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Context Gestational diabetes mellitus (GDM) is a pregnancy-complicated disease that poses a risk to maternal and infant health. However, the etiology of the disease has been not yet elucidated. Objective To detect the genetic susceptibility and construct a nomogram model with significantly associated polymorphisms and key clinical indicators for early prediction of GDM. Methods Eleven functional single nucleotide polymorphisms (SNPs) screened by genome-wide association study were genotyped in 554 GDM cases and 641 healthy controls. Functional analysis of GDM positively associated SNPs, multivariate mendelian randomization (MVMR), and a GDM early predictive nomogram model construction were performed. Result rs1965211, rs3760675, and rs7814359 were significantly associated with genetic susceptibility to GDM after adjusting age and prepregnancy body mass index (pre-BMI). It seems that GDM-associated SNPs have effects on regulating target gene transcription factor binding, posttranscriptional splicing, and translation product structure. Besides, rs3760675 can be expression quantitative trait loci and increase the XAB2 mRNA expression level (P =.047). The MVMR analysis showed that the increase of clinical variables of BMI, hemoglobin A1c (HbA1c), and fasting plasma glucose (FPG) had significant causal effects on GDM (BMI-ORMVMR = 1.52, HbA1c-ORMVMR = 1.32, FPG-ORMVMR = 1.78), P <.05. A nomogram model constructed with pre-BMI, FPG, HbA1c, and genotypes of rs1965211, rs3760675, and rs7814359 showed an area under the receiver operating characteristic curve of 0.824. Conclusion Functional polymorphisms can change women's susceptibility to GDM and the predictive nomogram model based on genetic and environmental factors can effectively distinguish individuals with different GDM risks in early stages of pregnancy. [ABSTRACT FROM AUTHOR]

Nucleotide excision repair pathway (NER) is an essential mechanism for single-strand breaks (SSB) repair while xeroderma pigmentosum family (XPA to XPG) is the most important system to NER. Myelodysplastic syndrome (MDS) is a heterogeneous hematological cancer characterized by cytopenias and risk of acute myeloid leukemia (AML) transformation. MDS pathogenesis has been associated with problems of DNA repair system. This report aimed to evaluate NER polymorphisms (XPA rs1800975, XPC rs2228000, XPD rs1799793 and XPF rs1800067) in 269 MDS patients of different populations in Latin America (173 Brazilian and 96 Argentinean). Genotypes were identified in DNA samples by RT-qPCR using TaqMan SNP Genotyping Assay. Regarding rs1799793 polymorphism of XPD for Brazilian population, the heterozygous genotype AG presented a high odds ratio (OR) to have a normal karyotype (p = 0.012, OR=3.000) and the mutant homozygous genotype AA was associated to a high OR of AML transformation (p = 0.034, OR=7.4). In Argentine population, the homozygous mutant AA genotype of rs1800975 polymorphism of XPA was associated with an increased odd to have hemoglobin levels below 8g/dL (p = 0.013, OR=10.000) while for the rs1799793 polymorphism of XPD, the heterozygous AG genotype decreased OR to be classified as good (p

Background & Aims: Limiting the dietary intake of certain carbohydrates has therapeutic effects in some but not all irritable bowel syndrome (IBS) patients. We investigated genetic variation in human Carbohydrate-Active enZYmes (hCAZymes) genes in relationship to the response to a FODMAP-lowering diet in the DOMINO study., Methods: hCAZy polymorphism was studied in patients with IBS from the dietary (FODMAP-lowering; n = 196) and medication (otilonium bromide; n = 54) arms of the DOMINO trial via targeted sequencing of 6 genes of interest (AMY2B, LCT, MGAM, MGAM2, SI, and TREH). hCAZyme defective (hypomorphic) variants were identified via computational annotation using clinical pathogenicity classifiers. Age- and sex-adjusted logistic regression was used to test hCAZyme polymorphisms in cumulative analyses where IBS patients were stratified into carrier and non-carrier groups (collapsing all hCAZyme hypomorphic variants into a single bin). Quantitative analysis of hCAZyme variation was also performed, in which the number of hCAZyme genes affected by a hypomorphic variant was taken into account., Results: In the dietary arm, the number of hypomorphic hCAZyme genes positively correlated with treatment response rate (P = .03; odds ratio = 1.51; confidence interval = 0.99-2.32). In the IBS-D group (n = 55), hCAZyme carriers were 6 times more likely to respond to the diet than non-carriers (P = .002; odds ratio = 6.33; confidence interval = 1.83-24.77). These trends were not observed in the medication arm., Conclusions: hCAZYme genetic variation may be relevant to the efficacy of a carbohydrate-lowering diet. This warrants additional testing and replication of findings, including mechanistic investigations of this phenomenon., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

APOBEC3‐related somatic mutations are predominant in biliary tract cancers (BTCs). We aimed to elucidate the roles of APOBEC3A/3B functional polymorphisms and their influencing factors on the development of cholangiocarcinoma (CCA) and gallbladder cancer (GBC). Polymorphisms at the promoter regions of APOBEC3A and APOBEC3B were genotyped in 3231 participants using quantitative PCR. Dual‐luciferase reporter assay was applied to investigate the promoter activity. The difference in gene accessibility between CCA cells and GBC cells was analyzed through single‐cell transposase accessible chromatin sequencing. The effect of APOBEC3A on apoptosis was examined by cytometry. It is found that rs2267401‐G at the APOBEC3B promoter decreases CCA risk (age‐, gender‐adjusted odds ratio [AOR], 0.69; 95% confidence interval [CI], 0.51‐0.94) but increases GBC risk (AOR, 2.04; 95% CI, 1.35‐3.10). rs2267401‐G confers a decreased APOBEC3B promoter activity in CCA cells but an increased activity in GBC cells, possibly because the transcriptional repressor TFAP2A is over‐expressed in CCA. Tumor necrosis factor‐α (TNF‐α) increases the level of APOBEC3B via inhibiting TFAP2A expression rather than directly increasing the accessibility of APOBEC3B promoter. APOBEC3A promoter rs12157810‐C decreased the risks of CCA and GBC, with an AOR (95% CI) of 0.80 (0.66‐0.97) and 0.75 (0.59‐0.95), respectively. rs12157810‐C upregulated the promoter activity in both CCA and GBC cells. TNF‐α upregulated the activity of the APOBEC3A promoter with rs12157810‐C via increasing the accessibility of Ets‐1 p68. APOBEC3A overexpression attenuates cancer evolution by causing apoptosis, in contrast to APOBEC3B. The heterogeneity in the transcriptional regulation of APOBEC3B affects the evolutionary potential of cancer cells in the inflammatory microenvironment. [ABSTRACT FROM AUTHOR]

Pyrabactin resistance 1-like proteins (PYLs) are direct receptors of abscisic acid (ABA). For the redundant and polymorphic functions, some members of the PYL family interact with components of other signaling pathways. Here, 253 positive colonies from a maize cDNA library were screened as interacting proteins with the members of ZmPYL family. After sequencing and function annotation, 17 of 28 interaction combinations were verified by yeast two-hybrid (Y2H). The germination potential, taproot length and proline content of a quartet mutant of Arabidopsis PYL genes were significantly deceased comparing to the wild type (WT) under alkaline stress (pH 8.5) and 100 µmol L−1 methyl jasmonate (MeJA) induction. The malondialdehyde (MDA) content was significantly increased. After germinating in darkness, the characteristics of dark morphogenesis of the quartet mutant seedlings were more obvious than those of the WT. The differential expression of the related genes of photomorphogenesis in the mutant was much more than that in the WT. Three light and two JA responsive cis-affecting elements were identified during the promoter sequences of the AtPYL1 and AtPYL2 genes. These results suggested that functional polymorphism has evolved among the members of ZmPYL family. In response to developmental and environmental stimuli, they not only function as direct ABA receptors but also interact with components of other signaling pathways mediated JA, brassinosteroid (BR), auxin, etc., and even directly regulate downstream stress-related proteins. These signaling pathways can interact at various crosstalk points and different levels of gene expression within a sophisticated network.

Repulsive guidance molecule a (RGMa) plays a vital role in the progression of numerous inflammatory diseases. However, whether it participates in atherosclerosis development is not known. Here, we explored the influence of RGMa in atherogenesis by investigating whether an association exists between functional polymorphisms in the RGMa promoter and cerebrovascular atherosclerosis burden (CAB) in Chinese Han patients diagnosed with acute ischemic cerebrovascular accident. To this end, we conducted a genetic association study on 201 patients with prior diagnoses of acute ischemic stroke or transient ischemic attack recruited from our hospital. After admission, we conducted three targeted single-nucleotide polymorphisms (SNPs) genotyping and evaluated CAB by computed tomography angiography. We used logistic regression modeling to analyze genetic associations. Functional polymorphism analysis indicated an independent association between the rs725458 T allele and increased CAB in patients with acute ischemic cerebrovascular accident [adjusted odds ratio (OR) = 1.66, 95% confidence interval (CI) = 1.01–2.74, P = 0.046]. In contrast, an association between the rs4778099 AA genotype and decreased CAB (adjusted OR = 0.10, 95% CI = 0.01–0.77, P = 0.027) was found. Our Gene Expression Omnibus analysis revealed lower RGMa levels in the atherosclerotic aortas and in the macrophages isolated from plaques than that in the normal aortas and macrophages from normal tissue, respectively. In conclusion, the relationship between RGMa and cerebrovascular atherosclerosis suggests that RGMa has a potential vasoprotective effect. The two identified functional SNPs (rs725458 and rs4778099) we identified in the RGMa promoter are associated with CAB in patients diagnosed with acute ischemic cerebrovascular accident. These findings offer a promising research direction for RGMa-related translational studies on atherosclerosis.

Introduction and purpose The prevalence of chronic pain is estimated at around 30% of the world's population. The risk of developing chronic pain depends, among others, on from genetic factors. Considering that chronic pain is a serious diagnostic and therapeutic problem, and if treated inadequately constitutes a serious threat to public health, focus should be on identifying the risk factors for its occurrence in order to establish an effective treatment. The aim of the work is to summarize the latest knowledge about the influence of functional polymorphism of the COMT gene on the formation of chronic pain. Material and methods The material for this literature review were publications on the subject of research from the last 5 years. Relevant articles have been identified by two authors using PubMed, Google Scholar and Researchgate publishing bases using key words: "gene COMT", "headache", "chronic pain", "chronic back pain", "fibromyalgia", "temporomandibular disorder", "postoperative pain" according to Medical Subject Headings. The review of articles consisted of 3 stages. Finally, 19 works were qualified for the review. Results Functional polymorphism of the COMT gene is one of the factors affecting the modulation of pain. Its single genetic variants will positively correlate with the occurrence of temporomandibular disorders and chronic lower back pain. Differences in genetic variants of the COMT gene will also affect the susceptibility to fibromyalgia and increase the severity of clinical symptoms. The COMT gene polymorphism does not seem to correlate with chronic headaches. Conclusions Research to determine the effect of COMT gene polymorphism can significantly affect the diagnosis and treatment of chronic pain.

Supplemental Digital Content is available in the text. Background: Bipolar disorder (BD) is a severe psychiatric illness attributable to multifactorial risk components (e.g. environmental stimuli, neuroinflammation, etc.), and genetic variations affecting these risk components are considered pivotal predisposing factors. The interleukin-1β (IL-1β) gene and its protein product have been repeatedly highlighted in the pathogenesis of BD. As functional polymorphisms and haplotypes linked with IL-1β mRNA expression have been reported, whether they are correlated with the risk of developing BD remains to be tested. Methods: To examine whether variations in the IL-1β gene locus confer genetic risk of BD, we recruited 930 BD patients and 912 healthy controls for the current study. All subjects were Han Chinese, and were age- and gender-matched. We tested seven functional single nucleotide polymorphisms (SNPs) spanning the IL-1β gene and one haplotype composed of three SNPs for their associations with risk of BD. Results: We found that the functional SNPs in the promoter region of IL-1β gene were significantly associated with risk of BD. The haplotype analyses further supported the involvement of IL-1β promoter SNPs in BD. The BD risk SNPs in our study have been previously reported to predict higher IL-1β levels in the brain and peripheral blood, which is consistent with the clinical observation of elevated IL-1β levels in the lymphocytes or peripheral blood of patients with BD compared with healthy subjects. Conclusion: Our results support the contention that IL-1β is likely a risk gene for BD, and further investigations on this gene may promote our understanding and clinical management of this illness. [ABSTRACT FROM AUTHOR]

Abstract 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.

The C4I (Command, Control, Communications, Computers and Intelligence) system is the integral part of soldier’s Individual Combat System. This subsystem establishes new standards by providing soldiers with supporting information and therefore improving their knowledge. For that reason, the C4I system integrates all radio, electronic and optoelectronic & IT components, which are a part of the soldiers equipment. The C4I system ensures exchange of data, imagery, and audio between its users and elements of its environment. For the above functionality to be implemented, the C4I subsystem needs a device which will integrate the above-mentioned functionality in its configuration. The Modular Integrator is this kind of device. This paper describes the design and the functionality of the Modular Integrator used for soldier’s C4I system management. The paper focuses on the design of the device and on the set of functions it can perform in the C4I system. An innovative concept, involving integration of three separate devices in a single enclosure, i.e. a personal radio, a portable digital assistant and a mobile phone with a power supply system allows the Modular Integrator to be referred to as a device with “functional multiformity”. A key aspect of the project implementation was also the adaptation of the device to psychological & physical attributes of its future users. This adaptation was accomplished through evaluation of the Modular Integrator in terms of ergonomics, technical aesthetics, anthropometrics and customization, user interaction, pressure force, thermal comfort and lateralization. This “3-in-1” researched and tested solution, developed to the 9th technology readiness level, has no match on national and on international markets.

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.

β-Lactoglobulin (β-LG) is the dominant non-casein whey protein found in milk of bovine and of most ruminants. The amino acid sequence of β-LG along with its 3-dimensional structure illustrates linkage with the lipocalin superfamily. Preliminary studies in goats indicated that milk yield can be influenced by polymorphism in genes coding for whey proteins. The aim of this study is to identify and evaluate the incidence of functional polymorphisms in the exonic and intronic portions of β-LG gene in native Saudi goat breeds (Ardi, Habsi and Harri). Blood samples were collected from 300 animals (100 for each breed) and genomic DNA was extracted using QIAamp DNA extraction kit. A fragment of the β-LG gene from exon 7 to 3' flanking region was amplified with pairs of specific primers. Subsequent digestion with Sac II restriction endonuclease revealed two alleles (A and B) and three different banding patterns or genotypes, i.e. AA, AB, and BB. The statistical analysis showed that β-LG AA genotype had higher milk yield than β-LG AB and β-LG BB genotypes. Nucleotide sequencing of the selected β-LG fragments was done and submitted to GenBank NCBI (Accession Nos. KJ544248, KJ588275, KJ588276, KJ783455, KJ783456, KJ874959, and KP269078). Two already established SNPs in exon 7 (+4601 and +4603) and one fresh SNP in the 3' UTR region were detected in the β-LG fragments with designated AA genotype. The exonic SNPs, i.e. +4601 (G/A) and +4603 (G/C), were found within the Sac II restriction site and accountable for generating the AA genotypic patterns. Hence, the allele characterized by the substitution G>A has been sub-designated as AAA, while the one characterized by the substitution G>C as AAC. The polymorphisms in exon 7 did not produce any amino acid substitution.

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. [ABSTRACT FROM AUTHOR]

In a recent study, we demonstrated that the variant allele of rs2480258 within intron VIII of CYP2E1 is associated with reduced levels of mRNA, protein, and enzyme activity. CYP2E1 is the most important enzyme in the metabolism of acrylamide (AA) by operating its oxidation into glycidamide (GA). AA occurs in food, is neurotoxic and classified as a probable human carcinogen. The goal of the present study was to further assess the role of rs2480258 by measuring the rate of AA > GA biotransformation in vivo. In blood samples from a cohort of 120 volunteers, the internal doses of AA and GA were assessed by AA and GA adducts to hemoglobin (Hb) measured by mass spectrometry. The rate of biotransformation was assessed by calculating the GA-Hb/AA-Hb ratio. To maximize the statistical power, 60 TT was compared to 60 CC-homozygotes and the results showed that TT homozygotes had a statistically significant reduced rate of biotransformation. Present results reinforced the notion that T-allele of rs2480258 is a marker of low functional activity of CYP2E1. Moreover, we studied the role of polymorphisms (SNPs) within glutathione-S-transferases (GSTs) enzymes and epoxide hydrolase (EPHX), verifying previous findings that SNPs within GSTs and EPHX influence the metabolism rate. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Nucleotide excision repair pathway (NER) is an essential mechanism for single-strand breaks (SSB) repair while xeroderma pigmentosum family (XPA to XPG) is the most important system to NER. Myelodysplastic syndrome (MDS) is a heterogeneous hematological cancer characterized by cytopenias and risk of acute myeloid leukemia (AML) transformation. MDS pathogenesis has been associated with problems of DNA repair system. This report aimed to evaluate NER polymorphisms (XPA rs1800975, XPC rs2228000, XPD rs1799793 and XPF rs1800067) in 269 MDS patients of different populations in Latin America (173 Brazilian and 96 Argentinean). Genotypes were identified in DNA samples by RT-qPCR using TaqMan SNP Genotyping Assay. Regarding rs1799793 polymorphism of XPD for Brazilian population, the heterozygous genotype AG presented a high odds ratio (OR) to have a normal karyotype (p = 0.012, OR=3.000) and the mutant homozygous genotype AA was associated to a high OR of AML transformation (p = 0.034, OR=7.4). In Argentine population, the homozygous mutant AA genotype of rs1800975 polymorphism of XPA was associated with an increased odd to have hemoglobin levels below 8g/dL (p = 0.013, OR=10.000) while for the rs1799793 polymorphism of XPD, the heterozygous AG genotype decreased OR to be classified as good (p < 0.001, OR=9.05 × 10 -10 ), and intermediate (p < 0.001, OR=3.08 × 10 -10 ), according to Revised-International Prognostic Scoring System. Regarding the rs1800067 polymorphisms of XPF, the homozygous mutant AA genotype showed a decreased OR to be classified as good (p < 0.001, OR=4.03 × 10 -13 ) and intermediate (p < 0.001, OR=2.54 × 10 -13 ). Our report reinforces the heterogeneity of MDS and demonstrates the importance of ethnic differences and regional influences in pathogenesis and prognosis of MDS., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2021 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier España, S.L.U. All rights reserved.)

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.

Germination and synchronous seedling emergence are necessary for crop yield. One differentially expressed Cupin protein during maize seed germination had been identified in our previous study. To elucidate the functional sites in its coding gene, ZmGLP, a diverse maize association population was assayed. In alignment with B73, the ZmGLP gene contains five exons and encodes 522 amino acids, and a potential signal peptide domain from the 7 to 22 amino acids and a typical Cupin domain from the 332 to 477 amino acids were identified. The ZmGLP has a quick linkage disequilibrium decay with about 300 bp physical distance in the analyzed sequences, which implied that human selection might be undone in this gene. High genetic variations were evidenced in ZmGLP gene with 118 polymorphic sites in the association population. An Indel9 (18 bp) in the fifth exon of the intermotif region of the second Cupin domain, which influences the formation of C coil in the barrel folding, was detected significantly associated with germination vigor of maize seeds. The 18-bp insertion, which might help keeping the barrel folding intact, was a favorable allele for relative high germination vigor. Evolution analysis showed that this 18-bp deletion was a loss-of-function mutation. However, the action mode of ZmGLP is still yet to be further studied for maize improvement. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Emerging evidence showed that functional polymorphisms in the IL-10 gene may have effects on individuals' susceptibility to nasopharyngeal, oral and esophageal cancers, yet individually published findings are inconsistent. We therefore designed the meta-analysis to investigate the correlations of IL-10 genetic polymorphisms with susceptibility to nasopharyngeal, oral and esophageal cancers. The EMBASE, MEDLINE, CINAHL, Web of Science and the Chinese Biomedical Database (CBM) databases were searched with no language restrictions. We use Comprehensive Meta-analysis 2.0 software to carry out statistical analysis. Ten case-control studies with a number of 1,883 patients and 2,857 healthy subjects were enrolled. Our results revealed that IL-10 rs1800872 T>G and rs1800896 A>G polymorphisms has a significantly association with the increased risk of esophageal cancer under the allele and dominant models; rs1800871 T>G, rs1800872 T>G and rs1800896 A>G under allele and dominant models could increase the risk of nasopharyngeal cancer; rs1800871T>G, rs1800872T>G and rs1800896 A>G SNPs under allele model were closely related to the susceptibility to oral cancer. Our findings support the point that IL-10 genetic polymorphisms may play essential role in identifying esophageal cancer, nasopharyngeal cancer and oral cancer at early stage. [ABSTRACT FROM AUTHOR]

Background Autism spectrum disorders (ASD) are neurodevelopmental disorders with a high degree of heritability, but the genetic basis is exceedingly heterogeneous. Microdeletions of chromosome 15q24 have been demonstrated to be recurrent genomic alterations in ASD patients. Of interest, neuronal migration genes are of particular relevance to the pathogenesis of ASD. NEO1 is located in 15q24 and encodes for neogenin, a membrane receptor involved in cortical interneuron migration and axon guidance. We postulated that the ASD patient has one copy of the NEO1 gene deleted and the other copy disrupted by intragenic mutation. Results We identify genetic changes in both alleles of NEO1 in two individuals from a cohort of 66 Han Chinese patients with ASD. In one patient, we detected a hemizygous 1.97-Mb deletion at 15q23q24.1 encompassing the NEO1 gene, a missense variant in NEO1 , c.3388C>T (p.Arg1130Cys), and a duplication, c.2204-14_2204-2dup, in the acceptor splice site of intron 14 of NEO1 . Furthermore, we identified a second patient was a compound heterozygote for NEO1 . A novel missense variant in NEO1 , c.302G>A (p.Arg101His), in addition to c.3388C>T and c.2204-14_2204-2dup was detected in the second patient. The c.3388C>T is a single nucleotide polymorphism with allele frequency of 0.045 in Han Chinese individuals. In silico and functional analyses indicated that p.Arg1130Cys, located at the nuclear localization signal (NLS) domain of neogenin led to defective nuclear translocation of neogenin. Conclusions The hemizygous 15q deletion unmasks the recessive functional polymorphism in NEO1 which plays a pivotal role in cortical interneuron development. Our study provides the first evidence linking NEO1 with ASD in humans. [ABSTRACT FROM AUTHOR]

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 (LDL-C), 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. [ABSTRACT FROM AUTHOR]

Accumulative epidemiological evidence suggests that single nucleotide polymorphisms (SNPs) in genes involved in homologous recombination (HR) DNA repair pathway play an important role in glioma susceptibility. However, the effects of such SNPs on glioma risk remain unclear. We used a used a candidate pathway-based approach to elucidate the relationship between glioma risk and 12 putative functional SNPs in genes involved in the HR pathway. Genotyping was conducted on 771 histologically-confirmed glioma patients and 752 cancer-free controls from the Chinese Han population. Odds ratios (OR) were calculated both for each SNP individually and for grouped analyses, examining the effects of the numbers of adverse alleles on glioma risk, and evaluated their potential gene-gene interactions using the multifactor dimensionality reduction (MDR). In the single-locus analysis, two variants, the NBS1 rs1805794 (OR 1.42, 95 % CI 1.15-1.76, P = 0.001), and RAD54L rs1048771 (OR 1.61, 95 % CI 1.17-2.22, P = 0.002) were significantly associated with glioma risk. When we examined the joint effects of the risk-conferring alleles of these three SNPs, we found a significant trend indicating that the risk increases as the number of adverse alleles increase ( P = 0.005). Moreover, the MDR analysis suggested a significant three-locus interaction model involving NBS1 rs1805794, MRE11 rs10831234, and ATM rs227062. These results suggested that these variants of the genes involved in the HR pathway may contribute to glioma susceptibility. [ABSTRACT FROM AUTHOR]

Schizophrenia has been associated with a large range of autoimmune diseases, with a history of any autoimmune disease being associated with a 45% increase in risk for the illness. The inflammatory system may trigger or modulate the course of schizophrenia through complex mechanisms influencing neurodevelopment, neuroplasticity and neurotransmission. In particular, increases or imbalance in cytokine before birth or during the early stages of life may affect neurodevelopment and produce vulnerability to the disease. A total of 27 polymorphisms of IL1N gene: rs1800587, rs17561; IL1B gene: rs1143634, rs1143643, rs16944, rs4848306, rs1143623, rs1143633, rs1143627; IL1RN gene: rs419598, rs315952, rs9005, rs4251961; IL6 gene: rs1800795, rs1800797; IL6R gene: rs4537545, rs4845617, rs2228145, IL10 gene: rs1800896, rs1800871, rs1800872, rs1800890, rs6676671; IL10RA gene: rs2229113, rs3135932; TGF1B gene: rs1800469, rs1800470; each selected on the basis of molecular evidence for functionality, were investigated in this study. Analysis was performed on a group of 621 patients with diagnosis of schizophrenia and 531 healthy controls in Polish population. An association of rs4848306 in IL1B gene, rs4251961 in IL1RN gene, rs2228145 and rs4537545 in IL6R with schizophrenia have been observed. rs6676671 in IL10 was associated with early age of onset. Strong linkage disequilibrium was observed between analyzed polymorphisms in each gene, except of IL10RA. We observed that haplotypes composed of rs4537545 and rs2228145 in IL6R gene were associated with schizophrenia. Analyses with family history of schizophrenia, other psychiatric disorders and alcohol abuse/dependence did not show any positive findings. Further studies on larger groups along with correlation with circulating protein levels are needed. [ABSTRACT FROM AUTHOR]

Introduction: The nicotinic a5 receptor subunit, encoded by CHRNA5, harbors multiple functional single nucleotide polymorphisms (SNPs) that affect mRNA expression and alter the encoded protein. These polymorphisms are most notably associated with drug-taking behaviors and cognition. We previously identified common SNPs in a distant regulatory element (DRE) that increase CHRNA5 mRNA expression in the human prefrontal cortex (PFC) and confer risk for nicotine dependence. Genome-wide epigenetic studies in PFC and adipose tissue find strong effects of the DRE SNPs on CpG methylation. However, it is unclear whether DRE SNPs influence CpG methylation en route to modulating CHRNA5 mRNA expression. It is also unclear whether these polymorphisms affect expression in other brain regions, especially those mediating drug-taking behaviors. Results: By measuring total and allelic CHRNA5 mRNA expression in human habenula and putamen autopsy tissues, we found that CHRNA5 DRE variants considerably increase mRNA expression by up to 3.5-fold in both brain regions. Our epigenetic analysis finds no association between CpG methylation and CHRNA5 mRNA expression in the PFC or adipose tissues. Conclusions: These finding suggests the mechanisms responsible for the genetic modulation of CpG methylation and mRNA expression are independent despite the DRE SNPs being highly associated with both measures. Our findings support a strong association between the DRE SNPs and mRNA expression or CpG methylation in the brain and periphery, but the independence of the two measures leads us to conclude that environmental factors affecting CpG methylation do not appear to directly modulate gene expression. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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) 103:847-856, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]