 CSM patients and 284 healthy controls were recruited. All patients received anterior cervical corpectomy and fusion (ACF) and were followed for 12 months. The genotypes for two HIF-1α variants (1772C>T and 1790G>A) were determined.

Results

In the present study, we found that the HIF-1α polymorphism at 1790G>A significantly affects the susceptibility to CSM and its clinical features, including severity and onset age. In addition, the 1790A>G polymorphism also determines the prognosis of CSM patients after ACF treatment. The GG genotype of 1790G>A polymorphism is associated with a higher risk to develop CSM, higher severity and earlier onset age. More importantly, we found that the 1790G>A polymorphism determines the clinical outcome in CSM patients who underwent ACF treatment.

Conclusion

Our findings suggest that the HIF-1α 1790G>A polymorphism is associated with the susceptibility to CSM and can be used as predictor for the clinical outcome in CSM patients receiving ACF treatment.     

ESR1 Gene Polymorphisms and Prostate Cancer Risk: A HuGE Review and Meta-Analysis

Background

Many published data on the association between single nucleotide polymorphisms (SNPs) in the ESR1 gene and prostate cancer susceptibility are inconclusive. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis is to derive a more precise estimation of this relationship.

Methods

A literature search of PubMed, Embase, Web of Science and Chinese Biomedical (CBM) databases was conducted from their inception through July 1st, 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of association.

Results

Twelve case-control studies were included with a total 2,165 prostate cancer cases and 3,361 healthy controls. When all the eligible studies were pooled into the meta-analysis, ESR1 PvuII (C>T) and XbaI (A>G) polymorphisms showed no association with the risk of prostate cancer. However, in the stratified analyses based on ethnicity and country, the results indicated that ESR1 PvuII (C>T) polymorphism was significantly associated with increased risk of prostate cancer among Asian populations, especially among Indian population; while ESR1 XbaI (A>G) polymorphism may significantly increase the risk of prostate cancer among American population. Furthermore, we also performed a pooled analysis for all eligible case-control studies to explore the role of codon 10 (T>C), codon 325 (C>G), codon 594 (G>A) and +261G>C polymorphisms in prostate cancer risk. Nevertheless, no significant associations between these polymorphisms and the risk of prostate cancer were observed.

Conclusion

Results from the current meta-analysis indicate that ESR1 PvuII (C>T) polymorphism may be a risk factor for prostate cancer among Asian populations, especially among Indian population; while ESR1 XbaI (A>G) polymorphism may increase the risk of prostate cancer among American population.     

Significant Impact of the MTHFR Polymorphisms and Haplotypes on Male Infertility Risk

Background

Methylenetetrahydrofolate reductase (MTHFR) converts 5,10-methylene tetrahydrofolate to 5-methyl tetrahydrofolate and affects the activity of cellular cycles participating in nucleotide synthesis, DNA repair, genome stability, maintenance of methyl pool, and gene regulation. Genetically compromised MTHFR activity has been suggested to affect male fertility. The objective of the present study was to find the impact on infertility risk of c.203G>A, c.1298A>C, and c.1793G>A polymorphisms in the MTHFR gene.

Methods

PCR-RFLP and DNA sequencing were used to genotype the common SNPs in the MTHFR gene in 630 infertile and 250 fertile males. Chi-square test was applied for statistical comparison of genotype data. Linkage disequilibrium between the SNPs and the frequency of common haplotypes were assessed using Haploview software. Biochemical levels of total homocysteine (tHcy) and folic acid were measured. Meta-analysis on c.1298A>C polymorphism was performed using data from ten studies, comprising 2734 cases and 2737 controls.

Results

c.203G>A and c.1298A>C were found to be unrelated to infertility risk. c.1793G>A was protective against infertility (P = 0.0008). c.677C>T and c.1793G>A were in significant LD (D’ = 0.9). Folic acid and tHcy level did not correlate with male infertility. Pooled estimate on c.1298A>C data from all published studies including our data showed no association of this polymorphism with male infertility (Odds ratio = 1.035, P = 0.56), azoospermia (Odds ratio = 0.97, P = 0.74), or oligoasthenoteratozoospermia (Odds ratio = 0.92, p = 0.29). Eight haplotypes with more than 1% frequency were detected, of which CCGA was protective against infertility (p = 0.02), but the significance of the latter was not seen after applying Bonferroni correction.

Conclusion

Among MTHFR polymorphisms, c.203G>A and c.1298A>C do not affect infertility risk and c.1793G>A is protective against infertility. Haplotype analysis suggested that risk factors on the MTHFR locus do not extend too long on the DNA string.     

Serum S100B: A Potential Biomarker for Suicidality in Adolescents?

Background

Studies have shown that patients suffering from depression or schizophrenia often have immunological alterations that can be detected in the blood. Others reported a possible link between inflammation, a microgliosis and the blood-brain barrier (BBB) in suicidal patients. Serum S100B is a marker of BBB function commonly used to study cerebrovascular wall function.

Methods

We measured levels of S100B in serum of 40 adolescents with acute psychosis, 24 adolescents with mood disorders and 20 healthy controls. Patients were diagnosed according to DSM-IV TR criteria. We evaluated suicidal ideation using the suicidality subscale of the Brief Psychiatric Rating Scale for Children (BPRS-C).

Results

Serum S100B levels were significantly higher (p<0.05) and correlated to severity of suicidal ideation in patients with psychosis or mood disorders, independent of psychiatric diagnosis. Patients with a BPRS-C suicidality subscores of 1–4 (low suicidality) had mean serum S100B values +/− SEM of 0.152+/−0.020 ng/mL (n = 34) compared to those with BPRS-C suicidality subscores of 5–7 (high suicidality) with a mean of 0.354+/−0.044 ng/mL (n = 30). This difference was statistically significant (p<0.05).

Conclusion

Our data support the use of S100B as an adjunctive biomarker to assess suicidal risk in patients with mood disorders or schizophrenia.     

DNA Methyltransferase Candidate Polymorphisms,Imprinting Methylation,and Birth Outcome

Background

Birth weight and prematurity are important obstetric outcomes linked to lifelong health. We studied a large birth cohort to look for evidence of epigenetic involvement in birth outcomes.

Methods

We investigated the association between birth weight, length, placental weight and duration of gestation and four candidate variants in 1,236 mothers and 1,073 newborns; DNMT1 (rs2162560), DNMT3A (rs734693), DNMT3B (rs2424913) and DNMT3L (rs7354779). We measured methylation of LINE1 and the imprinted genes, PEG3, SNRPN, and IGF2, in cord blood.

Results

The minor DNMT3L allele in the baby was associated with higher birth weight (+54 95% CI 10,99 g; p = 0.016), birth length (+0.23 95% CI 0.04,0.42 cm; p = 0.017), placental weight, (+18 95% CI 3,33 g; p = 0.017), and reduced risk of being in the lowest birth weight decile (p = 0.018) or requiring neonatal care (p = 0.039). The DNMT3B minor allele in the mother was associated with an increased risk of prematurity (p = 0.001). Placental size was related to PEG3 (p<0.001) and IGF2 (p<0.001) methylation. Birth weight was related to LINE1 and IGF2 methylation but only at p = 0.052. The risk of requiring neonatal treatment was related to LINE1 (p = 0.010) and SNRPN (p = 0.001) methylation. PEG3 methylation was influenced by baby DNMT3A genotype (p = 0.012) and LINE1 by baby 3B genotype (p = 0.044). Maternal DNMT3L genotype was related to IGF2 methylation in the cord blood but this effect was only seen in carriers of the minor frequency allele (p = 0.050).

Conclusions

The results here suggest that epigenetic processes are linked birth outcome and health in early life. Our emerging understanding of the role of epigenetics in health and biological function across the lifecourse suggests that these early epigenetic events could have longer term implications.