Asp Allele Research Articles

Genetic Polymorphisms of XPC, XPD, XPG Genes and their Association with Radiotherapy Induced Toxicity among Head and Neck Cancer Patients: A Hospital Based Study from Maharashtra.

The present study was planned to investigate possible association of single nucleotide polymorphisms (SNPs) of nucleotide excision repair (NER) genes such as XPC, XPD, XPG with acute radiation induced toxicities such as skin reactions and oral mucositis in normal tissue from head and neck cancer (HNC) patients receiving radiotherapy. Methods: Two hundred and fifty HNC patients receiving radiotherapy were enrolled in this study and the acute toxicity reactions and radiation response were recorded. Association of SNPs rs2228001 of XPC, rs238406, rs13181 of XPD and rs17655 of XPG gene with normal tissue reactions in the form of dermatitis and mucositis were studied by PCR-RFLP and direct DNA sequencing. The results of univariate analysis of SNPs of XPC, XPD and XPG showed that XPC polymorphism at codon 939 of exon 15 (A>C) was not associated with dermatitis (OR=0.30, 95% CI: 0.06-1.39; p=0.125), or oral mucositis (OR=1.14, 95% CI: 0.41-3.20; p=0.793). The XPD codon 156 of exon 6 (C>A) and codon 751 of exon-23 A>C) polymorphism showed no association with radiosensitivity in HNC patients (OR=1.50, 95% CI: 0.60-3.71; p=0.080) for dermatitis, (OR=1.54, 95% CI: 0.66-3.61; p=0.312) for oral mucositis. The 1104 Asp variant genotype or allele of XPG (OR=1.35 95% CI: 0.50-3.64; p=0.541) showed no association with degree of radiotherapy associated dermatitis or mucositis (OR=0.80, 95% CI: 0.32-2.03; p=0.648) in HNC patients. The variant C allele of 2920 A/C genotype of XPC gene at codon 939 of exon 15, found protective with developing skin reactions with grade >1 (OR=0.60, 95% CI: 0.36-0.97; p=0.039) in HNC patients treated with radiotherapy. The results obtained in this study concluded that the SNPs rs2228001of XPC, rs238406, rs13181 SNPs of XPD and rs17655 SNP of XPG are not associated with normal tissue toxicity in HNC patients treated with radiotherapy. Radiotherapy with high radiation dose was significantly associated with oral mucositis in response to radiotherapy.

Glu298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene (rs1799983) is associated with dysmenorrhea

BackgroundWith a huge impact on the quality of life and productivity of young women, dysmenorrhea remains a major gynecological disorder. Although abnormal myometrial activity and vasoconstriction are believed to play a major role, the pathophysiology of dysmenorrhea is not fully understood. Our aim was therefore to examine a possible relationship between the Glu298Asp polymorphism (rs1799983) of the endothelial nitric oxide synthase (eNOS) gene and dysmenorrhea. MethodsWe sought the participation of women of reproductive age (n = 239). Each participant completed a questionnaire to obtain data on their menstrual cycles and a Numeric Pain Rating Scale (NPRC) to rate their pain experience during menstrual periods. Genotyping was done by PCR-RFLP method while a possible association between the presence and severity of menstrual pain and genotypes was determined. ResultsAmong the participants, pain was reported by 167 (89.9%) while 72 (30.1%) reported no pain. Seventy-one (29.7%) and 93 (38.9%) participants reported moderate and severe pains respectively while others reported no or mild pain. The frequencies of G and T alleles were 316 and 162 while frequencies of GG, GT, and TT were 119, 78, and 42 respectively. The population deviated from Hardy-Weinberg equilibrium (χ2 = 17.6, df = 1, p < 0.01). Participants with a T allele were more than three times as likely as those without a T allele to report pain (OR = 3.3, p < 0.01 95%CI = 1.8–5.9). ConclusionCarrying a T (Asp298) allele of Glu298Asp polymorphism of the eNOS gene may predispose to dysmenorrhea indicating that nitric oxide might play a role in dysmenorrhea.

Antioxidant Genetic Profile Modifies Probability of Developing Neurological Sequelae in Long-COVID.

Understanding the sequelae of COVID-19 is of utmost importance. Neuroinflammation and disturbed redox homeostasis are suggested as prevailing underlying mechanisms in neurological sequelae propagation in long-COVID. We aimed to investigate whether variations in antioxidant genetic profile might be associated with neurological sequelae in long-COVID. Neurological examination and antioxidant genetic profile (SOD2, GPXs and GSTs) determination, as well as, genotype analysis of Nrf2 and ACE2, were conducted on 167 COVID-19 patients. Polymorphisms were determined by the appropriate PCR methods. Only polymorphisms in GSTP1AB and GSTO1 were independently associated with long-COVID manifestations. Indeed, individuals carrying GSTP1 Val or GSTO1 Asp allele exhibited lower odds of long-COVID myalgia development, both independently and in combination. Furthermore, the combined presence of GSTP1 Ile and GSTO1 Ala alleles exhibited cumulative risk regarding long-COVID myalgia in carriers of the combined GPX1 LeuLeu/GPX3 CC genotype. Moreover, individuals carrying combined GSTM1-null/GPX1LeuLeu genotype were more prone to developing long-COVID “brain fog”, while this probability further enlarged if the Nrf2 A allele was also present. The fact that certain genetic variants of antioxidant enzymes, independently or in combination, affect the probability of long-COVID manifestations, further emphasizes the involvement of genetic susceptibility when SARS-CoV-2 infection is initiated in the host cells, and also months after.

The hemoglobin Gly16\u03b21Asp polymorphism in turbot (Scophthalmus maximus) is differentially distributed across European populations

Turbot is an important flatfish widely distributed along the European coasts, whose fishery is centered in the North Sea. The commercial value of the species has boosted a successful aquaculture sector in Europe and China. Body growth is the main target of turbot breeding programs and is also a key trait related to local adaptation to temperature and salinity. Differences in growth rate and optimal growth temperature in turbot have been shown to be associated with a hemoglobin polymorphism reported more than 50 years ago. Here, we identified a Gly16Asp amino acid substitution in the β1 globin subunit by searching for genetic variation in the five functional globin genes within the whole annotated turbot genome. We predicted increased stability of the turbot hemoglobin by the replacement of the conserved Gly with the negative charged Asp residue that is consistent with the higher rate of αβ dimer assembly in the human J-Baltimore Gly16β->Asp mutant than in normal HbA. The turbot Hbβ1-Gly16 variant dominated in the northern populations examined, particularly in the Baltic Sea, while the Asp allele showed elevated frequencies in southern populations and was the prevalent variant in the Adriatic Sea. Body weight did not associate with the Hbβ1 genotypes at farming conditions (i.e., high oxygen levels, feeding ad libitum) after analyzing 90 fish with high growth dispersal from nine turbot families. Nevertheless, all data at hand suggest that the turbot hemoglobin polymorphism has an adaptive significance in the variable wild conditions regarding temperature and oxygen availability.

Systematic review and meta-analysis of the moderating effect of rs1799971 in OPRM1, the mu-opioid receptor gene, on response to naltrexone treatment of alcohol use disorder.

There is wide inter-individual variability in response to the treatment of alcohol use disorder (AUD) with the opioid receptor antagonist naltrexone. To identify patients who may be most responsive to naltrexone treatment, studies have examined the moderating effect of rs1799971, a single nucleotide polymorphism (SNP) that encodes a non-synonymous substitution (Asn40Asp) in the mu-opioid receptor gene, OPRM1. The aims of this study were to: (1) conduct a systematic review of randomized clinical trials (RCTs); (2) assess the bias of the available studies and gauge publication bias; and (3) meta-analyze the interaction effect of the Asn40Asp SNP on the response to naltrexone treatment. We searched for placebo-controlled RCTs that examined the effect of Asn40Asp on the response to naltrexone treatment of heavy drinking or AUD. We tested the hypothesis that the minor (Asp40) allele was associated with a greater reduction in five alcohol consumption measures (relapse to heavy drinking, abstinence, percentage of heavy drinking days, percentage of days abstinent and drinks per day) in naltrexone-treated participants by meta-analyzing the interaction effects using a random effects model. Seven RCTs met the study criteria. Overall, risk of bias was low and we observed no evidence of publication bias. Of the five alcohol consumption outcomes considered, there was a nominally significant moderating effect of the Asn40Asp SNP only on drinks per day (d=-0.18, P=0.02). However, the effect was not significant when multiple comparisons were taken into account. From the evidence to date, it remains unclear whether rs1799971, the OPRM1 Asn40Asp single nucleotide polymorphism, predicts naltrexone treatment response in individuals with alcohol use disorder or heavy drinking.

T190. ASSOCIATION OF THE HUMAN MU-OPIOID RECEPTOR GENE POLYMORPHISM ASN40ASP WITH SCHIZOPHRENIA

BackgroundIn humans, opioidergic neurotransmission appears to modulate a variety of behaviors, including the stress response and cognitive processes, as well as anxiety and psychosis. One neurobiological process which may be modified by the Asn40Asp polymorphism of the μ opioid receptor is the HPA axis response to stress. Hypothalamic corticotropin-releasing hormone (CRH) neurons, which affects glucocorticoid release by stimulating pituitary adrenocorticotropin (ACTH) secretion, are directly and indirectly inhibited by β-endorphin-producing neurons via the μ opioid receptor (OPRM). Both exaggerated and blunted HPA responses to stress have been associated with high risk for psychosis. Many studies have suggested that opioids play an important role in response to stress, motivation, and numerous psychiatric entities. The present association study tested the hypothesis that the Asn40Asp substitution polymorphism confers susceptibility to schizophrenia.MethodsAfter informed consent was obtained, 100 schizophrenia patients and 100 control subjects were enrolled in this study. Genomic DNAs were extracted from peripheral blood by using the modified SDS/Proteinase K procedure. The genotypes of the Asn40Asp polymorphism of the μ opioid receptor were assessed by allele-specific polymerase - chain reaction. The PCR products were digested by restricted enzyme.ResultsThe frequency of the Asp40 allele was significantly increased in all schizophrenia patients (Fisher’s Exact Test P= 0.0118). There were no associations the Asn40Asp polymorphism of the μ opioid receptor with substance dependence among schizophrenia patients and normal control.DiscussionThe opioidergic neurotransmitter system plays an important role in regulating activation of the hypothalamic-pituitary-adrenal (HPA) axis. Initial activation of the HPA axis occurs at the level of the paraventricular nucleus of the hypothalamus, where neurons that produce corticotropin releasing factor (CRF) are located [Bell et al., 1998]. CRF neurons in this area express μ-opioid receptors and are under tonic inhibition by neurons of the arcuate nucleus that contains β-endorphin [Wand et al., 1998]. Genetic factors appear to be important modulators of HPA axis activation. The HPA axis appears to be involved, including the normal stress response [Bond et al., 1998; LaForge et al., 2000] and psychosis in which HPA axis dynamics appear to be abnormal. Similarly, there is growing evidence that altered opioidergic neurotransmission and HPA axis dynamics may affect alcohol- and drug-seeking behaviors [Piazza and Le Moal, 1997; Kreek and Koob, 1998].

The major-effect quantitative trait locus CsARN6.1 encodes an AAA ATPase domain-containing protein that is associated with waterlogging stress tolerance by promoting adventitious root formation.

In plants, the formation of hypocotyl-derived adventitious roots (ARs) is an important morphological acclimation to waterlogging stress; however, its genetic basis remains fragmentary. Here, through combined use of bulked segregant analysis-based whole-genome sequencing, SNP haplotyping and fine genetic mapping, we identified a candidate gene for a major-effect QTL, ARN6.1, that was responsible for waterlogging tolerance due to increased AR formation in the cucumber line Zaoer-N. Through multiple lines of evidence, we show that CsARN6.1 is the most possible candidate for ARN6.1 which encodes an AAA ATPase. The increased formation of ARs under waterlogging in Zaoer-N could be attributed to a non-synonymous SNP in the coiled-coil domain region of this gene. CsARN6.1 increases the number of ARs via its ATPase activity. Ectopic expression of CsARN6.1 in Arabidopsis resulted in better rooting ability and lateral root development in transgenic plants. Transgenic cucumber expressing the CsARN6.1Asp allele from Zaoer-N exhibited a significant increase in number of ARs compared with the wild type expressing the allele from Pepino under waterlogging conditions. Taken together, these data support that the AAA ATPase gene CsARN6.1 has an important role in increasing cucumber AR formation and waterlogging tolerance.

The NOS3 G894T (rs1799983) and -786T/C (rs2070744) polymorphisms are associated with elite swimmer status.

Endothelial nitric oxide synthase (NOS3) generates nitric oxide in blood vessels and is involved in the regulation of vascular function, metabolism and muscle fibre type transformations. Evidence suggests that the NOS3 G894T (rs1799983) and -786T/C (rs2070744) polymorphisms are associated with athletic performance. The purpose of this study was to determine the association between the NOS3 G894T and -786T/C polymorphisms with elite swimmer status in Polish athletes. One hundred and ninety-seven Polish swimmers (104 males and 93 females), who competed in national and international events, and 379 healthy control subjects (222 males and 157 females) were recruited for this study. The swimmers were divided into two groups: short distance swimmers (SDS; n=147; 50-200 m) and long distance swimmers (LDS; n=49; more than 500 m). As expected, the frequencies of the -786T/C T allele (77.0 vs. 63.1%, p = 0.0085) and G-T haplotype (63.7 vs. 52.0, p=0.025) were significantly higher in the LDS group in comparison with controls. Compared with the -786T/C CC genotype, the chance of being a long distance swimmer was 8.49 times higher (CI=1.14-62.78, p=0.023) for the carriers of -786T/C T allele than in control subjects. On the other hand, the Asp allele frequency was significantly higher in the female SDS group compared with controls (34.3 vs. 18.5%, p=0.00043). In conclusion, our results demonstrate that the T allele and the G-T haplotype of the -786T/C and G894T polymorphisms may be beneficial for long distance swimmers.

Association between polymorphisms of DNA repair genes and risk of type 2 diabetes mellitus in the Turkish population

Abstract Objectives DNA repair mechanisms work insufficiently in T2DM patients and hyperglycemia seen in diabetes disturbs the oxidant-antioxidant balance thus cause oxidative damage on DNA. The effects of the DNA repair genes’ have not yet been investigated on diabetes. The aim of this study was to investigate the association between APE1 Asp148Glu and XPG Asp1104His polymorphisms with T2DM in the Turkish population. Material and methods Sixty-five T2DM patients and 54 healthy individuals were included to this study as control. The polymerase chain reaction-restriction fragment length polymorphism techniques were used. Results When the study groups were compared, serum HDL-cholesterol levels were found statistically elevated in the controls. Once the APE1 Asp148Glu polymorphism distribution between the patient and control groups was investigated, the Glu/Glu genotype ratio was found significantly higher in the control group. Furthermore, the Asp/Glu genotype and the Asp allele prevalences were observed to be higher in the patient group. Also, patients with the Asp/Asp genotype had higher serum HDL-cholesterol levels than the others. Conclusion Despite the small number of subjects included, it could be interpreted that the Glu allele of the APE1 Asp148Glu polymorphism might be protective against and the Asp allele may be contributing to the development of diabetes.

Predictors of Naltrexone Response in a Randomized Trial: Reward-Related Brain Activation, OPRM1 Genotype, and Smoking Status.

This corrects the article DOI: 10.1038/npp.2017.74.

Maternal/fetal eNOS-Glu298Asp genotypes and their influence on the severity, prognosis, and lipid profile of preeclampsia

Objectives: To analyze the contribution of maternal eNOS-Glu298Asp genotypes and also the association with fetal genotypes to the development of preeclampsia, prognosis, and maternal dyslipidemia.Methods: Sixty-nine pairs of preeclamptic mothers/newborns and 94 pairs of normotensive mothers/newborns were genotyped for eNOS-Glu298Asp using PCR-RFLP methods.Results: Women carriers of at least one Asp298 allele had a 1.53-fold (p = NS), 1.88-fold (p = NS), and 2.08-fold (p = .05), respectively, increased risk to develop PIH, mild, or severe preeclampsia. If both the mother and the newborn were carriers of the Asp298 allele, the risk for preeclampsia was 5.09-fold higher (p < .001). Preeclamptic women with severe preeclampsia had significantly higher cholesterol (mg/dl, 287.23 ± 43.01 versus 235.36 ± 45.01, p = .02) and LDL (mg/dl, 194.9 ± 42.8 versus 144.98 ± 54.84, p = .04) levels and lower HDL levels (mg/dl, 32.12 ± 5.48 versus 57.84 ± 20.59, p = .02) compared to noncarriers. Also, higher LDL levels (mg/dl, 188.76 ± 46.61 versus 136.75 ± 41.85, p = .03) and lower HDL levels (mg/dl, 32.8 ± 5.64 versus 61.06 ± 22.45, p = .02) were found in preeclamptic women with severe preeclampsia whose newborns were carriers of the Asp298 allele.Conclusions: The eNOS-Glu298Asp variant (in mothers and newborns) in association with dyslipidemia could affect bioavailability of NO and could represent an increased risk for preeclampsia.

Predictors of Naltrexone Response in a Randomized Trial: Reward-Related Brain Activation, OPRM1 Genotype, and Smoking Status.

Naltrexone reduces drinking among individuals with alcohol use disorders (AUDs), but it is not effective for everyone. Variability in its effects on reward-related brain activation, genetic variation, and/or cigarette smoking may account for this mixed response profile. This randomized clinical trial tested the effects of naltrexone on drinking and alcohol cue-elicited brain activation, evaluated whether OPRM1 A118G genotype or smoking moderated these effects, and explored whether the effects of medication on cue-elicited activation predicted subsequent drinking. One hundred and fifty-two treatment-seeking individuals with alcohol dependence, half preselected to carry at least one A118G G (Asp) allele, were randomized to naltrexone (50 mg) or placebo for 16 weeks and administered an fMRI alcohol cue reactivity task at baseline and after 2 weeks of treatment. Naltrexone, relative to placebo, significantly reduced alcohol cue-elicited activation of the right ventral striatum (VS) between baseline and week 2 and reduced heavy drinking over 16 weeks. OPRM1 genotype did not significantly moderate these effects, but G-allele carriers who received naltrexone had an accelerated return to heavy drinking after medication was stopped. Smoking moderated the effects of medication on drinking, such that naltrexone was superior to placebo only among smokers. The degree of reduction in right VS activation between scans interacted with medication in predicting subsequent drinking, such that individuals with greater reduction in activation who received naltrexone, but not placebo, experienced the least heavy drinking during the following 14 weeks. These data replicate previous findings that naltrexone reduces heavy drinking and reward-related brain activation among treatment-seeking individuals with AUDs, and indicate that smoking and the magnitude of reduction in cue-elicited brain activation may predict treatment response.

The relationship between the nitric oxide synthase gene and the risk of hypertension defi ned according to ambulatory blood pressures

Although nitric oxide (NO) plays an important role in blood pressure (BP) control, whether variation of genes involved in regulating the synthesis of NO infl uences BP is uncertain. As the heritability of BP is stronger for ambulatory than it is for conventional BP, we assessed the independent association of the well described functional exon 7 Glu298Asp variant of the eNOS gene with the presence of hypertension in 511 randomly selected normotensive control participants and 503 hypertensives with a diagnosis of hypertension confi rmed with 24-hour ambulatory BP profiles whilst off therapy. We also assessed the relationship between eNOS genotype and 24 hour ambulatory BP. Comparisons of genotype and allele frequencies indicated a lack of association of the exon 7 Glu298Asp gene variant with hypertension (Odds ratio of genotype predicting the presence of hypertension=0.97, confidence interval=0.70-1.30, p=0.92). However, patients with the Glu/Glu genotype of the Glu298Asp variant (n=424) had increased 24-hour systolic and diastolic blood pressures (152±1/97±1 mm Hg) in comparison to patients heterozygous for the Glu298Asp variant or homozygous for the 298Asp allele (n=79) (145±1/94±1 mm Hg, p‹0.005 for systolic BP and p‹0.001 for diastolic BP after multiple adjustments including age, gender, body mass index and the presence of diabetes mellitus). Differences in systolic and diastolic BP between genotype groups were noted during the day as well as at night. The association of eNOS genotype with ambulatory BP translated into an increased risk of more severe grades of hypertension in patients with the Glu/Glu genotype (grade II and III vs. grade I, Odds ratio=2.20, confidence interval=1.34-3.59, p‹0.0002). In conclusion, a functional gene variant (Glu298Asp) at the eNOS locus contributes ~1.4-2.5% to the variation in ambulatory blood pressure within hypertensives, but is not associated with the presence of hypertension in patients in whom the diagnosis has been confirmed by 24-hour ambulatory BP values. The relationship between eNOS genotype and 24-hour ambulatory BP and the severity of hypertension warrants further study.

Omentin Val109Asp polymorphism and risk of coronary artery disease.

Background Omentin is an adipocytokine with antiinflammatory properties. It has been reported to be involved in atherosclerosis and coronary artery disease. We aimed to investigate the association of omentin Val109Asp polymorphism with coronary artery disease in an Iranian population. Methods For a case-control study, 400 individuals were recruited: 200 with coronary artery disease and 200 healthy controls. Patients with coronary artery disease were diagnosed by angiography as having at least one main coronary artery with more than 50% stenosis. Genotyping of Val109Asp was carried out using a polymerase chain reaction DNA-restriction fragment length polymorphism technique. Results There was no association between Val109Asp polymorphism and the risk of coronary artery disease in our study population ( p = 0.20). However, when subgroup analysis was performed according to sex, there was a significant difference in the distribution of alleles between groups for men ( p = 0.031, odds ratio = 0.57, 95% confidence interval: 0.35-0.95) but not for women ( p = 0.88, odds ratio = 1.03, 95% confidence interval: 0.66-1.61). Conclusions Our results indicate that the Asp allele of Val109Asp (T allele of rs2274907) is more frequent among men with coronary artery disease than healthy men, so it is possibly a risk factor for coronary artery disease in men only. The difference in association between men and women may be due to the different distribution and metabolism of adipose tissue in men and women. More studies with larger sample sizes and in different populations are required to validate our study results.

COMT and OPRM1 genotype associations with daily knee pain variability and activity induced pain

BackgroundOsteoarthritis (OA) of the knee is a common and increasingly prevalent condition that is one of the primary causes of chronic pain. Staying physically active protects against disability from knee OA but is also very challenging. A critical but unexamined question is whether patients at greatest risk for becoming less active are those with a genetic predisposition for greater sensitivity to daily pain. AimsWe examined day-to-day variability in knee OA pain for patients with different variants of catechol-O-methyltransferase (COMT) and mu-opioid receptor (OPRM1) single nucleotide polymorphisms (SNPs), and whether patients with a specific genotype experience more pain following daily physical activity. We predicted that patients having one or more copies of the Met158 allele of COMT rs4680 (A-A or A-G) and one or more copies of the Asp40 allele of OPRM1 rs1799971 (A-G or G-G) would show greater pain variability. We expected to see the same pattern for these SNPs with regard to moderation (i.e., exacerbation) of the activity-pain association. MethodsA total of 120 knee OA patients reported on their pain 3 times per day over 22 days using handheld computers, and wore an accelerometer to capture daily physical activity. Multilevel modelling was used to examine the magnitude of within-person variability in pain by genetic group. We also examined whether lagged, within-patient associations between level of activity in the afternoon (i.e., minutes of moderate intensity activity, and number of steps) and knee pain at the end-of-day were moderated by between-patient differences in genotype. ResultsRegarding OPRM1 rs1799971 (Asn40Asp), patients with two copies of the Asn40 allele showed the greatest day-to-day pain variability. Regarding COMT rs4680 (Val158Met), patients with the Val/Val genotype showed the greatest pain variability and also experienced the greatest increase in pain as a result of physical activity. A similar pattern of findings across bi-directional temporal lags was consistent with a negative feedback loop between daily physical activity and pain according to genotype. Consistent with some previous studies, there were no significant between-person differences in daily pain when comparing patients according to COMT rs4680, or OPRM1 rs1799971. ConclusionThis study provides preliminary evidence that patients with certain genotypes for COMT rs4680 and OPRM1 rs1799971 (G-G and A-A, respectively) experience more variability in their day-to-day pain and exacerbation of pain after daily physical activity compared to patients with other genotypes. Our findings should be replicated in larger study populations. ImplicationsPrevious clinical research has focused primarily on differences in average level of pain between patients with and without a specific genotype. Assessment of within-person variability through repeated measurements in daily life enhances the reliability, power, and ecological validity of phenotypic measurement. PerspectiveThis study provides preliminary evidence that patients with certain variations in the COMT and OPRM1 SNPs experience more variability in their day-to-day pain and exacerbation of pain after daily physical activity.

GLU298ASP and 4G/5G Polymorphisms and the Risk of Ischemic Stroke in Young Individuals.

Polymorphisms in the endothelial nitric oxide synthase (eNOS) and in the plasminogen activator inhibitor -1 (PAI-1) genes have been implicated in stroke pathogenesis but results are still controversial. The aim of this study was to examine the possible contribution of Glu298Asp in the eNOS and 4G/5G in the PAI-1polymorphisms with ischemic stroke in a young Mexican population. In a case-control study, conducted between January 2006 and June 2010, 204 patients ≤45 years of age with ischemic stroke and 204 controls matched by age and gender, were recruited. The Glu298Asp and 4G/5G polymorphisms were determined in all participants by polymerase chain reaction-restriction fragment length polymorphism. There was a significant difference in the Glu298Asp genotype distribution (P=0.001) and allele frequency between the two groups (P=0.001). The 4G/5G genotype distribution (P=0.40) and the allele frequency was similar between groups; (P=0.13). There were independent factors for ischemic stroke: Asp carriage (GluAsp+AspAsp) (P=0.02); smoking (P=0.01); hypertension (P=0.03), and familial history of atherothrombotic disease (P=0.04). The Asp allele from the Gu298Asp gene represents an independent risk factor for ischemic stroke in a young Mexican population. In contrast, the 4G/5G was not associated with an increased risk for this disease in the same group of patients, as previously has been demonstrated in other populations.

Naltrexone vs Placebo for the Treatment of Alcohol Dependence: A Randomized Clinical Trial.

Alcohol use disorder is one of the leading causes of disability worldwide. While effective pharmacological treatments exist, they are efficacious only in certain individuals, contributing to their limited use. Secondary analysis of clinical trial data suggests that a functional polymorphism (rs1799971, Asn40Asp) of the µ-opioid receptor gene (OPRM1) is associated with the risk of relapse to heavy drinking following treatment with the opioid antagonist naltrexone. To prospectively examine whether rs1799971 is predictive of naltrexone treatment response. We conducted a 12-week, double-blind, randomized clinical trial of naltrexone vs placebo in individuals with alcohol dependence (intent-to-treat analysis). Participants were randomly assigned to study treatment based on the presence of 1 or 2 copies of the Asp40 allele compared with those homozygous for the Asn40 allele (2 × 2 cell design). Recruitment occurred between January 2009 and September 2013. All participants were seen in an outpatient clinical setting. A convenience sample of participants (n = 221) was recruited from 5 sites. All participants met DSM-IV criteria for alcohol dependence, with no concurrent psychotic or manic symptoms, no use of concurrent psychotropic medications, and no current dependence on illicit substances. The study drug was naltrexone (50 mg) given once daily or corresponding placebo. The primary study outcome measure was relapse to heavy drinking measured using the timeline follow-back method. There was no evidence of a genotype × treatment interaction on the primary outcome of heavy drinking (P = .32). In the Asn40 group, the observed effect of naltrexone was similar to that in previous trials (odds ratio, 0.69; 95% CI, 0.41-1.18; P = .17), with a very small naltrexone effect in the Asp40 group (odds ratio, 1.10; 95% CI, 0.52-2.31; P = .80), contrary to the pattern expected a priori. A significant reduction in heavy drinking occurred across all groups (P = .001). Other drinking outcomes, and all secondary outcomes, demonstrated similar time effects, with no genotype × treatment interaction. The results of this study do not support the hypothesis that the Asp40 allele moderates the response to naltrexone treatment. It is premature to use the Asn40Asp polymorphism as a biomarker to predict the response to naltrexone treatment of alcohol dependence. clinicaltrials.gov Identifier: NCT00831272.

Associations of DNA-repair gene polymorphisms with a genetic susceptibility to ionizing radiation in residents of areas with high radon (222Rn) concentration

Purpose: To investigate the individual radiosensitivity of the human genome in long-term residents of areas with high radon concentration.Materials and methods: The materials used for this investigation were venous blood samples extracted from children living in the boarding school of Tashtagol (Kemerovo Region, Russia). Cytogenetic damage assessment was performed using the cytokinesis-block micronucleus assay (CBMN) on peripheral blood lymphocytes. PCR, gel electrophoresis and product detection using a transilluminator were used to determine polymorphisms in the genes ADPRT (rs 1136410), hOGG1 (rs 1052133), NBS1 (rs 1805794), XRCC1 (rs 25487), XpC (rs 2228001), XpD (rs 13181), and XpG (rs 17655). Statistical analysis was performed using nonparametric methods. To ensure accurate results, FDR-correction for multiple comparisons was performed.Results: We discovered a significant increase in the frequency of binucleated lymphocytes with micronuclei (MN) in carriers of the His/His genotype of the XpG gene Asp1104His polymorphism in comparison to heterozygous and homozygous carriers of the Asp allele. In addition, the Ala/Ala genotype for the ADPRT gene Val762Ala polymorphism and the Glu/Gln genotype for the NBS1 gene Glu185Gln polymorphism were associated with the elevated frequency of binucleated lymphocytes with nucleoplasmic bridges (NPB).Conclusions: As a result of this study, the elevated frequency of cytogenetic damage in people with particular DNA-repair gene polymorphisms in response to chronic exposure to radon was demonstrated. It was shown that the genes and corresponding polymorphisms (the XpG gene Asp1104His polymorphism, the ADPRT gene Val762Ala polymorphism and the NBS1 gene Glu185Gln polymorphism) can be used as molecular genetic markers of increased individual radiosensitivity in long-term residents of areas with high concentrations of radon.

Type II deiodinase polymorphisms and serum thyroid hormone levels in patients with mild cognitive impairment.

We investigated type II deiodinase (DIO2) polymorphisms and serum thyroid hormone levels in subjects with mild cognitive impairment (MCI) in a Uygur population. We studied the DIO2 Thr92Ala (rs225014) and ORFa-Gly3Asp (rs12885300) polymorphisms of 129 unrelated MCI cases and 131 matched controls. All subjects were genotyped using SNaPshot SNP genotyping assays. Serum thyroid hormone levels were measured by radioimmunoassay. Levels of serum triiodothyronine and thyroxine in the MCI group were significantly lower than those in the control group. Genotype and allele frequencies in the DIO2 gene between the MCI and control groups were not significantly different. There was no association in genotype and allele frequencies of Thr92Ala between genders in both groups. ORFa-Gly3Asp genotype and allele frequencies were significantly different in patients and controls by gender. The Asp allele was less frequent among male MCI patients compared to controls (odds ratio = 0.471, 95% confidence interval = 0.261-0.848). However, female Asp carriers were more frequent among MCI patients than among controls (odds ratio = 2.842, 95% confidence interval = 1.326-6.09). Serum levels of triiodothyronine and thyroxine were lower in individuals of the Ala/Ala genotype than in those with the Thr/Thr or Thr/Ala genotype. Serum levels of triiodothyronine were lower in male Gly/Gly carriers than in Gly/Asp or Asp/Asp carriers. Decreased serum levels of triiodothyronine and thyroxine may influence the incidence of MCI in the Uygur population. DIO2 gene polymorphisms may play a role in the incidence of MCI in male patients.

The brown coat colour of Coppernecked goats is associated with a non-synonymous variant at the TYRP1 locus on chromosome 8.

The recent development of a goat SNP genotyping microarray enables genome-wide association studies in this important livestock species. We investigated the genetic basis of the black and brown coat colour in Valais Blacknecked and Coppernecked goats. A genome-wide association analysis using goat SNP50 BeadChip genotypes of 22 cases and 23 controls allowed us to map the locus for the brown coat colour to goat chromosome 8. The TYRP1 gene is located within the associated chromosomal region, and TYRP1 variants cause similar coat colour phenotypes in different species. We thus considered TYRP1 as a strong positional and functional candidate. We resequenced the caprine TYRP1 gene by Sanger and Illumina sequencing and identified two non-synonymous variants, p.Ile478Thr and p.Gly496Asp, that might have a functional impact on the TYRP1 protein. However, based on the obtained pedigree and genotype data, the brown coat colour in these goats is not due to a single recessive loss-of-function allele. Surprisingly, the genotype distribution and the pedigree data suggest that the (496) Asp allele might possibly act in a dominant manner. The (496) Asp allele was present in 77 of 81 investigated Coppernecked goats and did not occur in black goats. This strongly suggests heterogeneity underlying the brown coat colour in Coppernecked goats. Functional experiments or targeted matings will be required to verify the unexpected preliminary findings.