Search

Chronic periodontitis (CP) is a common inflammatory illness affecting a large proportion of humans. Genetic factors are thought to play important roles in its onset and development. A functional polymorphism (rs1800587) in the promoter of the interleukin-1α gene (−889 C/T) has been found to confer risk of CP primarily in Europeans, but the association between this variant and CP in the Chinese population remains less conclusive. In the current study, we aimed to investigate the association between rs1800587 and CP in case-control samples of Han Chinese origin. A total of 1,777 study subjects, including 884 CP patients and 893 healthy controls, were collected. Genotyping of rs1800587 was performed using the SNAPSHOT method, and statistical analyses were conducted to evaluate the association between rs1800587 and CP. In our sample, rs1800587 was significantly associated with the onset of CP (additive model, T-allele vs. C-allele, p = 0.00359, odds ratio = 1.446, 95% confidence intervals (CIs) = 1.127–1.855; dominant model, (TT + TC) vs. CC, p = 0.00250, odds ratio = 1.502, 95% CIs = 1.152–1.957; overdominant model, TC vs. (TT + CC), p = 0.00264, odds ratio = 1.508, 95% CIs = 1.152–1.976). The T-allele and [TC] genotypes of rs1800587 were significantly overrepresented in CP patients compared with controls. Our data suggest that rs1800587 of IL-1α is significantly associated with the risk of CP in Han Chinese subjects, further confirming its possible involvement in the disease.

Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10–1.54), pcorr = 0.015) and rs10488631 (OR 1.48 (1.14–1.92), pcorr = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18–1.73), pcorr = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24–2.39), pcorr = 0.0098), and rs2004640 (OR 1.39 (1.11–1.75), pcorr = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45–2.38), pcorr = 6.6 × 10−6). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51–0.85), pcorr = 0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD.Key points• We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole.• None of the tested SNPs were risk factors for SSc-ILD specifically.• The STAT4 rs7574865 T allele was protective against the development of lung fibrosis in SSc patients.• Further work is required to understand the genetic basis of lung fibrosis in association with scleroderma.

Recent results indicate that dysregulation of vitamin D-binding protein (VDBP) could be involved in the development of hypovitaminosis D, and it comprises a risk factor for adverse fetal, maternal and neonatal outcomes. Until recently, there was a paucity of results regarding the effect of maternal and neonatal VDBP polymorphisms on vitamin D status during pregnancy in the Mediterranean region, with a high prevalence of hypovitaminosis D. We aimed to evaluate the combined effect of maternal and neonatal VDBP polymorphisms and different maternal and neonatal 25-hydroxyvitamin D (25(OH)D) cut-offs on maternal and neonatal vitamin D profile. Blood samples were obtained from a cohort of 66 mother–child pairs at birth. Our results revealed that: (i) Maternal VDBP polymorphisms do not affect neonatal vitamin D status at birth, in any given internationally adopted maternal or neonatal cut-off for 25(OH)D concentrations, (ii) neonatal VDBP polymorphisms are not implicated in the regulation of neonatal vitamin D status at birth, (iii) comparing the distributions of maternal VDBP polymorphisms and maternal 25(OH)D concentrations, with cut-offs at birth, revealed that mothers with a CC genotype for rs2298850 and a CC genotype for rs4588 tended to demonstrate higher 25(OH)D (≥75 nmol/L) during delivery (p = 0.05 and p = 0.04, respectively), after adjustments for biofactors that affect vitamin D equilibrium, including UVB, BMI and weeks of gestation. In conclusion, this study from Southern Europe indicates that maternal and neonatal VDBP polymorphisms do not affect neonatal vitamin D status at birth, whereas mothers with CC genotype for rs2298850 and CC genotype for rs4588 demonstrate higher 25(OH)D concentrations. Future larger studies are required to establish a causative effect of these specific polymorphisms in the attainment of an adequate (≥75 nmol/L) maternal vitamin D status during pregnancy.

Rationale: Irritable bowel syndrome (IBS) is a multifactorial disease, the genetic aspect of which is being actively studied.Aim: To investigate functional polymorphism of the serotonin reuptake transporter (SERT) SLC6A4 gene of various clinical variants of IBS.Materials and methods: We performed a cross-sectional single center study in 79 Caucasian patients with IBS (according to the Rome criteria IV). The patients were divided into two groups: group 1, IBS with diarrhea (IBS-D, n = 45) and group 2, IBS with constipation (IBS-C, n = 34). The control group included 59 Caucasian patients with gastrointestinal disorders without IBS. Polymorphism 5-HTTLPR of the SLC6A4 gene was assessed in all subjects. In group 1 patients, blood serotonin levels were measured and psychological tests were performed, including Spielberger's State / Trait Anxiety Inventory, quality of life by SF36 and GSRS, Asthenia scale, VAS scores for pain intensity.Results: Thirty-five of 45 (77.8%) patients with IBS-D carried the mutant S allele, which was significantly more frequent than in the IBS-C group (p = 0.002) and in the control group (p = 0.005). There were no statistically significant differences (p = 0.54) in the frequency of detection of the homozygous LL genotype (normal allele) and the heteroand homozygous mutant alleles (SL and SS) genotype between the IBS-C and control patients. In the IBS-D group, a gender difference for the mutant SS allele of 5-HTTLPR was found, with significantly higher frequency in female patients (p = 0.0147). No significant gender differences in the genotype distribution between the patients with IBS-C and the control group were found. There were also no differences in blood serotonin levels in the IBS patients with various 5-HTTLPR types (p = 0.086); they were all in the reference range. However, there was a trend towards lower serotonin levels in the LL genotype carriers compared to those with the SS/SL polymorphisms. The Gastroenterological inventory GSRS demonstrated significantly higher total score for the constipation syndrome in the patients with homozygous LL 5-HTTLPR polymorphism, compared to that in the patients with the SS/SL genotype (p = 0.013).Conclusion: The results may be related to lower expression of the SLC6A4 gene in the carriers of the mutant allele in the 5-HTTLPR promoter and subsequent decreased rate of serotonin uptake, with resulting stimulation of the gastrointestinal tract. The SERT polymorphism of the SLC6A4 gene is worth further investigation as a potential candidate gene in the IBS pathophysiology.

Resorption of bones and cartilage coupled with structural changes in the inflamed joints are the major hallmark of rheumatoid arthritis (RA). Genetic polymorphisms in pro-inflammatory interleukins (ILs) appear to play an important role in the susceptibility towards progressive RA. We therefore aimed to investigate the association of single nucleotide polymorphisms (SNP), present in the hotspot coding/promoter regions of IL-6, -17 and -18, with RA susceptibility or severity in a larger study cohort from Pakistan together with finding clues as to how a functional SNP impacts the predisposition towards RA. TaqMan SNP genotyping approach was first used to assess IL-6 (rs1800795), IL-17 F (rs763780), IL-17A (rs2275913), and IL-18 (rs1946518) polymorphisms in 310 subjects (150 RA and 160 control). Molecular dynamic simulations (MDS) of wild- and mutant-type IL-17A with corresponding receptor were thereafter performed using AMBER-16; Chimera 1.13 was used for analyses. Our results showed the association of two SNPs, namely IL-6 - 174 G/C [allelic (OR = 0.960, 95% CI = 0.929-0.992

We have read with great interest the accepted manuscript of the meta-analysis performed by Huang, et al. titled “A functional polymorphism rs10830963 in melatonin receptor 1B associated with the risk of gestational diabetes mellitus” published online in the 2019 December 6 issue of Bioscience Reports (https://doi.org/10.1042/BSR20190744). We do agree with the authors’ final conclusion that such a meta-analysis should eventually confirm that the MTNR1B rs10830963 G allele is significantly associated with increased risk of gestational diabetes mellitus (GDM) development in pregnant populations with Asian and European ancestry. However we have surprisingly found that our genetic association study (PLoS One (2017), https://doi.org/10.1371/journal.pone.0169781) was included in this meta-analysis, but with mistakenly calculated odds ratios (OR). Therefore we would suggest to use the correct OR values based on our original publication that were already indicating a high genetic effect size for the MTNR1B rs10830963 risk variant on GDM development.

The protein tyrosine phosphatase nonreceptor 22 (PTPN22) is associated with susceptibility to autoimmune diseases. The functional polymorphism in PTPN22 at 1857 is a strong risk factor for vitiligo susceptibility in Europeans; however, controversy exits in other populations. Present study was aimed to determine whether the PTPN22 C1857T polymorphism confers susceptibility to vitiligo in Saudi Arabians. Genomic DNA was extracted and amplified using tetra primer amplification-refractory mutation system polymerase chain reaction (ARMS-PCR) method. The frequencies of allele T and genotype CT of PTPN22 C1858T polymorphism were significantly higher, whereas those of allele C and genotype CC were lower in patients as compared with controls ( P < 0.0001). The genotype TT was absent in both the patients and controls. It is concluded that PTPN22 C1858T polymorphism is strongly associated with vitiligo susceptibility. However, additional studies are warranted using large number of samples from different ethnicities and geographical areas.

IF 2.004 (2018); International audience; 15q24 microdeletion and microduplication syndromes are genetic disorders caused by non-allelic homologous recombination between low-copy repeats (LCRs) in the 15q24 chromosome region. Individuals with 15q24 microdeletion and microduplication syndromes share a common 1.2 Mb critical interval, spanning from LCR15q24B to LCR15q24C. Patients with 15q24 microdeletion syndrome exhibit distinct dysmorphic features, microcephaly, variable developmental delay, multiples congenital anomalies while individuals with reciprocal 15q24 microduplication syndrome show mild developmental delay, facial dysmorphism associated with skeletal and genital abnormalities. We report the first case of a 10 year-old girl presenting mild developmental delay, psychomotor retardation, epilepsy, ventricular arrhythmia, overweight and idiopathic central precocious puberty. 180K array-CGH analysis identified a 1.38 Mb heterozygous interstitial 15q24.1 BP4-BP1 microdeletion including HCN4 combined with a concomitant 2.6 Mb heterozygous distal 15q24.2q24.3 microduplication. FISH analysis showed that both deletion and duplication occurred de novo in the proband. Of note, both copy number imbalances did not involve the 1.2 Mb minimal deletion/duplication critical interval of the 15q24.1q24.2 chromosome region (74.3-75.5 Mb). Sequencing of candidate genes for epilepsy and obesity showed that the proband was hemizygous for paternal A-at risk allele of BBS4 rs7178130 and NPTN rs7171755 predisposing to obesity, epilepsy and intellectual deficits. Our study highlights the complex interaction of functional polymorphisms and/or genetic variants leading to variable clinical manifestations in patients with submicroscopic chromosomal aberrations.

Glioblastoma (GBM) is the most commonly diagnosed solid tumor outside the central nervous system. However, genetic factors underlying GBM remain largely unclear. Previous studies indicated that Glial fibrillary acidic protein (GFAP) might play an important role in the aggressiveness of GBM and also contributed to its poor overall survival. The present study aims to test (1) the associations between GFAP single nucleotide polymorphisms (SNPs) and GBM cells chemoresistance and metastasis, and (2) the molecular mechanism accounting for their effects. Four tagging SNPs of GFAP were initially genotyped in 667 subjects and the significant SNP was further analyzed via online bioinformatical tools. SNP rs11558961 was found to be significantly associated with GBM susceptibility. It was predicted to influence microRNA(miR)-139 binding to 3'UTR of GFAP gene. In functional experiments, we found that cells transfected with rs11558961 G-allele constructs had lower baseline luciferase activities and were more responsive to miR-139 changes, compared to C-allele constructs. Moreover, rs11558961 C>G variant reduced the chemoresistance of GBM cells and migration capability. In conclusion, rs11558961 might influence the chemoresistance and progression of GBM cells via promoting the binding of miR-139, ultimately decrease the susceptibility of GBM. This investigation will shed light on the optimizing for clinical trial design and individualizing of therapeutic plans.

Microseminoprotein-beta (MSMB) is one of the most abundant proteins in human seminal plasma. The current study was aimed to assess the impact of MSMB rs10993994, rs12770171, rs10994385 variants on prostate cancer (PCa) risk in a sample of Iranian population. This case-control study was executed on 169 pathologically confirmed PCa patients and 182 benign prostatic hyperplasia (BPH). Genotyping was performed by using the PCR-RFLP method. Our findings showed that rs10993994 variant significantly increased the risk of PCa in codominant (OR = 1.64, 95%CI = 1.04–2.59, P = 0.038, CT vs TT) and overdominant (OR = 1.64, 95%CI = 1.03–2.43, P = 0.039, TC vs TT + CC) models. However, no significant association was observed among rs10994385 G > C and rs12770171 C > T polymorphisms and PCa risk. In summary, the findings showed that MSMB rs10993994 polymorphism increased the risk of PCa in an Iranian population. To verify our findings, well-designed studies with larger sample sizes and representing various ethnicities are needed.

Aim. To study the parameters of aortic stiffness and polymorphisms of matrix metalloproteases genes MMP2 (-1306) and MMP9 (-1564) in patients with arterial hypertension (AH) of young and middle age. Material and methods. Totally, 58 patients studied with AH, age 25-60 y.o., and 59 healthy volunteers. The pulse wave velocity (PWV) assessed, and augmentation index (arteriography on TensioClinic TL1, Hungary). The specimens of DNA extracted, from blood leucocytes, and gene typing of promotor regions of the genes MMP2 (-1306) and MMP9 (-1564). Results. Genotypes MMP2 (-1306) (CT and ТТ) are found in AH patients with the signs of metabolic syndrome (MS) 1,72 times more commonly than in controls (p=0,23). Genotypes MMP9 (-1564) (CT and ТТ) are slightly more common in the general AH group comparing to controls (OR=1,4; p=0,39). In AH patients with no MS signs the genotypes MMP9 (-1564) (CT and ТТ) are predominant and found 2,66 times more frequently, than in the healthy (р=0,04). In cases of high PWV in AH, genotype MMP9 (-1564) (СТ and ТТ) is found 1,9 times more often than in controls with AH and normal PWV with no statistical significance (р=0,14). Conclusion. The polymorphism MMP9 (-1564 C/T) finding in AH patients can be used for prediction of additional risk for cardiovascular catastrophes with the individualized monitoring of collected factors.

// Philipp Hofer 1 , Cornelia Zochmeister 1 , Christian Behm 1 , Stefanie Brezina 1 , Andreas Baierl 2 , Angelina Doriguzzi 1 , Vanita Vanas 1 , Klaus Holzmann 1 , Hedwig Sutterluty-Fall 1 , Andrea Gsur 1 1 Medical University of Vienna, Institute of Cancer Research, A-1090 Vienna, Austria 2 University of Vienna, Department of Statistics and Operations Research, A-1010 Vienna, Austria Correspondence to: Andrea Gsur, email: andrea.gsur@meduniwien.ac.at Keywords: genetic variation, MNS16A, functional polymorphism, telomerase, TERT regulation Received: September 23, 2016 Accepted: February 21, 2017 Published: March 03, 2017 ABSTRACT MNS16A, a functional polymorphic tandem repeat minisatellite, is located in the promoter region of an antisense transcript of the human telomerase reverse transcriptase gene. MNS16A promoter activity depends on the variable number of tandem repeats (VNTR) presenting varying numbers of transcription factor binding sites for GATA binding protein 1. Although MNS16A has been investigated in multiple cancer epidemiology studies with incongruent findings, functional data of only two VNTRs (VNTR-243 and VNTR-302) were available thus far, linking the shorter VNTR to higher promoter activity. For the first time, we investigated promoter activity of all six VNTRs of MNS16A in cell lines of colorectal, lung and prostate cancer using Luciferase reporter assay. In all investigated cell lines shorter VNTRs showed higher promoter activity. While this anticipated indirect linear relationship was affirmed for colorectal cancer SW480 ( P = 0.006), a piecewise linear regression model provided significantly better model fit in lung cancer A-427 ( P = 6.9 × 10 –9 ) and prostate cancer LNCaP ( P = 0.039). In silico search for transcription factor binding sites in MNS16A core repeat element suggested a higher degree of complexity involving X-box binding protein 1, general transcription factor II–I, and glucocorticoid receptor alpha in addition to GATA binding protein 1. Further functional studies in additional cancers are requested to extend our knowledge of MNS16A functionality uncovering potential cancer type-specific differences. Risk alleles may vary in different malignancies and their determination in vitro could be relevant for interpretation of genotype data.

Recent studies have suggested that interleukin 1 receptor‐like 1 (ST2) plays a critical role in pathogenesis of several cardiovascular disease conditions. In this study, we examined association of 13 single nucleotide polymorphisms (SNPs) of ST2 gene with essential hypertension (EH) risk in 1151 patients with EH and 1135 controls. Our study showed that variants rs11685424, rs12999364 and rs3821204 are highly associated with an increase in risk of EH, while rs6543116 is associated with a decrease risk of EH. Notably, in silico analyses suggested the G>C change of rs3821204, which located within the 3′UTR of soluble ST2 mRNA, disrupted a putative binding site for miR202‐3p. Functional analyses suggested that miR‐202‐3p significantly decreased soluble ST2‐G mRNA stability and inhibited its endogenous expression. Furthermore, we found increased plasma‐soluble ST2 (sST2) level was highly associated with CC genotype of rs3821204 in vivo. Taken together, our findings provide the first evidence that genetic variants in ST2 gene are associated with EH risk and variant rs3821204 may influence the development of EH by controlling sST2 expression.

The melatonin receptor 1B (MTNR1B) polymorphism rs10830963 C>G has been reported to be associated with the risk of gestational diabetes mellitus (GDM) with inconsistent results. To clarify the effect of the polymorphism on the risk of GDM, a meta-analysis therefore was performed. Pooled OR with its corresponding 95%CI was used to estimate the strength of the association. Totally 14 eligible studies with a number of 5033 GDM patients and 5614 controls were included in this meta-analysis. Results indicated that the variant G allele was significantly associated with an increased GDM risk (CG vs. CC: OR = 1.25, 95% CI = 1.11−1.40, P < 0.001; GG vs. CC: OR = 1.78, 95% CI = 1.45−2.19, P < 0.001; G vs. C: OR = 1.33, 95% CI = 1.21−1.47, P < 0.001). In the stratified analysis by ethnicity, similar results were found in Asians (CG vs. CC: OR = 1.15, 95%CI = 1.02−1.28, P = 0.020; GG vs. CC: OR = 1.52, 95% CI = 1.23−1.89, P < 0.001; G vs. C: OR = 1.23, 95% CI = 1.10−1.37, P < 0.001) and in Caucasians (CG vs. CC: OR = 1.40, 95% CI = 1.16−1.70, P < 0.001; GG vs. CC: OR = 2.21, 95% CI = 1.54−3.17, P < 0.001; G vs. C: OR = 1.47, 95% CI = 1.24−1.73, P < 0.001). FPRP and TSA analyses confirmed findings support that the rs10830963 G allele increases the risk of GDM, and further functional experimental studies are warranted to explore and clarify the potential mechanism.

Purpose: The objective of this study was to evaluate the relationship between brain-derived neurotrophic factor (BDNF) gene (Val66Met, rs6265, G>A) polymorphism and breast cancer (BC) among females of Southern Pakistan. Methods: This case-control study consisted of 300 females (BC cases [n = 100] and controls [n = 200]) with age range of 18 to 45 years. All participants were recruited during January to December 2014 and were screened for depression using Zung depression scale. Isolation of genomic DNA (gDNA) followed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was done. All statistical analysis was carried out on IBM-SPSS version 22 at P-value Results: Genotype distribution of BDNF gene polymorphism lies in the goodness-of-fit model among controls. The statistical analyses reveal a significant association between genotype frequencies (χ2 = 12.709, P-value = .002) of BDNF and BC among cases and controls. The AA genotype (OR = 5.2, 95%CI = 0.632-42.804) increases the risk of having BC. Conclusions: Our results suggest that BDNF gene polymorphism may have an association with BC risk among Pakistani females. However, the present finding needs to be replicated with greater sample size with BC risk.

We attempted to determine whether a functional polymorphism of TRPM6 (rs2274924) is associated with susceptibility to epilepsy following ischemic stroke, and to further explore the effect of this polymorphism on serum levels of MgWe carried out a case-control study on 378 post-stroke epilepsy patients and 420 controls (stroke patients without secondary epilepsy). We used DNA sequencing to determine the genotypes of the TRPM6 rs2274924 polymorphism, and used the ion selective electrode method to measure serum levels of MgThe distribution of the CC genotype and the frequency of the C allele were significantly higher in the post-stroke epilepsy patients than in the controls (P 0.01). With regard to the post-stroke epilepsy patients, the serum levels of MgThe TRPM6 rs2274924 polymorphism may be associated with susceptibility to epilepsy following stroke, and the C allele may be associated with increased risk of post-stroke epilepsy. The TRPM6 rs2274924 polymorphism may also influence serum levels of Mg

[Objective] In view of the discrepant data regarding the association between the protein tyrosine phosphatase non-receptor 22 (PTPN22) rs2476601 (R620W, 1858C→T) polymorphism and susceptibility to autoimmune diseases including inflammatory bowel diseases (IBD), we investigated whether this functional single-nucleotide polymorphism influences IBD risk in a group of Moroccan patients., [Results] This is the first report on the prevalence of PTPN22 (R620W) variant in a Moroccan cohort. No evidence of statistically significant differences was observed when the PTPN22 (R620W) allele and genotype distribution among IBD, Crohn’s disease (CD), ulcerative colitis (UC) patients and healthy controls were compared. The frequency of the variant allele in healthy subjects was 1.77% compared to 2.56% in the IBD patients and 1.85% in CD patients. Furthermore, the frequency of this allele was increased in UC patients compared to controls (4.17% vs. 1.77%, OR = 2.42, 95% CI 0.82–7.08; P = 0.09), but the difference was not statistically significant. Our data suggest a lack of association between PTPN22 R620W variant and IBD susceptibility in Moroccan patients.

The interplay between genetic and environmental factors is likely involved in the pathogenesis of systemic sclerosis (SSc). Interstitial lung disease associated in the context of SSc (SSc-ILD) is associated with significant morbidity, and is the leading cause of death in SSc. The spectrum of SSc-ILD severity is wide, ranging from patients with only limited and inherently stable pulmonary involvement, to those with extensive and progressive pulmonary fibrosis. In order to provide accurate prognostic information for patients, and to initiate appropriate monitoring and treatment regimens, the ability to identify patients at risk of developing severe ILD early in the disease course is crucial. Identification of genetic variants involved in disease pathogenesis can not only potentially provide diagnostic/prognostic markers, but can also highlight dysregulated molecular pathways for therapeutic targeting. A number of genetic associations have been established for susceptibility to SSc, but far fewer studies have investigated genetic susceptibility to SSc-ILD specifically. In this review we present a summary of the studies assessing genetic associations with SSc-ILD.

Background: Psoriasis is a complex autoimmune disease caused by the interaction of genetic and environmental factors. PTPN22 gene polymorphism has been reported to affect psoriasis susceptibility; however, no data are available for Middle Eastern populations. Objective: The aim of this study was to investigate the association of PTPN22 (1858C/T) R620W polymorphism with psoriasis in a Saudi cohort. Methods: Saudi subjects (n = 306) including patients with psoriasis (n = 106) and matched controls (n = 200) were studied for PTPN22 variants using tetra-primer amplification refractory mutation system-polymerase chain reaction method. The frequencies of alleles and genotypes of PTPN22 (1858C/T) polymorphism were compared between patients and controls. Results: The frequency of CT genotype of PTPN22 (1858C/T) polymorphism was significantly higher, whereas that of CC genotype was lower in patients with psoriasis than in controls ( P Conclusions: PTPN22 (1858C/T) polymorphism is positively associated with susceptibility of psoriasis in Saudis and can be developed as biomarker for evaluating psoriasis risk. However, further studies on PTPN22 polymorphism in larger samples from different geographical areas and ethnicity are warranted.

Background Mutations or single nucleotide polymorphisms (SNPs) within the gene region of microRNAs play an important role for the development of hepatocellular carcinoma (HCC). Extensive studies have tried to investigate the susceptibility role of miR-146a rs2819164 and miR-196a-2 rs11614913. However, these results are still inconsistent and inconclusive. We undertook a meta-analysis containing primarily Asian studies to assess the associations of the two SNPs with HCC risk. Methods 19 studies including miR-146a (7170 cases and 9443 controls) and 15 studies including miR-196a-2 (6417 cases and 7627 controls) were used for meta-analysis. Odds ratios and 95% CI were calculated to assess the association in five different genetic models. Results For the rs2910164 polymorphism of miR-146a, significantly increased risks for HCC were observed when all studies were pooled under two models (CG vs CC: OR = 1.11, 95% CI = 1.02–1.21, P = 0.021; GG + CG vs CC: OR = 1.11, 95% CI = 1.01–1.22, P = 0.035). For the rs11614913 polymorphism of miR-196a-2, significant increased risks for HCC development were observed when all studies were pooled under four models (C vs T: OR = 1.14, 95% CI = 1.06–1.23, P = 0.001; CC vs TT: OR = 1.31, 95% CI = 1.12–1.53, P = 0.001; CC + TC vs TT: OR = 1.16, 95% CI = 1.03–1.31, P = 0.018; CC vs TC + TT: OR = 1.14, 95% CI = 1.00–1.30, P = 0.043). Conclusion Our results show that the two common SNPs within the miRNAs were associated with modest increased risk of HCC (OR

Supplemental Digital Content is Available in the Text. A catechol-O-methyltransferase genetic marker of pain led to the discovery of an alternative enzyme that acts through dopamine rather than epinephrine, characteristic of reference catechol-O-methyltransferase., Catechol-O-methyltransferase (COMT) metabolizes catecholaminergic neurotransmitters. Numerous studies have linked COMT to pivotal brain functions such as mood, cognition, response to stress, and pain. Both nociception and risk of clinical pain have been associated with COMT genetic variants, and this association was shown to be mediated through adrenergic pathways. Here, we show that association studies between COMT polymorphic markers and pain phenotypes in 2 independent cohorts identified a functional marker, rs165774, situated in the 3′ untranslated region of a newfound splice variant, (a)-COMT. Sequence comparisons showed that the (a)-COMT transcript is highly conserved in primates, and deep sequencing data demonstrated that (a)-COMT is expressed across several human tissues, including the brain. In silico analyses showed that the (a)-COMT enzyme features a distinct C-terminus structure, capable of stabilizing substrates in its active site. In vitro experiments demonstrated not only that (a)-COMT is catalytically active but also that it displays unique substrate specificity, exhibiting enzymatic activity with dopamine but not epinephrine. They also established that the pain-protective A allele of rs165774 coincides with lower COMT activity, suggesting contribution to decreased pain sensitivity through increased dopaminergic rather than decreased adrenergic tone, characteristic of reference isoforms. Our results provide evidence for an essential role of the (a)-COMT isoform in nociceptive signaling and suggest that genetic variations in (a)-COMT isoforms may contribute to individual variability in pain phenotypes.

The melatonin receptor 1B (MTNR1B) as a candidate gene for gestational diabetes mellitus (GDM) on the basis of its association with T2DM, β-cells function and fasting plasma glucose (FPG) level. Many studies have investigated the association between MTNR1B polymorphism rs10830963 C>G and GDM risk, but the conclusion is inconsistent. PubMed, Google Scholar and CNKI databases were searched to identify eligible studies. Pooled OR with corresponding 95% CI was used to estimate the strength of the association between rs10830963 and GDM risk using a fixed- or random-effect model. 12 eligible studies with a number of 4,782 GDM patients and 5,605 controls were included in this meta-analysis. Results indicated that the variant G allele of rs10830963 polymorphism was significantly associated with an increased risk of GDM (CG vs. CC: OR=1.23, 95% CI = 1.12–1.34, Pheterogeneity = 0.23; GG vs. CC: OR=1.74, 95% CI =1.41–2.15, Pheterogeneity = 0.002). In the stratified analysis by ethnicity, similar results were found in Asians (CG vs. CC: OR=1.15, 95% CI = 1.04–1.28, Pheterogeneity = 0.74; GG VS. CC: OR=1.48, 95% CI =1.23–1.78, Pheterogeneity = 0.08) and in Caucasians (CG vs. CC: OR=1.49, 95% CI =1.25–1.77, Pheterogeneity = 0.28; GG vs. CC: OR=2.68, 95% CI =2.03–3.54, Pheterogeneity = 0.58).

Summary Objective SCN1A encodes the alpha subunit of the voltage-gated sodium channel and plays a crucial role in several epilepsy syndromes. The common SCN1A splice-site polymorphism rs3812718 (IVS5N+5 G>A) might contribute to the pathophysiology underlying genetic generalized epilepsies and is associated with electrophysiologic properties of the channel and the effect of sodium-channel blocking antiepileptic drugs. We assessed the effects of the rs3812718 genotype on cortical excitability at baseline and after administration of carbamazepine in order to investigate the mechanism of this association. Methods Paired-pulse transcranial magnetic stimulation (TMS) was applied in 92 healthy volunteers with the homozygous genotypes AA or GG of rs3812718 at baseline and after application of 400 mg of carbamazepine or placebo in a double-blind, randomized, crossover design. Resting motor threshold (RMT), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP) were determined. Results At baseline there was no significant difference in any TMS parameter. Genotype GG was associated with a higher carbamazepine-induced increase in CSP duration as compared to AA (multivariate analysis of covariance [MANCOVA], p = 0.013). An expected significant increase in RMT was genotype independent. Significance We found that the rs3812718 genotype modifies the effect of carbamazepine on CSP duration (mainly reflecting modulation of γ-aminobutyric acid (GABA)ergic inhibition), but not on RMT (mainly reflecting modulation of voltage-gated sodium channels). This provides evidence that rs3812718 affects the pharmacoresponse to carbamazepine via an effect on GABAergic cortical interneurons. Our results also confirm that TMS is useful to investigate the effect of genetic variants on cortical excitability and pharmacoresponse.

Background/Aims: Several genetic factors have been identified that may contribute to the risk of coronary artery disease (CAD). Variants of the neuropeptide Y (NPY) gene, whose products play an important role in regulating several physiological functions, have been associated with the risk of CAD in some populations. The purpose of this study was to investigate the relationship between the NPY gene rs16147 polymorphism and the presence of CAD in an Iranian population. Methods: DNA samples of 922 subjects, including 433 with angiographically defined CAD (CAD+), 196 without angiographically defined significant CAD (CAD-) and 293 controls, were genotyped using polymerase chain reaction based on the amplification-refractory mutation system. Logistic regression analyses were performed to assess the association of rs16147 genotypes with the presence of significant CAD. Results: Although logistic regression analysis indicated that the NPY polymorphism rs16147 was nominally associated with an increased risk of CAD (p < 0.05), after adjustment for confounding factors, there was no evidence for any significantly increased or decreased risk of CAD with this polymorphism. However, in stratified analyses, the C allele was significantly associated with a reduced risk of CAD in males and subjects who were Conclusions: This study suggests that the rs16147 polymorphism in the NPY gene may not be a potential contributor to the risk of CAD in an Iranian population.

Objective: Obstructive sleep apnea syndrome (OSAS) is associated with increased cardiovascular morbidity and mortality. We aimed to investigate the matrix metalloproteinase-9 (MMP-9) level and MMP-9 gene polymorphism in sleep apnea patients with or without cardiovascular disease. Study Design: Case-control study. Material and Methods: Two hundred nine patients [Mean age (±SD), 47 (±12) yrs; M/F, 170/39] diagnosed with sleep-disordered breathing were included in the study. Serum MMP-9 level was performed using enzyme-linked immunosorbant assay (ELISA) and MMP-9 gene polymorphism with polymerase chain reaction-restriction fragment length polymorphism. We divided the patient group into two subgroups: (1) patients with confirmed cardiovascular disease, i.e. CV-P Group and (2) patients without cardiovascular disease, CV-N Group. We compared all parameters between the two groups. Results: There were 56 OSAS patients with cardiovascular disorder (CV-positive group) and 153 OSAS patients without cardiovascular disorder (CVnegative group). CC, CT and TT genotype distributions between groups were similar [31 (55%), 25 (45%), 0 (0%) vs 88 (57%), 61 (40%), 4 (3%); respectively, p>0.05]. MMP-9 level was significantly higher in CV-P patients (442.7±139.3 pg/mL) than in CV-N patients (364.4±165.0 pg/mL; p=0.0018). Conclusion: Our results showed that the presence of MMP-9 polymorphism was not associated with cardiovascular disease. MMP-9 level was higher in OSAS patients with cardiovascular disorders than without cardiovascular disorders. Finally, MMP-9 genotype was not associated with serum MMP-9 levels. Turkish Başlık: Kardiyovasküler Hastalığı olan ve olmayan Obstrüktif Uyku Apne Sendromlu Hastalarda Matriks Metalloproteinaz-9 Aktivitesi ile Gen Polimorfizmi Anahtar Kelimeler: Kardiyovasküler hastalıkları, MMP-9, polimorfizm, uyku apnesi, hipertansiyon Amaç: Obstrüktif uyku apne sendromu (OUAS) artmış kardiyovasküler morbidite ve mortalite ile ilişkilidir. Bu çalışmada kardiyovasküler hastalığı olan ve olmayan uyku apneli hastalarda matriks metalloproteinaz-9 (MMP-9) düzeyi ile MMP-9 gen polimorfizminin araştırılması amaçlandı. Gereç ve Yöntemler: Uykuda solunum bozukluğu teşhisi almış 209 hasta [Ortalama yaş (±SS), 47 (±12) yıl; E/K, 170/39] çalışmaya dahil edildi. Serum MMP-9 düzeyi ELISA, MMP-9 gen polimorfizmi polimeraz zincir reaksiyonu ve restriksiyon fragmanı uzunluk polimorfizmi ile DNA örneklerinde belirlendi. Hastalar kardiyovasküler hastalığı olan, KV-P grubu ve kardiyovasküler hastalığı olmayan, KV-N grubu olmak üzere iki alt gruba ayrıldı. Bulgular: Kardiyovasküler hastalığı olan (KV-P grup) 56 ve kardiyovasküler hastalığı olmayan (KV-N grup) 153 OUAS hasta tesbit edildi. Gruplar arası CC, CT ve TT genotip dağılımı benzer [31 (55%), 25 (45%), 0 (0%) vs 88 (57%), 61 (40%), 4 (3%); sırasıyla, p>0.05] tesbit edildi. MMP-9 düzeyi KV-P hastalarda (442.7±139.3 pg/mL) KV-N hastalara (364.4±165.0 pg/mL) göre anlamlı (p=0.0018) yüksek saptandı. Sonuç: Bulgularımız, MMP-9 polimorfizm varlığının kardiyovasküler hastalıklarla ilişkili olmadığını gösterdi. MMP-9 düzeyi kardiyovasküler hastalığı olan OUAS'lı hastalarda kardiyovasküler hastalığı olmayanlara göre yüksek saptandı. Sonuç olarak, MMP-9 genotipi serum MMP-9 düzeyi ile ilişkili bulunmadı.

NBS1, also known as NBN, plays an important role in maintaining genomic stability. Interestingly, rs2735383 G > C, located in a microRNA binding site in the 3'-untranslated region (UTR) of NBS1, was shown to be associated with increased susceptibility to lung and colorectal cancer. However, the relation between rs2735383 and susceptibility to breast cancer is not yet clear. Therefore, we genotyped rs2735383 in 1,170 familial non-BRCA1/2 breast cancer cases and 1,077 controls using PCR-based restriction fragment length polymorphism (RFLP-PCR) analysis, but found no association between rs2735383CC and breast cancer risk (OR = 1.214, 95% CI = 0.936-1.574, P = 0.144). Because we could not exclude a small effect size due to a limited sample size, we further analyzed imputed rs2735383 genotypes (r2 > 0.999) of 47,640 breast cancer cases and 46,656 controls from the Breast Cancer Association Consortium (BCAC). However, rs2735383CC was not associated with overall breast cancer risk in European (OR = 1.014, 95% CI = 0.969-1.060, P = 0.556) nor in Asian women (OR = 0.998, 95% CI = 0.905-1.100, P = 0.961). Subgroup analyses by age, age at menarche, age at menopause, menopausal status, number of pregnancies, breast feeding, family history and receptor status also did not reveal a significant association. This study therefore does not support the involvement of the genotype at NBS1 rs2735383 in breast cancer susceptibility. We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. This study would not have been possible without the contributions of the following: Paul Pharoah (BCAC), Andrew Berchuck (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai and Sara Benlloch (PRACTICAL), Antonis Antoniou, Lesley McGuffog and Ken Offit (CIMBA), Andrew Lee, Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, the staff of the CNIO genotyping unit, Francois Bacot, Daniel Vincent, Sylvie La Boissiere and Frederic Robidoux and the staff of the McGill University and Genome Quebec Innovation Centre, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility; ABCFS: Maggie Angelakos, Judi Maskiell, Gillian Dite; ABCS: Blood bank Sanquin (The Netherlands); ACP: The ACP study wishes to thank the participants in the Thai Breast Cancer study. Special Thanks also go to the Thai Ministry of Public Health (MOPH), doctors and nurses who helped with the data collection process. Finally, the study would like to thank Dr Prat Boonyawongviroj, the former Permanent Secretary of MOPH and Dr Pornthep Siriwanarungsan, the Department Director-General of Disease Control who have supported the study throughout; BBCS: Eileen Williams, Elaine Ryder-Mills, Kara Sargus; BIGGS: Niall McInerney, Gabrielle Colleran, Andrew Rowan, Angela Jones; BSUCH: Peter Bugert, Medical Faculty Mannheim; CGPS: Staff and participants of the Copenhagen General Population Study. For the excellent technical assistance: Dorthe Uldall Andersen, Maria Birna Arnadottir, Anne Bank, Dorthe Kjeldgard Hansen. The Danish Cancer Biobank is acknowledged for providing infrastructure for the collection of blood samples for the cases; CNIO-BCS: Guillermo Pita, Charo Alonso, Nuria Alvarez, Pilar Zamora, Primitiva Menendez, the Human Genotyping-CEGEN Unit (CNIO); CTS: The CTS Steering Committee includes Leslie Bernstein, Susan Neuhausen, James Lacey, Sophia Wang, Huiyan Ma, and Jessica Clague DeHart at the Beckman Research Institute of City of Hope, Dennis Deapen, Rich Pinder, and Eunjung Lee at the University of Southern California, Pam Horn-Ross, Peggy Reynolds, Christina Clarke Dur and David Nelson at the Cancer Prevention Institute of California, Hoda Anton-Culver, Argyrios Ziogas, and Hannah Park at the University of California Irvine, and Fred Schumacher at Case Western University. Hartwig Ziegler, Sonja Wolf, Volker Hermann, Christa Stegmaier, Katja Butterbach; GENICA: The GENICA Network: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tubingen, Germany [Hiltrud Brauch, Wing-Yee Lo, Christina Justenhoven], German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) [Hiltrud Brauch], Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian Baisch], Institute of Pathology, University of Bonn, Germany [HansPeter Fischer], Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany [Ute Hamann], Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany [Thomas Bruning, Beate Pesch, Sylvia Rabstein, Anne Lotz]; and Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany [Volker Harth]; HEBCS: Kristiina Aittomaki, Sofia Khan, Taru A. Muranen, Kirsimari Aaltonen, Karl von Smitten, Irja Erkkila; HMBCS: Peter Hillemanns, Hans Christiansen and Johann H. Karstens; pKARMA: The Swedish Medical Research Counsel; KBCP: Eija Myohanen, Helena Kemilainen; kConFab/AOCS: We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab; LAABC: We thank all the study participants and the entire data collection team, especially Annie Fung and June Yashiki; LMBC: Gilian Peuteman, Thomas Van Brussel, EvyVanderheyden and Kathleen Corthouts; MARIE: Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Judith Heinz, Nadia Obi, Ursula Eilber, Muhabbet Celik; MBCSG: Paolo Peterlongo of IFOM, the FIRC Institute of Molecular Oncology; Siranoush Manoukian, Bernard Peissel, Jacopo Azzollini, Daniela Zaffaroni and Lidia Pezzani of the Fondazione IRCCS Istituto Nazionale dei Tumori (INT); Bernardo Bonanni, and Irene Feroce of the Istituto Europeo di Oncologia (IEO) and the personnel of the Cogentech Cancer Genetic Test Laboratory; MTLGEBCS: We would like to thank Martine Tranchant (CHU de Quebec Research Center), Marie-France Valois, Annie Turgeon and Lea Heguy (McGill University Health Center, Royal Victoria Hospital; McGill University) for DNA extraction, sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. We thank study partcipants and research staff (particularly Patsy Ng, Nurhidayu Hassan, Yoon Sook-Yee, Daphne Lee, Lee Sheau Yee, Phuah Sze Yee and Norhashimah Hassan) for their contributions and commitment to this study; NBCS: OSBREAC Investigators: Prof. Solveig Hofvind, PhD (Cancer Registry of Norway, Oslo, Norway, Oslo and Akershus University College of Applied Sciences, Faculty of Health Science, Oslo, Norway), Prof. Tone F. Bathen, PhD (Department of Circulation and Medical Imaging, Norwegian University of Science and Technology NTNU), Trondheim, Norway), Dr. Elin Borgen, MD (Department of Pathology, Division of Diagnostics and Intervention, Oslo University Hospital, Oslo, Norway), Prof. Em. Oystein Fodstad, MD (Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway and Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway), Dr. Oystein Garred, MD (Department of Pathology, Oslo University Hospital, Oslo, Norway), Gry Aarum Geitvik, Unit leader (Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway), Prof. Gunhild Mari Maelandsmo, PhD (Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway, Department of Pharmacy, Faculty of Health Sciences, University of Tromso, Tromso, Norway), Dr. Hege G Russnes, MD (Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway and Department of Pathology, Oslo University Hospital, Oslo, Norway), Dr. Therese Sorlie, PhD (Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway), Prof. Ole Christian Lingjorde, PhD (Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway and Department of Computer Science, University of Oslo, Oslo, Norway), Dr. Helle Kristine Skjerven, MD (Breast and Endocrine Surgery, Department of Breast and Endocrine Surgery, Vestre Viken Hospital, Drammen, Norway), Dr. Britt Fritzman, MD (Ostfold Hospital, Ostfold, Norway); NBHS: We thank study participants and research staff for their contributions and commitment to this study; OBCS: We thank Arja Jukkola-Vuorinen, Mervi Grip, Saila Kauppila, Meeri Otsukka, Leena Keskitalo and Kari Mononen for their contributions to this study; OFBCR: Teresa Selander, Nayana Weerasooriya; PBCS: Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner; RBCS: Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens, Anja Kromwijk-Nieuwlaat, Annette Heemskerk, the Erasmus MC Family Cancer Clinic; SASBAC: The Swedish Medical Research Counsel; SBCGS: We thank study partcipants and research staff for their contributions and commitment to this study; SBCS: Sue Higham, Helen Cramp, Dan Connley, Ian Brock, Sabapathy Balasubramanian and Malcolm W.R. Reed; SEARCH: The SEARCH and EPIC teams; SGBCC: We thank the participants and research coordinator Ms Tan Siew Li; SKKDKFZS: We thank all study participants, clinicians, family doctors, researchers and technicians for their contributions and commitment to this study; SZBCS: Ewa Putresza; UKBGS: We thank Breast Cancer Now and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. This study was funded by the Cancer Genomics Netherlands (CGC.nl) and a grant for the Netherlands Organization of Scientific Research (NWO). J Liu received a scholarship from the China Scholarship Council (Beijing, China). BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community's Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Australian Breast Cancer Family Study (ABCFS) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]. The ACP study is funded by the Breast Cancer Research Trust, UK. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). ES is supported by NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, United Kingdom. IT is supported by the Oxford Biomedical Research Centre. The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ). The CECILE study was supported by Fondation de France, Institut National du Cancer (INCa), Ligue Nationale contre le Cancer, Agence Nationale de Securite Sanitaire, de l'Alimentation, de l'Environnement et du Travail (ANSES), Agence Nationale de la Recherche (ANR). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev and Gentofte Hospital. The CNIO-BCS was supported by the Instituto de Salud Carlos III (CEGEN) and grants from the Fondo de Investigacion Sanitario (PI11/00923 and PI12/00070) with FEDER funds and H2020 (BRIDGES project). The CTS was initially supported by the California Breast Cancer Act of 1993 and the California Breast Cancer Research Fund (contract 97-10500) and is currently funded through the National Institutes of Health (R01 CA77398, UM1 CA164917, and U01 CA199277). Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. HAC receives support from the Lon V Smith Foundation (LVS39420). The ESTHER study was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The HEBCS was financilly supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The HERPACC was supported by MEXT Kakenhi (No. 170150181 and 26253041) from the Ministry of Education, Science, Sports, Culture and Technology of Japan, by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from Ministry Health, Labour and Welfare of Japan, by Health and Labour Sciences Research Grants for Research on Applying Health Technology from Ministry Health, Labour and Welfare of Japan, by National Cancer Center Research and Development Fund, and "Practical Research for Innovative Cancer Control (15ck0106177h0001)" from Japan Agency for Medical Research and development, AMED, and Cancer Bio Bank Aichi. The HMBCS was supported by a grant from the Friends of Hannover Medical School and by the Rudolf Bartling Foundation. The pKARMA study was supported by Merit and Hans Rausings Initiative Against Breast Cancer. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, and by the strategic funding of the University of Eastern Finland. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer Council Tasmania and the National Health and Medical Research Council of Australia (NHMRC; 400413, 400281, 199600). G.C.T. and P.W. are supported by the NHMRC. RB was a Cancer Institute NSW Clinical Research Fellow. LAABC is supported by grants (1RB-0287, 3PB-0102, 5PB-0018, 10PB-0098) from the California Breast Cancer Research Program. Incident breast cancer cases were collected by the USC Cancer Surveillance Program (CSP) which is supported under subcontract by the California Department of Health. The CSP is also part of the National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. LMBC is supported by the 'Stichting tegen Kanker'. Diether Lambrechts is supported by the FWO. The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419, 110826, 110828], the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5 x 1000"). The MCBCS was supported by the NIH grants CA192393, CA116167, CA176785 an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], and the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. The MEC was support by NIH grants CA63464, CA54281, CA098758, CA132839 and CA164973. The work of MTLGEBCS was supported by the Quebec Breast Cancer Foundation, the Canadian Institutes of Health Research for the " CIHR Team in Familial Risks of Breast Cancer" program grant #CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade - grant # PSR-SIIRI-701. MYBRCA is funded by research grants from the Malaysian Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Malaysia. MYMAMMO is supported by research grants from Yayasan Sime Darby LPGA Tournament and Malaysian Ministry of Higher Education (RP046B-15HTM). The NBCS has been supported by the Research Council of Norway grant 193387/V50 (to A-L Borresen-Dale and V.N. Kristensen) and grant 193387/H10 (to A-L Borresen-Dale and V.N. Kristensen), South Eastern Norway Health Authority (grant 39346 to A-L Borresen-Dale and 27208 to V. N. Kristensen) and the Norwegian Cancer Society (to A-L Borresen-Dale and 419616-71248 -PR-2006-0282 to V. N. Kristensen). It has received funding from the K. G. Jebsen Centre for Breast Cancer Research (2012-2015). The NBHS was supported by NIH grant R01CA100374. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities. The Ontario Familial Breast Cancer Registry (OFBCR) was supported by grant UM1 CA164920 from the National Cancer Institute (USA). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The RBCS was funded by the Dutch Cancer Society (DDHK 2004-3124, DDHK 2009-4318). The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The SBCGS was supported primarily by NIH grants R01CA64277, R01CA148667, UMCA182910, and R37CA70867. Biological sample preparation was conducted the Survey and Biospecimen Shared Resource, which is supported by P30 CA68485. The scientific development and funding of this project were, in part, supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network U19 CA148065. The SBCS was supported by Sheffield Experimental Cancer Medicine Centre and Breast Cancer Now. SEARCH is funded by a programme grant from Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. SEBCS was supported by the BRL (Basic Research Laboratory) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012-0000347). SGBCC is funded by the NUS start-up Grant, National University Cancer Institute Singapore (NCIS) Centre Grant and the NMRC Clinician Scientist Award. Additional controls were recruited by the Singapore Consortium of Cohort Studies- Multi-ethnic cohort (SCCS-MEC), which was funded by the Biomedical Research Council, grant number: 05/1/21/19/425. SKKDKFZS is supported by the DKFZ. The SZBCS was supported by Grant PBZ_KBN_122/P05/2004. The TBCS was funded by The National Cancer Institute Thailand. The TNBCC was supported by: a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, a generous gift from the David F. and Margaret T. Grohne Family Foundation; the Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, the European Union (European Social Fund - ESF), and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - ARISTEIA. The TWBCS is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The UKBGS is funded by Breast Cancer Now and the Institute of Cancer Research (ICR), London. ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. Sí

Recently, microRNAs (miRNA) have been proposed as regulators in the different processes involved in alcohol intake, and differences have been found in the miRNA expression profile in alcoholics. However, no study has focused on analyzing polymorphisms in genes encoding miRNAs and daily alcohol consumption at the population level. Our aim was to investigate the association between a functional polymorphism in the pre-miR-27a (rs895819 A>G) gene and alcohol consumption in an elderly population. We undertook a cross-sectional study of PREvención con DIeta MEDiterránea (PREDIMED)-Valencia participants (n = 1007, including men and women aged 67 7 years) and measured their alcohol consumption (total and alcoholic beverages) through a validated questionnaire. We found a strong association between the pre-miR-27a polymorphism and total alcohol intake, this being higher in GG subjects (5.2 0.4 in AA, 5.9 0.5 in AG and 9.1 1.8 g/day in GG; padjusted = 0.019). We also found a statistically-significant association of the pre-miR-27a polymorphism with the risk of having a high alcohol intake (>2 drinks/day in men and >1 in women): 5.9% in AA versus 17.5% in GG; padjusted < 0.001. In the sensitivity analysis, this association was homogeneous for sex, obesity and Mediterranean diet adherence. In conclusion, we report for the first time a significant association between a miRNA polymorphism (rs895819) and daily alcohol consumption. This study was funded, by the Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Economía y Competitividad-Fondo Europeo de Desarrollo Regional (Projects CNIC-06/2007, RTIC G03/140, CIBER 06/03, PI06-1326, PI07-0954, PI11/02505, SAF2009-12304, AGL2010-22319-C03-03 and PRX14/00527), by the University Jaume I (Project P1-1B2013-54), by Contracts 53-K06-5-10 and 58-1950-9-001 from the U.S. Department of Agriculture Research Service, USA, by the Generalitat Valenciana (ACOMP2010-181, AP111/10, AP-042/11, ACOM2011/145, ACOMP/2012/190, ACOMP/2013/159 and ACOMP/213/165), and with the collaboration of the Real Colegio Complutense at Harvard University, Cambridge. MA, USA. Rocío Barragán’s contract is funded by the Ayudas para la contratación de personal investigador en formación de caracter predoctoral, Programa “VALencia Investigación más Desarrollo” (VALi+d). Conselleria d’Educació, Investigació, Cultura i Esport. Generalitat Valenciana, Spain (ACIF/2013/168).

Asthma is a heterogeneous disorder hallmarked by chronic inflammation in the respiratory system. Exacerbations of asthma are correlated with respiratory infections. Considering the implication of interferon regulatory factor 5 (IRF5) in innate and adaptive immunity, we investigated the preferential transmission patterns of ten IRF5 gene polymorphisms in two asthmatic family cohorts. A common IRF5 haplotype was found to be associated with asthma and the severity of asthmatic symptoms. Stratified analysis of subgroups of asthmatic individuals revealed that the associations were more pronounced in nonatopic asthmatic individuals. In addition, the risk alleles of IRF5 polymorphisms for asthma were almost completely opposite to those for autoimmune disorders. Our study provides the first evidence of association between IRF5 and asthma, and sheds light on the related but potentially distinct roles of IRF5 alleles in the pathogenesis of asthma and autoimmune disorders. (c) 2012 Elsevier B.V. All rights reserved.

Introduction: The 15q25 region has been associated with lung-cancer risk and might also be associated with the prognosis of lung cancer. This study was conducted to determine the impact of a functional polymorphism in the CHRNA3 gene on chromosome 15q25 in the survival of patients with early-stage non–small-cell lung cancer (NSCLC). Methods: Five hundred and eighty-three consecutive patients with surgically resected NSCLC were enrolled. The rs6495309C > T polymorphism in the promoter of the CHRNA3 gene was investigated. The association between genotype and overall survival (OS) and disease-free survival (DFS) was analyzed. Results: Patients with the rs6495309 CT or TT genotype had a significantly better OS and DFS than the rs6495309 CC genotype (adjusted hazard ratio for OS=0.56, 95% confidence interval=0.41–0.75, p = 0.0001; and adjusted hazard ratio for DFS=0.61, 95% confidence interval=0.48–0.79, p = 0.0001). An association between the rs6495309C > T polymorphism and survival outcome was demonstrated in smokers and never-smokers, and in squamous-cell carcinomas and adenocarcinomas. Conclusion: The CHRNA3 rs6495309C > T polymorphism may affect survival in patients with early-stage NSCLC. Analysis of the rs6495309C > T polymorphism can help identify patients at high risk of a poor disease outcome.

The functional polymorphism Ser326Cys (rs1052133) in the human 8-oxoguanine DNA glycosylase (hOGG1) gene has been implicated in bladder cancer risk. However, reports of this association between the Ser326Cys polymorphism and bladder cancer risk are conflicting. In order to help clarify this relationship, we made a meta-analysis of seven case-control studies, summing 2521 cases and 2408 controls. We used odds ratios (ORs) with 95% confidence intervals (95%CIs) to assess the strength of the association. Overall, no significant association between the hOGG1 Ser326Cys polymorphism and bladder cancer risk was found for Cys/Cys vs Ser/Ser (OR = 1.10, 95%CI = 0.74-1.65), Ser/Cys vs Ser/Ser (OR = 1.07, 95%CI = 0.81-1.42), Cys/Cys + Ser/Cys vs Ser/Ser (OR = 1.08, 95%CI = 0.87-1.33), and Cys/Cys vs Ser/Cys + Ser/Ser (OR = 1.04, 95%CI = 0.65-1.69). Even when stratified by ethnicity, no significant association was observed. We concluded that the hOGG1 Ser326Cys polymorphism does not contribute to susceptibility to bladder cancer.

Polymorphisms of monoamine-related genes have been associated with depression following life events. The peripartum is a physiologically and psychologically challenging period, characterized by fluctuations in depressive symptoms, therefore facilitating prospective investigations in this gene x environment (G x E) interaction.Eighty nine pregnant women filled in two Edinburgh Postpartum Depression Scale (EPDS) questionnaires during pregnancy and two in the postpartum period. MAOA, COMT and 5-HTT polymorphisms were analyzed.We found a significant interaction between the development of depressive symptoms in the course of pregnancy and polymorphisms in 5-HTT (p=0.019); MAOA (p=0.044) and COMT (p=0.026), and MAOA x COMT (p0.001). Particularly, women carrying the combination of low activity variants of MAOA and COMT showed increased EPDS scores at week 36 of pregnancy and 6 weeks postpartum, but not during early pregnancy or 12 weeks postpartum.We found that MAOA in combination with COMT appears to regulate not only the stress response in laboratory experiments, but also seems to influence the stress-evoked onset of mood during normal, mild, stressful events, such as experienced in the peripartum period. These findings support the GxE concept for depression, but they underline the complexity of this concept, as the cumulating effects of these polymorphic genes (i.e. MAOA+COMT) might be needed and the effects of these polymorphic genes becomes apparent in special environmental or physiological conditions (i.e. the peripartum period). We therefore suggest that G x E interactions become especially noticeable from longitudinal study designs in specific physiological or social challenging periods.

There is increasing evidence that people with autism spectrum disorders (ASDs) have abnormalities in the serotonergic system. For example, a functional polymorphism of the serotonin transporter gene promoter region (5HTTLPR long/short polymorphism) has been reported to confer risk for ASDs, and to affect cortical grey matter volume in young children. However, the persistence of this association later in development is unknown. Hence, we investigated whether variation in the 5HTTLPR long/short polymorphism modulates brain anatomy in older people with ASD. We related 5HTTLPR long/short polymorphism in 43 adolescents and adults with ASD to brain anatomy using structural magnetic resonance imaging and voxel-based morphometry. There were no significant associations between brain anatomy and genotype. When considered alongside evidence of a relationship between 5HTTLPR genotype and brain volume amongst children with autism, our findings raise the possibility that the relationship between 5HTTLPR polymorphism and brain anatomy in ASDs anatomy may differ as a function of age and/or ASD subdiagnosis.

Objectives The stress response is related to both physiological and psychological factors and is strongly marked by a neuroendocrine component. Genetic factors are believed to underlie individual differences in the degree of stress resilience and thereby contribute in determining susceptibility to stress-related pathologies like major depressive disorder (MDD). Little, however, is known about the genetic influence on the endocrine and behavioural stress response in relation to MDD.Methods Here, we sought to examine the effects of the catechol-o-methyltransferase polymorphism on psychological stress in three groups of individuals with different degrees of susceptibility to MDD (i.e. healthy controls, healthy high risk probands to MDD and those suffering from MDD). This genotype is involved in the metabolism of catecholamines (dopamine, norepinephrine and epinephrine).Results Allelic variations of this polymorphism were found to influence the degree of subjective stress experience and plasma epinephrine stress response. Interactions between catechol-o-methyltransferase polymorphism and diagnostic group in measures of plasma epinephrine, cortisol and subjective responses to psychological stress were also found, with the influence of the different alleles on these measures differing between healthy controls relative to MDD patients and high risk probands. Conclusion These observations support a possible role for catechol-o-methyltransferase polymorphism in the endocrine and subjective response to psychological stress and thus may qualify as a possible candidate gene involved in the pathogenesis of MDD.

The aim of this study was to investigate the association between a potentially functional polymorphism (rs153109, -964A G) in the promoter region of interleukin-27 (IL-27) gene and the risk of papillary thyroid cancer (PTC) in a Chinese population. Genotype of IL-27 -964A G polymorphism was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Serum IL-27p28 levels were determined using enzyme-linked immunosorbent assay (ELISA). No significant difference was noticed in IL-27 -964A G polymorphism between PTC patients and healthy controls in the overall analysis. However, analysis of clinical features showed that PTC patients carrying the GG genotype or G allele had significantly decreased risks for developing lymph node metastasis compared with those carrying the AA genotype or A allele (GG vs. AA: OR = 0.38, 95 % CI, 0.20-0.72; G vs. A: OR = 0.63, 95 % CI, 0.44-0.86). Furthermore, ELISA results demonstrated that serum IL-27p28 levels were significantly decreased in PTC patients compared with those in controls (P 0.05). Serum IL-27p28 levels in healthy controls with the GG genotype were significantly high compared with those carrying AA genotype or the AG genotype (P 0.05). In conclusion, our results suggest that IL-27 -964A G polymorphism may be associated with the decreased risk for lymph node metastasis of PTC.

In Huntington's disease (HD), genetic factors in addition to the HD CAG repeat mutation play a significant role in determining age at neurologic onset. Brain-derived neurotrophic factor (BDNF), a survival factor for striatal neurons, has been implicated as a target of regulation by huntingtin and is an attractive candidate as a genetic modifier. We tested this hypothesis by genotyping a SNP known to alter BDNF function (rs6265, also termed Val66Met) and a SNP associated with Alzheimer disease (BDNF C270T), along with two BDNF intronic SNPs (rs7103411, rs11030104), in 228 cases with extreme young onset and 329 cases with extreme old onset of HD. No differences were seen between groups for allele frequencies or genotype frequencies for any SNP. Furthermore, no association to onset age was seen in GEE models controlling for HD repeat size or in haplotype analyses of these SNPs. These results indicate that BDNF does not influence significantly the mechanisms in HD pathogenesis that lead to neurologic onset.

Objectives Initial and secondary ischaemia are important determinants of outcome after subarachnoid haemorrhage (SAH). Cerebral ischaemia is a potent stimulus for expression of genes that may influence recovery. We investigated whether functional polymorphisms in the apolipoprotein E ( APOE), insulin-like growth factor-1 (IGF-1), tumor necrosis factor-A (TNF-A), interleukin-1A (IL-1A), interleukin-1B (IL-1B), and interleukin-6 (IL-6) genes are related with outcome after aneurysmal SAH. Methods Genotyping of the polymorphisms was performed in a consecutive series of 167 patients with aneurysmal SAH. The risk of a poor outcome was analysed with logistic regression with adjustment for prognostic factors for outcome after SAH, using the homozygotes for the wild type alleles as a reference. Results Patients carrying any IGF-1 non-wild type allele had a lower risk of a poor outcome ( OR 0.4, 95% CI 0.2 - 1.0), while carriers of the TNF-A non-wild type allele had a higher risk ( OR 2.3, 95% CI 1.0 - 5.4). We could not demonstrate an association with outcome for APOE ( APOE epsilon 4 OR 0.4, 95% CI 0.1 - 1.2; APOE epsilon 2 OR 0.7, 95% CI 0.2 - 2.4), IL-1A ( OR 1.8, 95% CI 0.8 - 4.0), IL-1B ( OR 0.7, 95% CI 0.3 - 1.5) and IL-6 ( OR 0.7, 95% CI 0.3 - 1.8) polymorphisms. Conclusions Variation in some genes that are expressed after cerebral ischaemia may partly explain the large differences in outcome between patients with aneurysmal SAH. SAH patients homozygote for the IGF-1 wild type allele or carriers of the TNF-A non-wild type allele have a higher risk of poor outcome. Additional studies in other populations are needed to assess the generalisability of our results.

The genes responsible for obesity are also candidate genes for obesity-related conditions, such as hypertension and type 2 diabetes. A functional polymorphism in the uncoupling protein 2 (UCP2) promoter has been reported to be associated with obesity in Caucasians. To clarify the contribution of this polymorphism to obesity and related conditions, we studied the association of the -866 G/A polymorphism of the UCP2 gene with obesity, hypertension and type 2 diabetes mellitus.A total of 632 unrelated Japanese subjects were studied: 342 type 2 diabetic patients (among them, 158 patients complicated with hypertension), 156 hypertensive patients without diabetes mellitus and 134 control subjects. The -866 G/A polymorphism of UCP2 was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP).The frequency of the minor A allele was significantly higher in Japanese than in Caucasians (48.9 versus 37.2%, P=0.01). In contrast to the significant association with obesity in Caucasians, the polymorphism was not associated with obesity in Japanese. The polymorphism, however, was significantly associated with hypertension in Japanese (frequency of A allele: 51.8% in hypertensives versus 46.6% in normotensives, P0.05). No significant difference was observed in body mass index (BMI), fasting insulin level or HOMA-R between patients with different genotypes.These data indicate that the polymorphism of the UCP2 gene is associated with hypertension, and suggest the possibility of UCP2 as a target molecule for studies on the etiology and treatment of hypertension.

Notch signaling pathway has been implicated in the prognosis of non-small cell lung cancer (NSCLC). This study was conducted to determine the association between single nucleotide polymorphisms (SNPs) in the Notch pathway genes and survival outcomes of surgically resected NSCLC. Among the 64 SNPs analyzed in the discovery set, 8 SNPs were significantly associated with overall survival (OS) or disease-free survival (DFS). Among the 8 SNPs, the association was consistently observed only for DTX1 rs1732786A>G in the validation sets. In combined analysis, the rs1732786A>G was significantly associated with better OS and DFS (adjusted HR aHR for OS, 0.81; 95% CI, 0.68-0.95; P = 0.01; aHR for DFS, 0.82; 95% CI, 0.72-0.94; P = 0.003; under codominant model). To verify the functional relevance of the rs1732786A>G in DTX1 promoter region, we conducted dual-luciferase reporter assays. The G allele showed significantly higher luciferase activity than the A allele (P < 0.005) in lung cancer cell lines. The relative expression level of DTX1 mRNA was significantly lower in tumor tissues than in nonmalignant lung tissue (P = 0.003). Moreover, the level of DTX1 mRNA expression in tumor tissue increased as the number of G allele increased (P trend = 0.02). Higher levels of DTX1 mRNA expression were significantly correlated with a better OS and DFS (P = 0.03 and P = 0.002). Our results suggest that the DTX1 rs1732786 A>G polymorphism may affect DTX1 expression and may be a useful marker for predicting the prognosis of patients with early stage NSCLC. Citation Format: Shin Yup Lee, Janghyuck Lee, Kyung Min Shin, Ji Woong Son, Jae Yong Park. A functional polymorphism in DTX1 gene of Notch pathway predicts the prognosis of surgically resected non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5727. doi:10.1158/1538-7445.AM2017-5727

Substance use often starts in adolescence and poses a major problem for society and individual health. The dopamine system plays a role in substance use, and catechol-O-methyltransferase (COMT) is an important enzyme that degrades dopamine. The Val(108/158)Met polymorphism modulates COMT activity and thus dopamine levels, and has been linked to substance use. COMT gene methylation, on the other hand, may affect expression and thus indirectly COMT activity. We investigated whether methylation of the COMT gene was associated with adolescents' substance use. Furthermore, we explored whether the COMT Val(108/158)Met polymorphism interacts with COMT gene methylation in association with substance use. In 463 adolescents (mean age=16, 50.8% girls), substance use (cigarette smoking, alcohol and cannabis use) was assessed with self-report questionnaires. From blood samples, COMT Val(108/158)Met genotype and methylation rates of membrane bound (MB) and soluble (S) COMT promoters were assessed. MB-COMT promoter methylation was associated with non-daily smoking [odds ratio (OR)=1.82, P=0.03], but not with daily smoking (OR=1.20, P=0.34), MB-COMT promoter methylation was not associated with alcohol use. Adolescents with the Met/Met genotype and high rates of MB-COMT promoter methylation were less likely to be high-frequent cannabis users than adolescents with the Val/Val or Val/Met genotype. S-COMT promoter methylation was not associated with substance use. These results indicate that there is an association between substance use and COMT gene methylation. Although this association is complex, combining genetic and epigenetic variation of the COMT gene may be helpful in further elucidating the influence of the dopamine system on substance use in adolescence.

Catalase (CAT) activity is likely to be affected by functional polymorphism of C-262 T (rs1001179) in the CAT gene (OMIM: 115500). It is hypothesized that individuals with the lower expressing forms of the CAT polymorphism may be more susceptible to breast cancer. Therefore, the present case-control study and meta-analysis were carried out. The present case-control study consisted of 407 females with breast cancer and a total of 395 healthy female from population matched with patients according to age. Genotypic analysis for the CAT C-262 T polymorphism was determined by PCR. We identified 7 eligible studies, including 10,471 subjects (4,959 patients, and 5,512 healthy controls) in relation to the CAT C-262 T polymorphism and breast cancer risk. Based on the present case-control study, the CT (OR = 0.90, 95% CI: 0.66-1.22, P = 0.484) and TT (OR = 0.68, 95% CI: 0.35-1.30, P = 0.245) genotypes were not associated with breast cancer risk compared to the CC genotype. For meta-analysis including all studies, there was significant heterogeneity between studies. The overall ORs of the breast cancer risk were not associated with the CT (Q-statistic = 14.90, df = 6, P0.05; OR = 1.01, 95% CI: 0.92-1.09, P = 0.862) and TT (Q-statistic = 2.57, df = 6, P0.05; OR = 1.03, 95% CI: 0.85-1.24, P = 0.770) genotypes. There was no association between C-262 T polymorphism of the CAT and risk of breast cancer.

BackgroundPrimary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts, frequently necessitating orthotopic liver transplantation (OLT), often accompanied by inflammatory bowel disease (IBD). Matrix metalloproteinases (MMPs) are associated with fibrotic diseases caused by the involvement in tissue remodelling.AimTo evaluate the contribution of MMP-2 and -9 promoter polymorphisms to disease severity in PSC, as assessed by death or need for OLT.MethodsMatrix metalloproteinase-2 (-1306 C/T) and -9 (-1562 C/T) gene promoter polymorphisms were analyzed in 132 PSC patients. Follow-up was from onset PSC until death, OLT or end of follow-up.ResultsTwenty-year cumulative incidence (CI) of death or OLT for PSC patients with MMP-2 CT genotype was 86.5% compared to 52.8% for CC genotype (P=0.030) and reached 100% at 11.3years for TT genotype. In patients with IBD, CIs were similar: 20-years CI of death or OLT for MMP-2 CT genotype was 86.0% compared to 49.0% for CC genotype and 100% at 11.3years for TT genotype. Patients without IBD showed a similar trend in 20years CI for MMP-2 CT (77.8%) compared to CC (57.8%) and CI for TT genotype reached 100% at 9.3years. Multivariate analysis showed, along with age at diagnosis, a stepwise increase in hazard ratio for MMP-2 T-allele polymorphism for death or OLT. MMP-9 genotype was not associated with disease severity in PSC.ConclusionMatrix metalloproteinase-2 C to T-1306 gene promoter polymorphism in PSC is an independent risk factor for disease severity as reflected by the need for OLT or disease progression leading to mortality.

A functional polymorphism in the NQO1 gene, featuring a 609C>T substitution,leading to proline to serine amino-acid and enzyme activity changes, has been implicated in cancer risk. However, individually published investigations showed inconclusive results, especially for leukemia. In this study, we therefore performed a meta- analysis of 21 publications with a total of 3,634 cases and 4,827controls, mainly for leukemia. We summarized the data on the association between the NQO1 609C>T polymorphism and risk of leukemia and performed subgroup analyses by ethnicity and leukemia type. We found that the variant TT homozygous genotype o was associated with a modestly increased risk of leukemia (TT versus CT/CC: OR = 1.23, 95%CI = 1.00 - 1.51, heterogeneity = 0.76; I 2 = 0%). Following further stratified analyses, increased risk was only observed in subgroups of Caucasians. This meta-analysis suggests that the NQO1 609T allele is a high-penetrance risk factor for leukemia in Caucasians. The effect on leukemia may be modified by ethnicity and leukemia type, and the small sample sizes of the subgroup analyses suggest that further larger studies are needed.