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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

Objectives. SSc is an autoimmune disease characterized by alteration of the immune response, vasculopathy and fibrosis. Most genetic studies on SSc have been performed in European-ancestry populations. The aim of this study was to analyse the genetic component of SSc in Middle Eastern patients from Iran and Turkey through a genome-wide association study. Methods. This study analysed data from a total of 834 patients diagnosed with SSc and 1455 healthy controls from Iran and Turkey. DNA was genotyped using high-throughput genotyping platforms. The data generated were imputed using the Michigan Imputation Server, and the Haplotype Reference Consortium as a reference panel. A meta-analysis combining both case-control sets was conducted by the inverse variance method. Results. The highest peak of association belonged to the HLA region in both the Iranian and Turkish populations. Strong and independent associations between the classical alleles HLA-DRB1*11:04 [P = 2.10 x 10(-24), odds ratio (OR) = 3.14] and DPB1*13:01 (P = 5.37 x 10(-14), OR = 5.75) and SSc were observed in the Iranian population. HLA-DRB1*11:04 (P = 4.90 x 10(-11), OR = 2.93) was the only independent signal associated in the Turkish cohort. An omnibus test yielded HLA-DRB1 58 and HLA-DPB1 76 as relevant amino acid positions for this disease. Concerning the meta-analysis, we also identified two associations close to the genome-wide significance level outside the HLA region, corresponding to IRF5-TNPO3 rs17424921-C (P = 1.34 x 10(-7), OR = 1.68) and NFKB1 rs4648133-C (P = 3.11 x 10(-7), OR = 1.47). Conclusion. We identified significant associations in the HLA region and suggestive associations in IRF5-TNPO3 and NFKB1 loci in Iranian and Turkish patients affected by SSc through a genome-wide association study and an extensive HLA analysis., This work was supported by the Spanish Ministry of Economy and Competitiveness [SAF2015-66761-P to J.M. and SAF2015-66761-P to D.G.S.] and The Cooperative Research Thematic Network (RETICS) program, from the Instituto de Salud Carlos III (ISCIII, Health Ministry, Madrid, Spain) [RD16/0012/0004].

Genetic biomarkers of neuroplasticity in deaf children treated with cochlear implantation (CI) might facilitate their clinical management, especially giving them better chances of developing proficient spoken language. We investigated whether carrying certain variants of the genes encoding matrix metalloproteinase MMP9 and neurotrophin brain-derived neurotrophic factor ( BDNF), involved in synaptic plasticity, can be taken as prognostic markers of how well auditory skills might be acquired. Association analysis of functional MMP9 rs3918242 and BDNF rs6265 variants and the child’s auditory development measured at CI activation and 1, 5, 9, 14, and 24 months post CI activation with LittlEARS Questionnaire (LEAQ) was conducted in a group of 100 children diagnosed with DFNB1-related deafness, unilaterally implanted before the age of 2 years. Statistical analysis in the subgroup implanted after 1 year of life ( n = 53) showed significant association between MMP9 rs3918242 and LEAQ scores at 1 month ( p = .01), at 5 months ( p = .01), at 9 months ( p = .01), and at 24 months ( p = .01) after CI activation. No significant associations in the subgroup implanted before 1 year of life were observed. No significant associations between the BDNF rs6265 and LEAQ score were found. Multiple regression analysis ( R2 = .73) in the subgroup implanted after 1 year of life revealed that MMP9 rs3918242 was a significant predictor of treatment outcome. In conclusion, C/C rs3918242 MMP9 predisposes their deaf carriers to better CI outcomes, especially when implanted after the first birthday, than carriers of C/T rs3918242 MMP9.

The present study sought to examine the relationship between Chinese high school students’ academic self-efficacy and their academic-related boredom. Another objective was to explore the moderating effects of mono-amine-oxidase type A ( MAOA) gene polymorphism on this relationship. In a sample of 514 Chinese high school students, we measured their academic self-efficacy and academic-related boredom from Grades 10 to 12. In addition, we collected their DNA. Data were analyzed by using a linear mixture model. The results indicated that students’ academic self-efficacy negatively predicted their academic-related boredom. The relationship between academic self-efficacy and academic-related boredom was more reliable for students with the 3-repeat allele than for the students with the 4-repeat allele. The findings suggested that the functional polymorphism of MAOA gene moderated the relationship between academic self-efficacy and academic-related boredom.

Genome-wide association studies have confirmed the involvement of non-coding angiopoietin-like 3 (ANGPTL3) gene variants with coronary artery disease, levels of low-density lipoprotein cholesterol (LDLC), triglycerides and ANGPTL3 mRNA transcript. Extensive linkage disequilibrium at the locus, however, has hindered efforts to identify the potential functional variants. Using regulatory annotations from ENCODE, combined with functional in vivo assays such as allele-specific formaldehyde-assisted isolation of regulatory elements, statistical approaches including eQTL/lipid colocalisation, and traditional in vitro methodologies including electrophoretic mobility shift assay and luciferase reporter assays, variants affecting the ANGPTL3 regulome were examined. From 253 variants associated with ANGPTL3 mRNA expression, and/or lipid traits, 46 were located within liver regulatory elements and potentially functional. One variant, rs10889352, demonstrated allele-specific effects on DNA-protein interactions, reporter gene expression and chromatin accessibility, in line with effects on LDL-C levels and expression of ANGPTL3 mRNA. The ANGPTL3 gene lies within DOCK7, although the variant is within non-coding regions outside of ANGPTL3, within DOCK7, suggesting complex long-range regulatory effects on gene expression. This study illustrates the power of combining multiple genome-wide datasets with laboratory data to localise functional non-coding variation and provides a model for analysis of regulatory variants from GWAS. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.

[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 -94 ATTG insertion/deletion polymorphism (rs28362491) is an important functional polymorphism in the NFKB1 gene. It has been shown that rs28362491 is associated with many diseases. The purpose of this study was to establish a simple and reliable method to detect the ATTG insertion/deletion polymorphism.On the basis of the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method, a single-tube tri-primer ARMS-PCR method was developed to detect the ATTG insertion/deletion polymorphism in 93 samples. The results of the single-tube tri-primer ARMS-PCR method were validated by DNA sequencing.After optimization of the PCR conditions, the single-tube tri-primer ARMS-PCR was established to detect the insertion/deletion polymorphism using agarose gel electrophoresis. In 93 volunteers, the genotype frequencies were 30.1% for Ins/Ins, 19.4% for Del/Del, and 50.5% for Ins/Del, respectively. The results of the single-tube tri-primer ARMS-PCR method were consistent with the results of DNA sequencing.This single-tube tri-primer ARMS-PCR is a reliable, simple, and cost-efficient genotyping method for the detection of the ATTG insertion/deletion polymorphism in the NFKB1 gene.

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.

Amaç: Psikotik bozukluklar ile Katekol-O-metiltransferaz (COMT) val158met (rs4680) ve beyin kökenli nörotrofik faktör (Brain-derived neurotrophic factor; BDNF) val66met (rs6265) polimorfizmleri arasında ilişki olabileceği düşünülmektedir. Bu araştırmada genel toplumdan seçilmiş bir örneklemde eşik altı psikotik yaşantılardan şizofreniye geniş psikoz fenotipi boyunca bu polimorfizmlerin dağılımının incelenmesi amaçlanmıştır. Yöntem: Örneklem, uzunlamasına bir izlem araştırması olan Psikozlarda Gen-Çevre Etkileşimi İçin İzmir Akıl Sağlığı Araştırması’na (TürkSch) dayanmaktadır ve psikotik yaşantı ve bozuklukların tarandığı bir genel toplum örneklemi içinden seçilen 437 kişiden oluşmaktadır. Geniş psikoz fenotipi, tarama ve klinik tanı görüşmelerine göre psikotik yaşantısı olmayanlar (n: 194), eşik altı psikotik yaşantısı olanlar (n: 87), psikotik yaşantısı olanlar (n: 104) ve şizofreni-benzeri bozukluk (n: 52) grupları olarak oluşturulmuştur. BDNF rs6265 genotiplendirmesi araştırmaya katılan tüm kişilerde ve COMT rs4680 genotiplendirmesi ise 366 kişide yapılmıştır. Bulgular: Geniş psikoz fenotipi grupları arasında BDNF rs6265 ve COMT rs4680 polimorfizmleri açısından anlamlı farklılık bulunmamıştır. Sadece herhangi bir psikotik yaşantı bildirmeyenlere göre eşik altı psikotik yaşantı bildirenlerde BDNF rs6265 genotipinde met taşıyanların bulunma olasılığı anlamlılığa yakın düzeyde daha düşük bulunmuştur (p=0,08). Sonuç: Geniş psikoz fenotipinin farklı basamakları ile BDNF rs6265 ve COMT rs4680 arasında bir ilişki bulunmaması altta yatan gen-gen etkileşimi, gen-çevre ve gen-gen-çevre etkileşimi gibi daha karmaşık mekanizmaların varlığıyla ilişkili olabilir., Objective: Psychotic disorders were previously associated with catechol- O-methyltransferase (COMT) val158met (rs4680) and brain-derived neurotrophic factor (BDNF) val66met (rs6265) polymorphisms. This article evaluates the association between COMT/BDNF polymorphisms and the extended psychosis phenotype which covers not only schizophrenia but also subclinical expressions of psychotic experiences. Method: The participants of this study were part of the TürkSch (Izmir Mental Health Survey for Gene-Environment Interaction in Psychoses), a longitudinal study Psychotic experiences and disorders were screened 437. The extended psychosis phenotype was grouped into four: (1) no psychotic experiences (n: 194), (2) subclinical psychotic experiences (n: 87), (3) clinically relevant psychotic experiences (n: 104), and (4) schizophrenia-like disorders (n: 52). BDNF rs6265 was genotyped occurred in every participant whereas COMT rs4680 genotyping could be done on 366 individuals. Results: There was no association between the extended psychosis phenotype and BDNF rs6265/COMT rs4680 polymorphisms. The frequency of met carriers in the BDNF rs6265genotype was slightly higher in individuals with subclinical psychotic experiences than in the group with no psychotic experiences, which was just below the significance level (p=0.08). Conclusion: The lack of an association between different expression levels of the extended psychosis phenotype and the BDNF rs6265/ COMT rs4680 polymorphism might be related to sample characteristics, underlying gene-gene, gene-environment and gene-environment-gene interactions.

The microRNA-17-92 (miR-17-92) cluster is one of the most extensively studied miRNA clusters. Abnormal expression of the cluster has been found to play important role in different kinds of human diseases, including ischemic stroke (IS). The aim of our study was to investigate the association between three polymorphisms (rs1491034, rs9301654 and rs982873) in the promoter of the miR-17-92 cluster and risk of IS.Three hundred and ninety-eight patients with IS and 397 control subjects were included. The genotypes of the three polymorphisms were determined by Snapshot SNP genotyping assay. Relative expression of the cluster in peripheral blood mononuclear cells (PBMCs) of cases and controls were examined by quantitative real-time PCR.Significant association between rs9301654 polymorphism and risk of IS were observed basing on genotype, model and allele analyses (GA vs. AA: adjusted OR = 0.63, 95% CI: 0.41~0.97, P = 0.037; GG vs. AA: adjusted OR = 0.23, 95% CI: 0.07~0.78, P = 0.018; GA + GG vs. AA: adjusted OR = 0.57, 95% CI: 0.38~0.87, P = 0.009; GA + AA vs. GG: adjusted OR = 0.27, 95% CI: 0.08~0.89, P = 0.032; G vs. A: adjusted OR = 0.58, 95% CI: 0.40~0.83). Haplotype analysis showed that TGC and TGT haplotypes were associated with decreased risk of IS (OR = 0.59, 95% CI: 0.40~0.87, P = 0.007 for TGC haplotype; OR = 0.21, 95% CI: 0.06~0.75, P = 0.009 for TGT haplotype). Importantly, we found the expression of miR-17-5p was significant higher while miR-19a-3p was significant lower in patient with IS compared with the control group (P 0.01), and patients with rs9301654GG or GA genotype displayed lower level of miR-19a-3p compared with the AA genotype (P 0.01).Our findings indicated that rs9301654 polymorphism in the promoter of miR-17-92 cluster may be associated with susceptibility of IS in the Chinese population. However, we found that rs9301654 polymorphism and its respective gene expression did not demonstrate consistent association with IS in the Chinese population. Further studies such as gene-gene interaction are warranted to reveal the role of miR-19a and its regulatory genes in the etiology of IS.

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.

A functional polymorphism in the CEBPE gene promoter influences acute lymphoblastic leukemia risk through interaction with the hematopoietic transcription factor Ikaros

Background The locus on chromosome 15q13.3 containing GREM1 is correlated with the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P). The aim of the present study was to find the GREM1 functional variants implicated in the aetiology of this common developmental anomaly in the Polish population. Methods Eight polymorphisms were genotyped in 334 NSCL/P patients and 955 controls. In addition, the GREM1 protein-coding region was sequenced in 96 NSCL/P patients. Results Significant association with a risk of oral clefts was found for 5 tested polymorphisms. The lowest ptrend values were identified for rs16969681, rs16969816, and rs1258763 (ptrend 4.09E-05, 3.35E-05, and 0.0002, respectively). The putative functional variant rs16969681, located in a region that has enhancer activity, was associated with a 2.6-fold lower risk for NSCL/P (odds ratio [OR] = 0.38; 95% confidence interval [CI], 0.24–0.61, p = 2.37E-05). The previously reported association of rs1258763 with NSCL/P was replicated (OR = 0.57; 95% CI, 0.44–0.73; p = 1.10E-05). For all tested GREM1 variants, no significant sex-by-genotype interaction effects were observed. The sequencing analysis did not detect any rare variants implicated in the development of oral clefts. Conclusion Our results might suggest that variants influencing GREM1 expression levels, rather than variants affecting the function of the encoded protein, are significant factors in NSCL/P etiology. Birth Defects Research (Part A), 2015. © 2015 Wiley Periodicals, Inc.

A functional polymorphism in the monoamine oxidase A (MAOA) gene located on the X chromosome (Xp11.23-11.4) has earned the nickname “warrior gene” because of its association with antisocial behavior and delinquency. Previous findings on adults and adolescents have found some evidence that the MAOA gene moderates the impact of childhood abuse experiences on the risk of developing aggressive behavior. Thus far, however, attempts to replicate these findings have been mixed. The aims of the present study were to investigate whether the MAOA polymorphism affects aggressive behavior alone and in combination with childhood abuse experiences. We tried to replicate this using a sample of 1447 male and 2179 female Finnish twins and their siblings. In the present study, the Childhood Trauma Questionnaire and Aggression Questionnaire were used. There was a positive correlation between childhood abuse experiences and later aggressive behavior in adolescence or adulthood both for men and women. The results showed the e...

Background Alike to Reduced height-1 (Rht-1) genes in wheat and the semi dwarfing (sd-1) gene in rice, the sdw1/denso locus involved in the metabolism of the GA, was designated as the ‘Green Revolution’ gene in barley. The recent molecular characterization of the candidate gene HvGA20ox2 for sdw1/denso locus allows to estimate the impact of the functional polymorphism of this gene on the variation of agronomically important traits in barley. Results We investigated the effect of the 7-bp deletion in exon 1 of HvGA20ox2 gene (sdw1.d mutation) on the variation of yield-related and malting quality traits in the population of DHLs derived from cross of medium tall barley Morex and semi-dwarf barley Barke. Segregation of plant height, flowering time, thousand grain weight, grain protein content and grain starch was evaluated in two diverse environments separated from one another by 15° of latitude. The 7-bp deletion in HvGA20ox2 gene reduced plant height by approximately 13 cm and delayed flowering time by 3–5 days in the barley segregating DHLs population independently on environmental cue. On other hand, the sdw1.d mutation did not affect significantly either grain quality traits (protein and starch content) or thousand grain weight. Conclusions The beneficial effect of the sdw1.d allele could be associated in barley with lodging resistance and extended period of vegetative growth allowing to accumulate additional biomass that supports higher yield in certain environments. However, no direct effect of the sdw1.d mutation on thousand grain weight or grain quality traits in barley was detected. Electronic supplementary material The online version of this article (10.1186/s12870-017-1121-4) contains supplementary material, which is available to authorized users.

microRNAs (miRNAs) are widely involved in craniofacial development, and genetic variants of miRNAs may be associated with the risk of nonsyndromic orofacial cleft (NSOC). Here, we systematically selected five single nucleotide polymorphisms (SNPs) of miRNAs and investigated the associations between these variants and NSOC susceptibility in a two-stage case-control study including 1,406 NSOC patients and 1,578 controls from the Chinese population. We found that compared with the C allele, the rs2910164 G allele of pre-miR-146a was associated with an increased risk of NSOC (additive model: odds ratio [OR] = 1.17, 95% confidence interval [CI]: 1.06-1.30, P = 0.002), including both cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO). Bioinformatic prediction and functional assays revealed that the C allele of rs2910164 was significantly associated with inhibited HEK-293 and HEPM cell proliferation and decreased abundance of TRAF6. Both miR-146a and TRAF6 were expressed in the lip tissue samples of NSOC patients, and a moderate inverse correlation was observed between them. Taken together, these results demonstrated that miR-146a/rs2910164 is associated with susceptibility to NSOC, providing novel insights into the genetic etiology and underlying biology of NSOC.

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).

OBJECTIVE The aim of this study was to examine a possible association between depressive symptoms and a functional polymorphism (rs686) that modulates the regulation of DRD1 gene by miR-504. METHODS A total of 239 young Colombian subjects were evaluated with the Patient Health Questionnaire-9 (PHQ-9) scale and genotyped for the rs686 polymorphism. A linear regression model, corrected by age and gender, was used. RESULTS A significant association between the rs686 polymorphism and PHQ-9 scores was found, under a dominant genetic model (p=0.0094). CONCLUSION These results provide novel evidence about the growing role of inherited variants in binding sites for brain-expressed miRNAs on depressive symptomatology.

Background: Human aggression is a heterogeneous behavior with biological, psychological, and social backgrounds. As the biological mechanisms that regulate aggression are components of both reward-seeking and adversity-fleeing behavior, these phenomena are difficult to disentangle into separate neurochemical processes. Nevertheless, evidence exists linking some forms of aggression to aberrant serotonergic neurotransmission. We determined possible associations between 6 serotonergic neurotransmission-related gene variants and severe criminal offenses. Methods: Male Russian prisoners who were convicted for murder (n = 117) or theft (n = 77) were genotyped for variants of the serotonin transporter (5HTTLPR), tryptophan hydroxylase, tryptophan-2,3-dioxygenase, or type 2C (5-HT2C) receptor genes and compared with general-population male controls (n = 161). Prisoners were psychologically phenotyped using the Buss-Durkee Hostility Inventory and the Beck Depression Inventory. Results: No differences were found between murderers and thieves either concerning genotypes or concerning psychological measures. Comparison of polymorphism distribution between groups of prisoners and controls revealed highly significant associations of 5HTTLPR and 5-HTR2C (rs6318) gene polymorphisms with being convicted for criminal behavior. Conclusions: The lack of biological differences between the 2 groups of prisoners indicates that the studied 5HT-related genes do not differentiate between the types of crimes committed.

We investigated the role of a single nucleotide polymorphism rs3764030 (G>A) within the human GRIN2B promoter in mental processing speed in healthy, cognitively intact, older adults. In vitro DNA-binding and reporter gene assays of different allele combinations in transfected cells showed that the A allele was a gain-of-function variant associated with increasing GRIN2B mRNA levels. We tested the hypothesis that individuals with A allele will have better memory performance (i.e. faster reaction times) in older age. Twenty-eight older adults (ages 65-86) from a well-characterized longitudinal cohort were recruited and performed a modified delayed match-to-sample task. The rs3764030 polymorphism was genotyped and participants were grouped based on the presence of the A allele into GG and AA/AG. Carriers of the A allele maintained their speed of memory retrieval over age compared to GG carriers (p = 0.026 slope of the regression line between AA and AG versus GG groups). To validate the results, 12 older adults from the same cohort participated in a different version of the short-term memory task. Reaction times were significantly slower with age in older adults with G allele (p < 0.001). These findings support a role for rs3764030 in maintaining faster mental processing speed over aging.

a b s t r a c t Using a discovery and replication sample from a U.S. representative data set, we show that a functional polymorphism on the MAOA gene is associated with credit card borrowing behavior. For the combined sample of approximately 12,000 individuals we find that having one or both MAOA alleles of the less transcriptionally efficient type raises the average likelihood of reporting credit card debt by about 4%. These results suggest that behavioral models benefit from integrating genetic variation and that economists should consider the welfare consequences of possible discrimination by lenders on the basis of genotype. © 2014 Elsevier B.V. All rights reserved.

Harsh parenting and child characteristics such as opposition and aggression have been found to relate to bullying, victimization, and bullying-victimization, yet not all children display equal vulnerability to harsh parenting. The monoamine oxidase A gene (MAOA; low-activity variant) may be a key vulnerability allele as it relates to aggression on experience of harsh parenting, and opposition in children, and may therefore be associated with children who become bullies and victims. Using multiple-informant data from 4,893 mother-child pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC), we found that (a) harsh parenting increased subsequent victimization in boys, and the risk was higher for those with the low-activity allele; that (b) harsh parenting (mother reported) increased bullying, victimization, bullying-victimization (child self-reported) for boys but not for girls, via irritable opposition (mother and teacher reported); but that (c) this indirect effect was not moderated by MAOA. The results suggest that vulnerable boys who are treated harshly by their parents have increased victimization experiences, whereas irritable opposition appears related to bullying with and without victimization and related to victimization alone.

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.

During leaf ontogenesis in Clivia miniata epidermal and guard cell plastids differing in structure and function differentiate from morphologically equal proplastids. Plastid differentiation proceeds in parallel to cellular differentiation and stops in cells reaching maturity. It is suggested that the developmental sequence of plastids is fixed within cells and controlled by the inner mechanisms.

Background/Aims: End-stage renal disease (ESRD) is simultaneously associated with immune activation, systemic inflammation and immune deficiency. Toll-like receptor 3 (TLR3), a receptor for viral double-stranded RNA, is involved in immune cell activation in renal diseases and may contribute to chronic inflammatory disease progression. To date, effects of TLR3 polymorphisms on ESRD remain unknown. Therefore, we determined the predictive value of TLR3 polymorphisms and further functionally studied ESRD. Methods: We performed a case-control association study and genotyped 616 ESRD patients and 813 healthy controls. Patients were genotyped for -7C/A, 1377C/T and 1234C/T polymorphisms of TLR3 using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The Haplotype association analysis was performed using the Haploview package. A luciferase reporter assay and real-time PCR were used to test the function of the -7C/A promoter polymorphism in TLR3 expression in human embryonic kidney 293 (HEK293) cells. Results: Genotype distributions of -7C/A and 1377C/T in TLR3 were significantly different in ESRD patients and healthy controls. The ATC haplotype of TLR3 was associated with a decreased risk of ESRD. We also found significant differences in TLR3 expression by dexamethasone treatment between various genotypes of -7C/A (p = 0.02). TLR3 transcriptional activity of the variant -7 C allele was higher than that of the -7 A allele after dexamethasone treatment. Conclusion: Results indicate that, in our population, the presence of the C allele of -7C/A in TLR3 increases the susceptibility to ESRD. In vitro studies demonstrated that -7C/A may be involved in ESRD development through transcriptional modulation of TLR3.

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

Background Drought stress tolerance for crop improvement is an important goal worldwide. Drought is a complex trait, and it is vital to understand the complex physiological, biochemical, and molecular mechanisms of drought tolerance to tackle it effectively. Osmotic adjustment, oxidative stress management (OSM), and cell membrane stability (CMS) are major components of cellular tolerance under drought stress. In the current study, we explored the molecular basis of OSM in the drought tolerant rice variety, Nagina 22 and compared it with the popular drought sensitive rice variety, IR 64, under drought imposed at the reproductive stage, to understand how the parental polymorphisms correlate with the superiority of Nagina 22 and tolerant bulk populations under drought. Results We generated recombinant inbred lines (RIL) from contrasting parents Nagina 22 and IR 64 and focussed on spikelet fertility (SF), in terms of its correlation with OSM, which is an important component of drought tolerance in Nagina 22. Based on SF under drought stress and its correlations with other yield related traits, we used superoxide dismutase (SOD), glutathione reductase (GR), and ascorbate peroxidase (APX) activity assays to establish the relationship between SF and OSM genes in the tolerant and sensitive lines. Among the OSM enzymes studied, GR had a significant and positive correlation with single plant yield (SPY) under drought stress. GR was also positively correlated with APX but negatively so with SOD. Interestingly, none of the enzyme-morphology correlations were significant under irrigated control (IC). Through genome-wide SNP analysis of the 21 genes encoding for OSM enzymes, we identified the functional polymorphisms between the parents and identified superior alleles. By using network analysis of OSM genes in rice, we identified the genes that are central to the OSM network. Conclusions From the biochemical and morphological data and the SNP analysis, the superiority of Nagina 22 in spikelet fertility under drought stress is because of its superior alleles for SOD (SOD2, SODCC1, SODA) and GR (GRCP2) rather than for APX, for which IR 64 had the superior allele (APX8). Nagina 22 can bypass APX8 by directly interacting with SODA. For nine of the 11 genes present in the central network, Nagina 22 had the superior alleles. We propose that Nagina 22 tolerance could mainly be because of SODA which is a reactive oxygen scavenger in mitochondria which is directly associated with spikelet fertility. Electronic supplementary material The online version of this article (doi:10.1186/s12864-016-3131-2) contains supplementary material, which is available to authorized users.

22q11.2 Deletion Syndrome (22q11DS) is a multisystem disorder caused by a hemizygous deletion within 22q11.2. Patients with the deletion display a wide range of cognitive deficits. The gene catechol-O-methyl-transferase (COMT) resides in the typically deleted region of 22q11.2 and is rendered hemizygous in individuals affected by the 22q11DS. COMT is a critical enzyme in the degradation of catecholamine neurotransmitters in the brain. A functional polymorphism, Val158 Met, has been associated with a variety of neurocognitive outcomes. In this study, 159 patients with 22q11DS were analyzed for a potential association between intelligence quotient (IQ) and COMT genotype. We performed a univariate analysis for overall influence and modified our analysis to focus on possible differences between average, borderline, and intellectually impaired patients. No correlation between COMT genotype and IQ performance was found. © 2016 Wiley Periodicals, Inc.

Studies in vitro suggest that the expression of the serotonin transporter (5-HTT) is regulated by polymorphic variation in the promoter region of the 5-HTT gene (5-HTTLPR); however, results from human brain imaging studies examining the relation between 5-HTT genotype and 5-HTT radioligand binding in vivo have been inconsistent. This inconsistency could reflect small participant numbers or the use of sub-optimal radiotracer for measuring the 5-HTT. We used positron emission tomography in conjunction with the selective 5-HTT ligand [(11)C] DASB to examine the availability of the 5-HTT in seven brain regions in 63 healthy European caucasian volunteers who were genotyped for short (S) and long (L) variants (SLC6A4 and rs25531) of the 5-HTTLPR. [(11)C] DASB binding potential was not influenced by the allelic status of participants whether classified on a biallelic or triallelic basis in any of the regions studied. Our PET findings, in a relatively large sample with a near optimal radiotracer, suggest that 5-HTTLPR polymorphic variation does not affect the availability of 5-HTT to [(11)C] DASB binding in adult human brain. The reported impact of 5-HTTLPR polymorphic variation on emotional processing and vulnerability to depression are more likely therefore to be expressed through effects exerted during neurodevelopment.

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).

Inhalants are neurotoxic substances abused worldwide, in particular by adolescents. Symptoms of inhalant addiction are comparable to those of other substances, including nicotine, alcohol, or methamphetamine. Craving for inhalants is inducible by inhalant cues, such as exposure to pictures of the inhalants. Glutamate, γ-aminobutyric acid, and dopamine are key neurotransmitters mediating the neurobehavioral effects of inhalants. The genetic markers for inhalant addiction or inhalant-related neurobehavioral effects are understudied. A functional polymorphism in the gene encoding catechol-O-methyltransferase (COMT Val158Met) predicts inhalant abuse and dependence in a methamphetamine-treatment cohort. Inhalants such as toluene additionally activate immune–inflammatory and oxidative stress pathways, explaining increased neuroinflammatory and neuroprogressive processes and consequently the neurocognitive and neuropsychiatric effects of inhalant abuse.

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.