SOD2 genetic polymorphism (rs4880) has no impact on 6‐month response to antidepressant treatment and inflammatory biomarkers in depressed patients

Two thirds of patients suffering from a major depressive episode (MDE) do not reach a complete response with antidepressant drugs. This lack of response is due to several factors, including genetic determinants. Since major depressive disorder is associated with inflammatory and oxidative stress abnormalities, the metabolism of superoxide anions might be involved in non‐response to antidepressant drugs. Superoxide anions are metabolized by manganese‐dependent superoxide dismutase (SOD2) in the mitochondria. A functional genetic polymorphism (SOD2, rs4880), responsible of a 40% reduction in enzyme activity, is associated with anti‐inflammatory response of rosuvastatin. We investigated the association of ala‐allele of SOD2 rs4880 and both antidepressant efficacy and inflammatory parameters in patients treated for a MDE with antidepressant drugs. The Hamilton Depression Rating Scale (HDRS) score and levels of plasma CRP and inflammatory cytokines were assessed at baseline, one month (M1), 3 months (M3) and 6 months (M6) after antidepressant treatment. They were compared according to SOD2 genetic polymorphism. Of the 484 patients studied, 361 (74.6%) carried the ala‐allele (Ala group), 123 (25.4%) of them had Val/Val genotype (Val/Val group). No significant difference was observed between the Ala and Val/Val groups neither for baseline clinical characteristics, nor for HDRS scores, response/remission rates, plasma CRP and cytokine levels throughout the study. The rs4880 SOD2 genetic polymorphism was not associated with the clinical response and cytokines levels after antidepressant treatment. These data suggest that SOD2 is not a major genetic determinant of antidepressant response. Other genes of the oxidative stress pathways should be explored in further studies.     

A Schizophrenia Risk Gene, ZNF804A, Influences Neuroanatomical and Neurocognitive Phenotypes

ZNF804A is one of the strongest candidate genes for schizophrenia (SZ), yet its function and role in disease pathophysiology are largely unknown. The only in vivo endophenotype study of the SZ-associated SNP (rs1344706) pointed towards effects on brain functional connectivity. We examined the relationship of this SNP to neuroanatomical and neurocognitive phenotypes that were assessed in healthy individuals. Volunteers with no history of psychiatric illness were assessed with structural magnetic resonance imaging (1.5T GE scanner, standard gradient-echo acquisition). Carriers of the minor allele were compared with homozygotes for the T (SZ-associated) allele on measures of total volume of the white matter (WM), gray matter (GM), and cerebrospinal fluid compartments, as well as on voxel-wise measurements of regional brain volumes. After examining the correlation between genotype-associated regions of interest and neurocognitive performance measures, the effects of rs1344706 genotype on a measure of visuomotor performance speed (trails A) were examined in an independent cohort of volunteers. Among healthy subjects, risk allele homozygotes showed larger total WM volumes than carriers of the other allele. Controlling for WM volumes, these same subjects showed reduced GM volumes in several regions comprising the ‘default mode network,'' including angular gyrus, parahippocampal gyrus, posterior cingulate, and medial orbitofrontal gyrus/gyrus rectus (FDR-corrected p<0.05). The risk allele dosage also predicted impairments on a timed visuomotor performance task (trails A). Results support a role of ZNF804A in phenotypes reflecting altered neural connectivity.     

Antioxidative Defense Genes and Brain Structure in Youth Bipolar Disorder

BackgroundOxidative stress is implicated in the neuropathology of bipolar disorder (BD). We investigated the association of single-nucleotide polymorphisms (SNPs) in the antioxidative genes superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3) with structural neuroimaging phenotypes in youth BD.Methods SOD2 rs4880 and GPX3 rs3792797 SNP genotypes, along with structural magnetic resonance imaging, were obtained from 147 youth (BD = 75; healthy controls = 72). Images were processed using FreeSurfer, yielding surface area, volume, and thickness values for regions of interest (prefrontal cortex [PFC], caudal anterior cingulate cortex, hippocampus) and for vertex-wise whole-brain analysis. Analyses controlled for age, sex, race, and intracranial volume for volume, area, and thickness analyses.ResultRegions of interest analyses revealed diagnosis-by-SOD2 rs4880 interaction effects for caudal anterior cingulate cortex volume and surface area as well as PFC volume; in each case, there was lower volume/area in the BD GG genotype group vs the healthy controls GG genotype group. There was a significant BD diagnosis × GPX3 rs3793797 interaction effect for PFC surface area, where area was lower in the BD A-allele carrier group vs the other genotype groups. Vertex-wise analyses revealed significant interaction effects in frontal, temporal, and parietal regions related to smaller brain structure in the BD SOD2 rs4880 GG group and BD GPX3 rs3793797 A-allele carrier group.ConclusionWe found preliminary evidence that SOD2 rs4880 and GPX3 rs3792797 are differentially associated with brain structures in youth with BD in regions that are relevant to BD. Further studies incorporating additional neuroimaging phenotypes and blood levels of oxidative stress markers are warranted.     

KCNJ6 is Associated with Adult Alcohol Dependence and Involved in Gene × Early Life Stress Interactions in Adolescent Alcohol Drinking

Alcohol abuse and dependence have proven to be complex genetic traits that are influenced by environmental factors. Primate and human studies have shown that early life stress increases the propensity for alcohol abuse in later life. The reinforcing properties of alcohol are mediated by dopaminergic signaling; however, there is little evidence to indicate how stress alters alcohol reinforcement. KCNJ6 (the gene encoding G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2)) is a brain expressed potassium channel with inhibitory effects on dopaminergic tone. The properties of GIRK2 have been shown to be enhanced by the stress peptide corticotrophin-releasing hormone. Therefore, we sought to examine the role of KCNJ6 polymorphisms in adult alcohol dependence and stress-related alcohol abuse in adolescents. We selected 11 SNPs in the promoter region of KCNJ6, which were genotyped in 1152 adult alcohol dependents and 1203 controls. One SNP, rs2836016, was found to be associated with alcohol dependence (p=0.01, false discovery rate). We then assessed rs2836016 in an adolescent sample of 261 subjects, which were characterized for early life stress and adolescent hazardous drinking, defined using the Alcohol Use Disorders Identification Test (AUDIT), to examine gene–environment interactions. In the adolescent sample, the risk genotype of rs2836016 was significantly associated with increased AUDIT scores, but only in those individuals exposed to high levels of psychosocial stress in early life (p=0.01). Our findings show that KCNJ6 is associated with alcohol dependence and may moderate the effect of early psychosocial stress on risky alcohol drinking in adolescents. We have identified a candidate gene for future studies investigating a possible functional link between the response to stress and alcohol reinforcement.     

Lack of association of GPX1 and MnSOD genes with symptom severity and response to clozapine treatment in schizophrenia subjects

Abnormal activities of critical antioxidant enzymes and other indices of lipid peroxidation in plasma and red blood cells were detected in patients with schizophrenia. Other results have shown that oxidative stress may be modulated by clozapine. Based on that and some studies already found different clinical relations between reactive oxygen species and negative and positive symptoms, we evaluated association between clinical response and the polymorphism in the human glutathione peroxidase (GPX1) (Pro200Leu, rs1050450) and manganese SOD (MNSOD) (Ala16Val, rs4880) gene in 216 clozapine‐treated patients with schizophrenia. No association was found with these two functional polymorphisms and clozapine response and symptom change after 6 months. No correlations were found between positive/negative symptoms score and both polymorphisms. Our results present that GPX1 (Pro200Leu) and MNSOD (Ala16Val) polymorphisms seem do not play a central role in the clozapine response, although studies in larger and independent samples are necessary to confirm our findings. Copyright © 2009 John Wiley & Sons, Ltd.     

Genetic polymorphisms in glutathione S-transferase (GST) superfamily and arsenic metabolism in residents of the Red River Delta, Vietnam

To elucidate the role of genetic factors in arsenic metabolism, we investigated associations of genetic polymorphisms in the members of glutathione S-transferase (GST) superfamily with the arsenic concentrations in hair and urine, and urinary arsenic profile in residents in the Red River Delta, Vietnam. Genotyping was conducted for GST ω1 (GSTO1) Ala140Asp, Glu155del, Glu208Lys, Thr217Asn, and Ala236Val, GST ω2 (GSTO2) Asn142Asp, GST π1 (GSTP1) Ile105Val, GST μ1 (GSTM1) wild/null, and GST θ1 (GSTT1) wild/null. There were no mutation alleles for GSTO1 Glu208Lys, Thr217Asn, and Ala236Val in this population. GSTO1 Glu155del hetero type showed higher urinary concentration of As^V than the wild homo type. Higher percentage of DMA^V in urine of GSTM1 wild type was observed compared with that of the null type. Strong correlations between GSTP1 Ile105Val and arsenic exposure level and profile were observed in this study. Especially, heterozygote of GSTP1 Ile105Val had a higher metabolic capacity from inorganic arsenic to monomethyl arsenic, while the opposite trend was observed for ability of metabolism from As^V to As^III. Furthermore, other factors including sex, age, body mass index, arsenic level in drinking water, and genotypes of As (+ 3 oxidation state) methyltransferase (AS3MT) were also significantly co-associated with arsenic level and profile in the Vietnamese. To our knowledge, this is the first study indicating the associations of genetic factors of GST superfamily with arsenic metabolism in a Vietnamese population.     

A significantly joint effect between arsenic and occupational exposures and risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2 on risk of urothelial carcinoma

Cigarette smoking, arsenic and occupational exposures are well-known risk factors for the development of urothelial carcinoma (UC). Therefore, the aim of this study is to investigate whether the effect of cigarette smoking, alcohol consumption, arsenic and occupational exposures on risk of UC could be modified by genetic polymorphisms of cytochrome P450 2E1 and glutathione S-transferase omega. A hospital-based case-control study consisted of 520 histologically confirmed UC cases, and 520 age- and gender-matched cancer-free controls were carried out from September 1998 to December 2007. Genotyping of CYP2E1, GSTO1 and GSTO2 was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Subjects with both of cigarette smoking and alcohol consumption have a significantly increased UC risk (odds ratio [OR] = 2.9; 95% confidence interval [CI] = 1.9-4.4). Significantly increased UC risks of 1.5 and 1.9 were found for study subjects with high arsenic exposure and those who have been exposed to two or more occupational exposures, respectively. A significantly increased UC risk of 3.9 was observed in study subjects with H2-H2 diplotype of GSTO1 and GSTO2. The significantly highest UC risk of 9.0 was found for those with all environmental risk factors of cigarette smoking, alcohol consumption, arsenic and occupational exposures and two or more risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2. Our findings suggest that a significantly joint effect of cigarette smoking, alcohol consumption, arsenic and occupational exposures and risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2 on risk of UC was found.     

Association study between BDNF gene variants and Mexican patients with obsessive–compulsive disorder

Obsessive–compulsive disorder (OCD) is a psychiatric disorder whose etiology is not yet known. We investigate the role of three variants of the BDNF gene (rs6265, rs1519480 and rs7124442) by single SNP and haplotype analysis in OCD Mexican patients using a case–control and family-based association design. BDNF gene variants were genotyped in 283 control subjects, 232 OCD patients and first degree relatives of 111 OCD subjects. Single SNP analysis in case–control study showed an association between rs6265 and OCD with a high frequency of Val/Val genotype and Val allele (p=0.0001 and p=0.0001, respectively). Also, genotype and allele analysis of rs1519480 showed significant differences (p=0.0001, p=0.0001; respectively) between OCD and control groups. Haplotype analysis showed a high frequency of A–T (rs6265–rs1519480) in OCD patients compared with the control group (OR=2.06 [1.18–3.59], p=0.0093) and a low frequency of haplotype A–C in the OCD patients (OR=0.04 [0.01–0.16], p=0.000002). The family-based association study showed no significant differences in the transmission of any variant. Our study replicated the association between BDNF Val66Met gene polymorphism and OCD. Also, we found a significant association of rs1519480 in OCD patients compared with a control group, region that has never been analyzed in OCD. In conclusion, our findings suggest that BDNF gene could be related to the development of OCD.     

Genetic association of aromatic hydrocarbon receptor (AHR) and cytochrome P450, family 1, subfamily A,polypeptide 1 (CYP1A1) polymorphisms with dioxin blood concentrations among pregnant Japanese women

Dioxins are metabolized by cytochrome P450, family 1 (CYP1) via the aromatic hydrocarbon receptor (AHR). We determined whether different blood dioxin concentrations are associated with polymorphisms in AHR (dbSNP ID: rs2066853), AHR repressor (AHRR; rs2292596), CYP1 subfamily A polypeptide 1 (CYP1A1; rs4646903 and rs1048963), CYP1 subfamily A polypeptide 2 (CYP1A2; rs762551), and CYP1 subfamily B polypeptide 1 (CYP1B1; rs1056836) in pregnant Japanese women. These six polymorphisms were detected in 421 healthy pregnant Japanese women. Differences in dioxin exposure concentrations in maternal blood among the genotypes were investigated. Comparisons among the GG, GA, and AA genotypes of AHR showed a significant difference (genotype model: P = 0.016 for the mono-ortho polychlorinated biphenyl concentrations and toxicity equivalence quantities [TEQs]). Second, we found a significant association with the dominant genotype model ([TT + TC] vs. CC: P = 0.048 for the polychlorinated dibenzo-p-dioxin TEQs; P = 0.035 for polychlorinated dibenzofuran TEQs) of CYP1A1 (rs4646903). No significant differences were found among blood dioxin concentrations and polymorphisms in AHRR, CYP1A1 (rs1048963), CYP1A2, and CYP1B1. Thus, polymorphisms in AHR and CYP1A1 (rs4646903) were associated with maternal dioxin concentrations. However, differences in blood dioxin concentrations were relatively low.     

eNOS gene polymorphisms modify the association of PM10 with oxidative stress

Previous studies have suggested that air pollution increases various health outcomes through oxidative stress and oxidative stress-related genes modify the relationship between air pollution and health outcomes. Therefore, we evaluated the effect of PM₁₀ on the levels of malondialdehyde (MDA), oxidative stress biomarker, and the effect modification by genetic polymorphisms of eNOS, oxidative stress-related gene, in the 560 Korean elderly. We obtained urine samples repeatedly from participants during five medical examinations between 2008 and 2010 and all ambient air pollutant concentration data from the Korea National Institute of Environmental Research air quality monitoring system. We measured urinary levels of MDA to assess oxidative stress and genotyped eNOS (rs1799983, rs2853796, and rs7830). Mixed-effect model was used to estimate the effect of PM₁₀ on the level of oxidative stress biomarker and their modification by genotypes. PM₁₀ showed apparent positive effect on MDA level after adjusting for age, sex, BMI, cotinine level, temperature, dew point, levels of SO₂, O₃, NO₂, and CO, and season (p = 0.0133). Moreover, the association of PM₁₀ with MDA was found only in participants with eNOS GG genotype for rs1799983 (p = 0.0107), TT genotype for rs2853796 (p = 0.0289), or GT genotype for rs7830 (p = 0.0158) and in participants with a set of risky haplotypes (GTT, GTG, GGT, and TGT) (p = 0.0093). Our results suggest that PM₁₀ affect oxidative stress in the elderly and eNOS genotype affect the oxidative stress level in regard of exposure to PM₁₀.     

NCAN Cross-Disorder Risk Variant Is Associated With Limbic Gray Matter Deficits in Healthy Subjects and Major Depression

Genome-wide association studies have reported an association between NCAN rs1064395 genotype and bipolar disorder. This association was later extended to schizophrenia and major depression. However, the neurobiological underpinnings of these associations are poorly understood. NCAN is implicated in neuronal plasticity and expressed in subcortical brain areas, such as the amygdala and hippocampus, which are critically involved in dysfunctional emotion processing and regulation across diagnostic boundaries. We hypothesized that the NCAN risk variant is associated with reduced gray matter volumes in these areas. Gray matter structure was assessed by voxel-based morphometry on structural MRI data in two independent German samples (healthy subjects, n=512; depressed inpatients, n=171). All participants were genotyped for NCAN rs1064395. Hippocampal and amygdala region-of-interest analyses were performed within each sample. In addition, whole-brain data from the combined sample were analyzed. Risk (A)-allele carriers showed reduced amygdala and hippocampal gray matter volumes in both cohorts with a remarkable spatial overlap. In the combined sample, genotype effects observed for the amygdala and hippocampus survived correction for entire brain volume. Further effects were also observed in the left orbitofrontal cortex and the cerebellum/fusiform gyrus. We conclude that NCAN genotype is associated with limbic gray matter alterations in healthy and depressed subjects in brain areas implicated in emotion perception and regulation. The present data suggest that NCAN forms susceptibility to neurostructural deficits in the amygdala, hippocampus, and prefrontal areas independent of disease, which might lead to disorder onset in the presence of other genetic or environmental risk factors.     

Impact of Adjunctive Therapy with Chlorellav ulgaris Extract on Antioxidant Status, Pulmonary Function, and Clinical Symptoms of Patients with Obstructive Pulmonary Diseases

This present trial investigated the efficacy of supplementation with Chlorella vulgaris, a bioactive microalga rich in macro- and micronutrients, in the improvement of biochemical and clinical symptoms in patients with obstructive pulmonary disorders. Ninety-seven patients with chronic obstructive pulmonary disease (COPD) or asthma who were under conventional treatment regimens were randomly assigned to C. vulgaris extract (CVE) (n=48; 2700 mg/day) or no adjunctive therapy (n=49) for eight weeks. Serum levels of antioxidants along with spirometric parameters and clinical symptoms were evaluated pre- and post-trial. The magnitude of increases in the concentrations of glutathione, vitamin E, and vitamin C, and activities of glutathione peroxidase, catalase, and superoxide dismutase enzymes were all significantly greater in the CVE vs. control group (p<0.05). In spite of increases, none of the assessed spirometric parameters (FVC, FEV1, FEV1/FVC, and FEF_25–75%) did significantly differ by the end of the trial in the study groups, apart from a significant elevation of FEV1 in the control group (p=0.03). The frequency of coughing, shortness of breath, wheezing, and sputum brought up were all significantly reduced in both CVE and control groups (p<0.05). The rate of improvement for sputum brought up and wheezing were significantly greater in the CVE group compared to the control group (p<0.05). Although CVE was found to ameliorate serum antioxidant status, its supplementation was not associated with any bronchodilatory activity. The results of the present trial do not support any clinical efficacy for CVE in patients with obstructive pulmonary disorders.     

Pharmacogenetics of Naltrexone in Asian Americans: A Randomized Placebo-Controlled Laboratory Study

Recent clinical and laboratory studies have shown that the effects of naltrexone for alcoholism may be moderated by the Asn40Asp single-nucleotide polymorphism (SNP) of the μ-opioid receptor gene (OPRM1). Allele frequencies for this polymorphism, however, have been shown to vary substantially as a function of ethnic background, such that individuals of Asian descent are more likely to carry the minor (Asp40) allele. The objective of this study is to test the naltrexone pharmacogenetic effects of the Asn40Asp SNP in a sample of Asian Americans. This study consists of a double-blinded, randomized, placebo-controlled laboratory trial of naltrexone. Participants (n=35, 10 females; 13 Asn40Asn and 22 Asp40 carriers) were non-treatment-seeking heavy drinkers recruited from the community. After taking naltrexone or placebo, participants completed an intravenous alcohol administration session. The primary outcome measures were subjective intoxication and alcohol craving. Results suggested that Asp40 carriers experienced greater alcohol-induced sedation, subjective intoxication, and lower alcohol craving on naltrexone, as compared to placebo, and to Asn40 homozygotes. There results were maintained when controlling for ALDH2 (rs671) and ADH1B (rs1229984) markers and when examining the three levels of OPRM1 genotype, thereby supporting an OPRM1 gene dose response. These findings provide a much-needed extension of previous studies of naltrexone pharmacogenetics to individuals of Asian descent, an ethnic group more likely to express the minor allele putatively associated with improved biobehavioral and clinical response to this medication. These findings help further delineate the biobehavioral mechanisms of naltrexone and its pharmacogenetics.     

Insulin Resistance,Diabetes Mellitus,and Brain Structure in Bipolar Disorders

Type 2 diabetes mellitus (T2DM) damages the brain, especially the hippocampus, and frequently co-occurs with bipolar disorders (BD). Reduced hippocampal volumes are found only in some studies of BD subjects and may thus be secondary to the presence of certain clinical variables. Studying BD patients with abnormal glucose metabolism could help identify preventable risk factors for hippocampal atrophy in BD. We compared brain structure using optimized voxel-based morphometry of 1.5T MRI scans in 33 BD subjects with impaired glucose metabolism (19 with insulin resistance/glucose intolerance (IR/GI), 14 with T2DM), 15 euglycemic BD participants and 11 euglycemic, nonpsychiatric controls. The group of BD patients with IR, GI or T2DM had significantly smaller hippocampal volumes than the euglycemic BD participants (corrected p=0.02) or euglycemic, nonpsychiatric controls (corrected p=0.004). Already the BD subjects with IR/GI had smaller hippocampal volumes than euglycemic BD participants (t(32)=−3.15, p=0.004). Age was significantly more negatively associated with hippocampal volumes in BD subjects with IR/GI/T2DM than in the euglycemic BD participants (F(2, 44)=9.96, p=0.0003). The gray matter reductions in dysglycemic subjects extended to the cerebral cortex, including the insula. In conclusion, this is the first study demonstrating that T2DM or even prediabetes may be risk factors for smaller hippocampal and cortical volumes in BD. Abnormal glucose metabolism may accelerate the age-related decline in hippocampal volumes in BD. These findings raise the possibility that improving diabetes care among BD subjects and intervening already at the level of prediabetes could slow brain aging in BD.     

The ZNF804A Gene: Characterization of a Novel Neural Risk Mechanism for the Major Psychoses

Schizophrenia and bipolar disorder share genetic risk, brain vulnerability, and clinical symptoms. The ZNF804A risk variant, rs1344706, confers susceptibility for both disorders. This study aimed to identify neural mechanisms common to both schizophrenia and bipolar disorder through this variant''s potential effects on cortical thickness, white matter tract integrity, and cognitive function. Imaging, genetics, and cognitive measures were ascertained in 62 healthy adults aged between 18 and 59 years. High-resolution multimodal MRI/DTI imaging was used to measure cortical thickness and major frontotemporal and interhemispheric white matter tracts. The general linear model was used to examine the influence of the ZNF804A rs1344706 risk variant on cortical thickness, white matter tract integrity, and cognitive measures. Individuals homozygous for the risk variant (‘A'' allele) demonstrated reduced cortical gray matter thickness in the superior temporal gyrus, and in the anterior and posterior cingulate cortices compared with C-allele carriers. No effect of the risk variant on microstructural integrity of white matter tracts was found. Reduced attention control was found in risk allele homozygotes, aligning with findings in the anterior cingulate cortex. Our data provide a novel, genetically based neural risk mechanism for the major psychoses by effects of the ZNF804A risk variant on neural structures and cognitive function susceptible in both disorders. Our findings link genetic, imaging, and cognitive susceptibility relevant to both schizophrenia and bipolar disorder.     

The Galanin Receptor 1 Gene Associates with Tobacco Craving in Smokers Seeking Cessation Treatment

Craving for tobacco is a major challenge for people with nicotine dependence (ND) who try to quit smoking. Galanin (GAL) and its receptors (GALRs) can alter addiction-related behaviors and are therefore good candidates for modulators of behavioral parameters associated with smoking. We performed a genetic association study in 486 subjects (432 European American, EA) recruited for smoking cessation trials. Twenty-six candidate genes for ND-related phenotypes were selected based on the literature. Subjects were assessed using the Minnesota Withdrawal Scale (MWS), which included a specific item for craving, the Fagerström Scale of Nicotine Dependence (FTND), and other ND-related instruments. One single-nucleotide polymorphism (SNP) in GALR1, rs2717162, significantly associated with severity of craving in EA samples (p=6.48 × 10⁻⁶) and in the combined sample (p=9.23 × 10⁻⁶). Individuals with TT and TC genotypes had significantly higher craving scores than CC subjects. We also observed that SNPs in the CHRNA5 locus, rs16969968 and rs684513, which have been associated with ND-related phenotypes in previous studies, were nominally associated with FTND scores, although these results did not meet Bonferroni-adjusted criteria for experiment-wide significance. Our findings suggest that variation at GALR1 associates with differences in the severity of past craving for tobacco among smokers motivated to quit. Taken together with preclinical evidence, these results, if replicated, suggest that GAL and GALRs may be useful therapeutic targets for the pharmacological treatment of ND. Our results also confirm previously reported associations between variation at CHRNA5 and ND.     

Antiurolithiatic and antioxidant activity of Mimusops elengi on ethylene glycol-induced urolithiasis in rats

Objective:

To evaluate the potential of Mimusops elengi in the treatment of renal calculi.

Materials and Methods:

Petroleum ether, chloroform, and alcohol extracts of Mimusops elengi bark were evaluated for antiurolithiatic and antioxidant activity in male albino Wistar rats. Ethylene glycol (0.75%) in drinking water was fed to all the groups (Groups II–IX) except normal control (Group I) for 28 days to induce urolithiasis for curative (CR) and preventive (PR) regimen. Groups IV, V, and VI served as CR, and groups VII, VIII, and IX as PR were treated with different extracts of M. elengi bark. Groups I, II, and III served as normal control, positive control (hyperurolithiatic), and standard (cystone 750 mg/kg), respectively. Oxalate, calcium, and phosphate were monitored in the urine and kidney. Serum BUN, creatinine, and uric acid were also recorded. In vivo antioxidant parameters such as lipid peroxidation (MDA), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were also monitored.

Results:

All the extracts of M. elengi were safe orally and exhibited no gross behavioral changes in the rats. In hypercalculi animals, the oxalate, calcium, and phosphate excretion grossly increased. However, the increased deposition of stone forming constituents in the kidneys of calculogenic rats were significantly (P < 0.001) lowered by curative and preventive treatment with alcohol extract (AlE) of M. elengi. It was also observed that alcoholic extract of M. elengi produced significant (P < 0.001) decrease in MDA, and increased GSH, SOD, and CAT. These results confirm that AlE of M. elengi possess potent antiurolithiatic activity.

Conclusion:

The results obtained suggest potential usefulness of the AlE of M. elengi bark as an antiurolithiatic agent.     

Association of ALOX15 gene polymorphisms with obesity-related phenotypes in Chinese nuclear families with male offspring

Aim:

Genetic variation in ALOX12, which encoded human 12-lipoxygenase, was found to be associated with fat mass in young Chinese men. The objective of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) and haplotypes in the ALOX15 gene and obesity-related phenotypes in Chinese nuclear families with male offspring.

Methods:

We recruited 1,296 subjects from 427 nuclear families with male offspring and genotyped five SNPs (rs9894225, rs748694, rs2619112, rs2619118, and rs916055) in the ALOX15 gene locus. The total fat mass (TFM), trunk fat mass (tFM), leg fat mass (LFM) and arm fat mass (AFM) were measured using dual-energy X-ray absorptiometry (DXA). The percentage of fat mass (PFM) was the ratio of TFM and body weight. The association between SNPs and haplotypes of ALOX15 and obesity-related phenotypic variation was measured using quantitative transmission disequilibrium test (QTDT).

Results:

Using QTDT to measure family-based genetic association, we found that rs916055 had a statistically significant association with PFM (P=0.038), whereas rs916055 had a marginal but statistically insignificant association with tFM (P=0.093). The multiple-parameter 1000 permutations test agreed with the family-based association results: both showed that rs916055 had a statistically significant association with PFM (P=0.033).

Conclusion:

rs916055 in ALOX15 gene was significantly associated with the percentage of fat mass in Chinese nuclear families with male offspring in the family-based association study using QTDT approach.