A-allele Carriers Research Articles

DRD2/ANKK1 TaqI A1 polymorphism associates with overconsumption of unhealthy foods and biochemical abnormalities in a Mexican population.

The dopamine receptor 2/ankyrin repeat domain and content kinase 1 (DRD2/ANKK1) TaqIA polymorphism (rs1800497) has been associated with rewarding behaviors. This study aimed to investigate the association of DRD2/ANKK1 TaqIA polymorphism with the dietary intake, the intake frequency of food groups and biochemical profile in Mexican mestizo subjects. A cross-sectional/analytical study with 276 Mexican subjects was performed. Dietary intake was assessed with a 24-h recall and a food frequency questionnaire (FFQ). An allelic discrimination assay evaluated DRD2/ANKK1 TaqIA genotypes. Anthropometric and biochemical data were evaluated. Genotype frequencies were A1A1 (18.48%), A1A2 (45.29%) and A2A2 (36.23%). TaqI A1 allele carriers had a higher intake of carbohydrates (p = 0.038), meats (p = 0.005), fried dishes (p = 0.039), and sugars (p = 0.009). Male TaqI A1 carriers consumed more carbohydrates (p = 0.009) and meats (p = 0.018) while females consumed fewer legumes (p = 0.005). TaqI A1 carriers had glucose (p = 0.037) and triglycerides (p = 0.011) abnormalities. TaqI A1 was associated with higher risk of consumption of unhealthy foods such as fried dishes (OR 3.79, 95% CI 1.53-9.35, p = 0.002) and meats (OR 2.31, 95% CI 1.32-4.05, p = 0.003), and lower healthy foods (OR 1.89, 95% CI 1.04-3.29, p = 0.038). TaqI A1 allele was associated with risk of abnormal glucose, triglycerides, and VLDL levels (OR 2.148, 95% CI 1.068-4.322, p = 0.036; OR 1.999, 95% CI 1.194-3.348, p = 0.011; OR 2.021, 95% CI 1.203-3.392, p = 0.007), respectively. The presence of the TaqI A1 allele in Mexicans is a genetic risk factor for detrimental dietary quality that may predispose to metabolic disturbances. Level III, case-control analytic study.

Cholesteryl Ester Transfer Protein Variant (RS1800777) with Liver Histology in Non-Alcoholic Fatty Liver Disease Patients

Introduction and Aims: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of diseases ranging from simple steatosis without inflammation or fibrosis to nonalcoholic steatohepatitis and in the Western countries has become one of the most prevalent chronic liver diseases related to metabolic and lipid alterations. Cholesteryl ester transfer protein (CETP) participates in high density lipoprotein (HDL)-cholesterol metabolism. The aim of our study was to investigate the influence of polymorphism (rs1800777) of CETP gene on liver histological changes, biochemical parameters, and serum adipokines levels in patients with NAFLD. Material and Methods: A population of 90 patients with NAFLD was recruited in a cross-sectional study. A biochemical analysis (glucose, c-reactive protein, insulin, homeostasis model assessment-insulin resistance, total cholesterol, low density lipoprotein (LDL)-cholesterol, HDL-cholesterol, triglycerides blood, and adipokines (leptin, adiponectin, and resistin) was realized. Genotype of polymorphism (rs1800777) of CETP gene was studied. Results: Eighty-three patients (92.2%) had the genotype GG (wild type group) and 7 patients (7.8%) had the genotype GA (n = 7) or AA (n = 0; mutant type group). Patients with A allele show significant decrease in liver biochemistry parameters – Alanine amino transferase (delta 10.1 ± 9.9 UI/L; p = 0.01), aspartate aminotransferase activity (delta 13.3 ± 9.5 UI/L; p = 0.02), and gammaglutamine transferase levels (delta 39 ± 30.1 UI/L; p = 0.01). Logistic regression analysis indicated that subjects with A-allele carriers were associated with a decreased risk of lobulillar inflammation (OR 0.18, 95% CI 0.04–0.95, p = 0.04) and a decreased risk of steatosis (OR 0.13, 95% CI 0.02–0.89, p = 0.04). Conclusions: A variant of the polymorphism rs1800777 of CETP gene is independently associated with the presence of steatosis and lobulillar inflammation in subjects with proven biopsy NAFLD.

Impact of FAAH genetic variation on fronto-amygdala function during emotional processing.

Recent translational studies identified a common endocannabinoid polymorphism, FAAH C385A, in the gene for the fatty acid amide hydrolase (FAAH). This polymorphism alters endocannabinoid anandamide levels, which are known to be involved in the fronto-amygdala circuitry implicated in mood regulation and anxiety-like behaviors. While it has been shown that the variant that selectively enhances fronto-amygdala connectivity at rest is associated with decreased anxiety-like behaviors, no study so far has investigated whether this finding of FAAH-related differential plasticity extends to task-related differential functional expression and regulation during negative emotional processing. Using an imaging genetics approach, this study aimed to replicate and extend prior findings by examining functional activity and task-related connectivity in fronto-amygdala regions during emotion reactivity and emotional down-regulation of negative affect. Therefore, 48 healthy young adults underwent a functional MRI resting state measurement, completed an emotion regulation paradigm and provided self-reports on anxiety and use of emotion regulation strategies. In line with previous studies, preliminary evidence suggests that A-allele carriers demonstrate stronger fronto-amygdala connectivity during rest. In addition, exploratory whole-brain analyses indicate differential functional activity of A-allele carriers during emotion reactivity and emotion regulation. There were no associations with anxiety-related self-reports and use of emotional regulation strategies. Further research using larger samples and polygenic approaches is indicated to clarify the precise role and its underlying mechanisms in emotion processing.

Research of distribution pattern of allelic genes and genotypes of C/A polymorphism of COL1A1_1 collagen gene (RS1107946) in children with nasal obstruction of allergic genesis and orthodontic pathology

Purpose. Determination of the genotypes of C/A polymorphism of COL1A1_1 collagen gene (rs1107946) and patterns of distribution of allelic genes in children with nasal obstruction and orthodontic pathology. Materials and methods. A molecular-genetic study for determination of C/A polymorphism of COL1A1_1 collagen gene (rs1107946) was performed in 99 children at the age of 6 to 17 years, for 11 months and 30 days inclusive; 30 children of which had nasal obstruction due to allergic rhinitis without abnormal distal occlusion (the first group); 23 children had just the distal occlusion (the second group); 26 children had allergic rhinitis and distal occlusion (the third group); 20 almost healthy children (the fourth group). Genotyping was performed by the polymerase chain reaction method (Applied Biosystems, USA) using the total DNA samples isolated from whole venous blood using a set of reagents SNP-Screen (Syntol manufacturer) on the CFX96TM Real-Time PCR Detection Systems amplifier (Bio-Rad Laboratories, Inc., USA). Non-parametric statistic methods of the licensed software package Statistica for Windows 6.1.RU, serial number AXXR712D833214SAN5 was used for processing the research results. Results. Molecular-genetic study of the distribution patterns of allelic genes and genotypes of the C/A polymorphism of the COL1A1_1 (rs1107946) collagen gene in the examined children showed that the frequency of occurrence of the C allele was significantly higher than the A allele (71.72 % and 28.28 %, respectively). In this case, the homozygous C/C genotype was registered most often (68.69 %), homozygous genotype A/A (25.25 %) was rarely registered and heterozygous C/A (6.06 %) was very rarely registered. In the observation groups, in children with allergic rhinitis, distal occlusion and a combination of allergic and orthodontic pathology, the genotypes had the following distribution: the C/C genotype – 76.67 %; 34.78 %; 73.00 %; A/A genotype – 20.00 %; 56.52 %; 17.39 %; A/C genotype – 3.33 %; 8.70 %; 11.54 %. The occurrence frequency of alleles of the C/A polymorphism of the COL1A1_1 collagen gene (rs1107946) in the examined children showed that the children with distal occlusion were significantly frequent carriers of A allele (60.87 %), whereas the carriers of C allele were predominantly children with allergic rhinitis (78.33 %), with combined allergic and orthodontic pathology (78.85 %) and healthy (90.00 %), P < 0.05. The correlation between the results of the study conducted in groups of children with the distal occlusion and practically healthy showed that the sensitivity of the presence of A allelic gene was equal to 60.87 %, specificity – 90.00 %, accuracy – 61.54 %. Since the sensitivity and specificity of the diagnostic test exceeded 50.00 %, the prognostic value for the positive result was equal to 87.50 % and for the negative result – 66.67 % and confirm this prognostic significance for the development of the orthodontic pathology in children. This will allow improving the preventive measures in children with orthodontic pathology. Conclusions. The molecular-genetic studies for determining the A allele (rs1107946) of the COL1A1_1 collagen gene in children could be recommended to determine the risk of development and the need for early prevention of the distal occlusion in children.

Topiramate versus naltrexone for alcohol use disorder: study protocol for a genotype-stratified, double-blind randomised controlled trial (TOP study)

BackgroundCurrent treatments for alcohol use disorders have limited efficacy and there is a high degree of variability in treatment response. In a randomised, placebo-controlled clinical trial, there was a large effect size for topiramate in people homozygous for the GRIK1 rs2832407*C allele. The primary aim of the TOP study is to examine prospectively the therapeutic and cost-effectiveness of topiramate versus an active control (naltrexone) in improving treatment outcomes for alcohol dependence. Participants will be stratified on rs2832407 to compare C-allele homozygotes with A-allele carriers to examine the moderating effect of rs2832407 on drinking outcomes. An exploratory aim is to examine the moderating effects of rs1799971, a polymorphism in OPRM1, on the response to naltrexone by comparing Asn40 homozygotes with Asp40 carriers.Methods/designThis double-blind trial will randomise 180 alcohol-dependent participants to a 12-week regime of either topiramate (titrating the dose up to 200 mg/day) or naltrexone (50 mg/day). Participants will be stratified on the two polymorphisms before randomisation. All participants will receive medical management. The primary drinking outcome will be the number of heavy drinking days per week and secondary drinking outcomes will include the time to relapse, the time to lapse and the percentage of abstinent days. Other secondary outcomes will include body mass index, tobacco use, anxiety symptoms and depressive symptoms.DiscussionIf successful, the TOP study will improve management strategies for alcohol dependence by providing support for the use of genetic biomarkers to inform medication selection.Trial registrationClinicalTrials.gov, NCT03479086. Registered on 27 March 2018.

The OXTR Single-Nucleotide Polymorphism rs53576 Moderates the Impact of Childhood Maltreatment on Empathy for Social Pain in Female Participants: Evidence for Differential Susceptibility.

Previous research has associated genetic variations of the oxytocin receptor with individual differences in human social behavior. Specifically, homozygous carriers of the G-allele of the single nucleotide polymorphism rs53576 have been reported to display more trust, empathy, and prosocial behavior and were less sensitive toward stress and maltreatment during childhood when compared to A-allele carriers. With regard to Borderline Personality Disorder (BPD), a psychiatric condition that is often associated with the experience of childhood adversity, it has been suggested that A-allele carriers are more vulnerable to developing psychopathological signs and symptoms. In the present study we investigated whether childhood trauma, as assessed by the Childhood Trauma Questionnaire (CTQ), affects empathy for somatic and psychological pain, and how this is moderated by genotype, in a sample of 302 individuals (148 of whom were diagnosed with BPD). We found a three-way interaction between genotype, group and pain condition. Posthoc comparisons revealed that patients with BPD carrying at least one A-allele, rated psychological pain as more intense compared to controls, whereas no difference between groups emerged in GG homozygotes. Moreover, a moderating effect of genotype appeared on the impact of childhood trauma on empathy for psychological pain. In addition, a positive correlation of CTQ scores and empathy appeared only in A-allele carriers (GA + AA), independent of diagnosis. Together, A-allele carriers, especially those with BPD, seemed to be responsive to the impact of adversity on empathy-for-pain, while GG homozygotes were not, which is compatible with the idea of differential susceptibility.

Family environment interacts with CRHR1 rs17689918 to predict mental health and behavioral outcomes

BackgroundCorticotrophin-releasing hormone receptor-1 gene (CRHR1) variants have been implicated in mental health. However, little is known of the effects of CRHR1 on long-term mental health and behavior in presence of environmental stressors. We assess the effects of CRHR1 variant (rs17689918)-by-environment interactions on emotionality and behavioral traits, including anxiety, depression, aggression and antisocial behaviors. We also determine effects of rs17689918-by-environment-by-sex interactions on the above-mentioned outcomes. MethodsGenotypic assessments were carried out in 564 children (mean age 10 years, 52.5% females) from the ongoing longitudinal Estonian Children Personality Behaviour and Health Study (ECPBHS). Information on stressful life events and family relationships were available at baseline and information on behavioral and mental health outcomes (self- and parent-reports) were available at follow-up ages of 18 and 25 years. ANOVAs were used to determine associations of two-way CRHR1-by-environment and three-way CRHR1-by-sex-by-environment interactions on behavioral and mental health outcomes. ResultsTwo-way CRHR1 interaction effects showed associations between low familial warmth and hostility in individuals with the GG genotype. Associations of low familial warmth with aggression, of higher number of stressful life events with aggression, and of stressful live events with anxious-depressive symptoms were noted in male A-allele carriers and female GG homozygotes. ConclusionCRHR1-by-familial environment interactions influence both outwardly-directed aggression as well as mood and anxiety disorder symptoms in a sex-specific manner. The type of environmental stressor can also influence effects of CRHR1 on behavioral and mental health outcomes.

The Variants in the 3' Untranslated Region of the Matrix Metalloproteinase 9 Gene as Modulators of Treatment Outcome in Children with Asthma.

The maintaining of asthma control is difficult due to high variability in response to therapy among patients. Since matrix metalloproteinase 9 (MMP9) is implicated in inflammation and remodeling of asthmatic airways, it could be associated with adequate response to asthma therapy. The aim of this study was to investigate whether variants in 3' end of the MMP9 gene are associated with clinical phenotype and responsiveness to treatment in children with asthma. The study included 127 asthmatic children from Slovenia. Variants in the 3' end of the MMP9 gene were analyzed by direct DNA sequencing and the obtained results were correlated with clinical parameters. Two variants were detected, rs13925 and rs20544. For the variant rs20544, statistically significant difference in airway hyperresponsiveness (p = 0.011) and asthma control (p = 0.049) between genotypes was found. Patients with TT genotype had lower airway sensitivity, and after 12 months of treatment showed significant improvement in Asthma Control Test (ACT) scores compared to CC and CT genotype. For the variant rs13925, the association with lung function was observed. The carriers of A allele showed noticeable improvement of lung function after the first 6 months of treatment in comparison to the carriers of G allele (p = 0.046). The main finding of our study is the association of MMP9 genotypes rs20544 TT and rs13925 AA and AG with better asthma control, and indirectly better response to treatment. Based on these results, MMP9 deserves further research as a potential predictive biomarker for asthma.

Influence of the DRD2/ANKK1 Taq1A polymorphism on caudate volume in older adults without dementia

Dopaminergic neuromodulation is critically important for brain and cognitive integrity. The DRD2/ANKK1 Taq1A polymorphism is associated with striatal dopamine (DA) D2 receptor availability. Some previous studies have found that the A allele of the Taq1A polymorphism influences brain structure, but the results are inconsistent, likely due to population heterogeneity and small sample sizes. We investigated the genetic effect on caudate volume in a large sample of older adults without dementia. Results show that A-allele carriers have smaller caudate volume compared to non-carriers in relatively older adults (n = 167; Mage = 77.8 years), whereas the genotype did not influence caudate volume in a younger age group (n = 220; Mage = 62.8 years). Cognitive performance was not significantly affected by the DRD2 gene. Our findings extend previous observations by showing magnified genetic effects on brain volume in old age, and provide evidence for a link between a DA-related genetic polymorphism and grey matter volume in a brain region within the nigrostriatal dopaminergic pathway.

ADIPOR2 variant is associated with higher fasting glucose level in non-diabetic Chinese Han population

A high but normal fasting plasma glucose level in adults is a marker for insulin resistance and future development of type 2 diabetes mellitus. We aimed to investigate whether ADIPOR2 variants are associated with increased fasting plasma glucose (FPG) in non-diabetic Chinese Han subjects who had normal FPG levels. This study included 2038 subjects among the non-diabetic Chinese Han population. The ADIPOR2 polymorphisms were genotyped by the TaqMan method. For the analysis, participants were divided into low-normal FPG group (FPG FPG ≥ 4.88 mmol/L). We identified five single nucleotide polymorphisms (SNPs) of ADIPOR2 gene: rs10773989, rs2370055, rs9300298, rs10773983, and rs13611594. There was no significant difference in FPG levels between different genotypes of rs10773989, rs2370055, rs9300298, and rs13611594. Our data showed a significant association of rs10773983 with higher FPG levels, fasting insulin levels, and homeostatic model assessment of insulin resistance (HOMA-IR) in A-allele carriers (p = 0.006, p < 0.001, and p < 0.001, respectively). The subjects in high FPG group had higher median fasting insulin level (9.25 vs 8.16 μIU/mL, p = 0.003) and higher HOMA-IR (2.21 vs 1.58, p < 0.001) than those in normal FPG group. Subjects with the A-allele of rs10773983 compared to subjects with G-allele had 1.222-fold higher risk for high-normal FPG (OR = 1.222, 95%CI = 1.010–1.478, p = 0.039). Our findings suggest that ADIPOR2 rs10773983 polymorphism may be associated with an increased risk of high-normal FPG among non-diabetic Chinese Han subjects who have normal FPG levels.

Assessment of the sufficiency of Moscow population with folic acid, depending on the combined effect of polymorphism of MTHFR and FTO genes

The results of assessing the sufficiency of folic acid of the residents of the Moscow region have been presented depending on rs1801133 MTHFR gene polymorphism and rs9939609 FTO gene polymorphism. A total of 326 people were examined, including 74 men and 252 women aged 20 to 65 years. The results of determining the level of folic acid in blood serum showed insufficiency of this vitamin among the population of the Moscow region of the Russian Federation. The expressed vitamin deficit (level <3,0 ng/ml) was detected in 24.2% of the surveyed residents, in 22.8% folic acid level was at the lower bound of the norm (3.0-4.5 ng/ml). The results of genotyping showed a statistically significant association of low folic acid level with rs1801133 MTHFR gene polymorphism in carriers of A allele of rs9939609 FTO gene polymorphism both in the homozygous state (genotype AA) and in the heterozygous (genotype AT) state, OR=4.26; CI (1.40-12.9), p=0.008, as well as with rs9939609 FTO gene polymorphism in carriers of the T allele of rs1801133 MTHFR gene polymorphism both in the homozygous (genotype TT) and heterozygous (CT genotype) state, OR=3.29; CI (1.07-10.1), p=0.03. In carriers of 3 alleles of risk of folic acid deficiency [rs9939609 FTO gene polymorphism and rs1801133 MTHFR gene polymorphism (genotypes CT/AA and TT/AT)] blood serum level of folic acid was below the norm, that indicated folate deficiency in this category of persons.

Fat Mass and Obesity-Related Gene Variants rs9939609 and rs7185735 are Associated with Second-Generation Antipsychotic-Induced Weight Gain

Weight gain is a limiting and frequent adverse effect of second-generation antipsychotic therapy. Identifying genetic risk factors would significantly improve pharmacotherapy. We focused on rs7185735 and rs9939609, 2 common single nucleotide polymorphisms of the fat mass and obesity-associated (FTO) gene reported to be associated with obesity. Three-hundred fifty Caucasian inpatients were included in a naturalistic study. After 4 weeks of treatment, we did not observe any significant association of polymorphisms with weight change in the whole study population (p>0.05). In a subpopulation without additional weight-inducing comedication (n=178), G-allele carriers of rs7185735 gained 3.4 times more weight (1.69 kg±3.1 kg, p=0.019) than AA genotypes (0.49 kg±3.1 kg). A-allele carriers of rs9939609 gained 3.1 times more weight (1.65 kg±3.1 kg, p=0.029) than TT genotypes (0.54 kg±3.2 kg). Our findings confirm the role of the FTO gene as a high-potential risk factor for obesity and indicate a value for predicting a weight gain induced by second-generation antipsychotics. Further, we detected an additive effect of FTO rs7185735 and MC4R rs17782313.

XKR4 Gene Effects on Cerebellar Development Are Not Specific to ADHD.

A single-nucleotide polymorphism (SNP) of the XKR4 gene has been linked to Attention-Deficit/Hyperactivity Disorder (ADHD). This gene is preferentially expressed in cerebellum, a brain structure implicated in this disorder. This study investigated the effects of this SNP on cerebellar development in children with and without ADHD. We collected 279 longitudinal T1-weighted structural images and DNA from 58 children with ADHD and 64 typically developing (TD) children matched for age, IQ, and gender. Groups were divided by the XKR4 rs2939678 SNP into A-allele carriers versus subjects homozygous for the G-allele. Cerebellar lobular volumes were segmented into 35 regions of interest using MAGeTBrain, an automated multi-atlas segmentation pipeline for anatomical MRI, and statistically analyzed using linear mixed models. We found decreased gray matter (GM) volumes in ADHD compared to TD children in bilateral lobules VIIIA, left VIIIB, right VIIB, and vermis VI. Furthermore, we found a linear age by gene interaction in left lobule VIIB where subjects homozygous for the G-allele showed a decrease in volume over time compared to A-allele carriers. We further found quadratic age × gene and age × diagnosis interactions in left lobule IV. Subjects homozygous for the G-allele (the genotype overtransmitted in ADHD) showed more suppressed, almost flat quadratic growth curves compared to A-allele carriers, similar to individuals with ADHD compared to controls. However, there was no interaction between genotype and diagnosis, suggesting that any effects of this SNP on cerebellar development are not specific to the disorder.

Genetic variation in bone morphogenetic proteins family members (BMPs 2 and 4) and hypertension risk in middle-aged men

Bone morphogenetic proteins (BMPs) are important regulators of iron metabolism affecting hepcidin expression. We have previously shown that 2 genetic polymorphisms in different genes (histocompatibility complex class I-like transmembrane protein, hemojuvelin) involved in the regulation of hepcidin expression pathways are associated with hypertension. In this study, we analyzed genetic variation sites in BMP2 (rs235756, rs235768) and BMP4 (rs4901474) to get more evidence linking iron metabolism to hypertension risk in the Finnish population.The study included 321 hypertensive cases and 463 controls from the Tampere Adult Population Cardiovascular Risk study cohort. Genotyping of polymorphisms was done by polymerase chain reaction using DNAs extracted from buccal swabs.We found that men carrying the GG genotype of BMP2 rs235756 (A>G) polymorphic site had a 4.09-fold risk (confidence interval [CI] 1.61–10.39, P = .003) for hypertension at the age of 50 years compared with A-allele carriers. The risk was significant in the age groups of 45 and 40 years as well. In addition, the 15-year follow-up period of the same individuals showed that carriers of the GG-genotype had also significantly higher readings of both systolic (P < .001) and diastolic (P = .01) blood pressure during the follow-up time. No significant association between BMP2 rs235768 (A>T) and hypertension was found. BMP4 polymorphic site rs4901474 (T>C) also had an effect on hypertension. CC genotype carriers had a 1.48-fold risk (CI 1.03–2.13, P = .033) for hypertension at the age of 50 years when compared with T-allele carriers.In conclusion, BMP2 polymorphic site rs235756 was associated with hypertension in Finnish men. An effect of BMP4 polymorphic site on hypertension was also found.

Effects of artichoke leaf extract supplementation on metabolic parameters in women with metabolic syndrome: Influence of TCF7L2‐rs7903146 and FTO‐rs9939609 polymorphisms

The metabolic syndrome (MetS) is a multicomponent condition with a complex etiology involving genetic and environmental factors. Artichoke leaf extract (ALE) has shown favorable effects on lipid and glucose metabolism. The present study aimed to investigate the effects of ALE supplementation on metabolic parameters in women with MetS, using a nutrigenetics approach. In this double-blind randomized clinical trial, 50 women (aged 20-50years) with MetS were randomly allocated into the two groups: "ALE group" (received 1,800mg hydroalcoholic extract of artichoke as four tablets per day) and "placebo group" (received placebo consisted of corn starch, lactose, and avicel as four tablets per day) for 12weeks. The biochemical and anthropometric parameters were determined before and after the intervention. The FTO-rs9939609 and the TCF7L2-rs7903146 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism. In carriers of A allele of the FTO-rs9939609, ALE supplementation resulted in a statistically significant decrease in serum triglyceride level compared with placebo (-19.11% vs. 10.83%; p<.05), with no other significant differences between the two groups. The TCF7L2-rs7903146 polymorphism showed no interaction with response to ALE (p>.05). These findings suggest that ALE supplementation may improve serum triglyceride level in A allele genotype of FTO-rs9939609 polymorphism in women with MetS.

Polymorphism rs3123554 in the cannabinoid receptor gene type 2 (CNR2) reveals effects on body weight and insulin resistance in obese subjects

BackgroundFew studies assessing the relationship between single nucleotide polymorphisms in CNR2 and obesity or its related metabolic parameters are available. ObjectiveTo investigate the influence of polymorphism rs3123554 in the CNR2 receptor gene on obesity anthropometric parameters, insulin resistance, and adipokines in subjects with obesity. DesignThe study population consisted of 1027 obese subjects, who were performed bioelectrical impedance analyses, blood pressure measurements, serial assessments of dietary intake during three days, and biochemical tests. ResultsGenotypes GG, GA, and AA were found in 339 (33.0%), 467 (45.5%), and 221 (21.5%) respectively. Body mass index, weight, fat mass, waist circumference, insulin, HOMA-IR, and triglyceride and leptin levels were higher in A-allele carriers as compared to non A-allele carriers. No differences were seen in these parameters between the GA and AA genotypes. There were no statistical differences in dietary intake. ConclusionThe main study finding was the association of the minor allele of the SNP rs3123554 in the CNR2 gene with body weight and triglyceride, HOMA-IR, insulin, and leptin levels.

The DRD2 Taq1A A1 Allele May Magnify the Risk of Alzheimer's in Aging African-Americans.

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys cognitive skills and the ability to perform the simplest tasks. More than 5 million Americans are afflicted with Alzheimer's; a disorder which ranks third, just behind heart disease and cancer, as a cause of death for older people. With no real cure and in spite of enormous efforts worldwide, the disease remains a mystery in terms of treatment. Importantly, African-Americans are two times as likely as Whites to develop late-onset Alzheimer's disease and less likely to receive timely diagnosis and treatment. Dopamine function is linked to normal cognition and memory and carriers of the DRD2 Taq1A A1 allele have significant loss of D2 receptor density in the brain. Recent research has shown that A1 carriers have worse memory performance during long-term memory (LTM) updating, compared to non-carriers or A2-carriers. A1carriers also show less blood oxygen level-dependent (BOLD) activation in the left caudate nucleus which is important for LTM updating. This latter effect was only seen in older adults, suggesting magnification of genetic effects on brain functioning in the elderly. Moreover, the frequency of the A1 allele is 0.40 in African-Americans, with an approximate prevalence of the DRD2 A1 allele in 50% of an African-American subset of individuals. This is higher than what is found in a non-screened American population (≤28%) for reward deficiency syndrome (RDS) behaviors. Based on DRD2 known genetic polymorphisms, we hypothesize that the DRD2 Taq1A A1 allele magnifies the risk of Alzheimer's in aging African-Americans. Research linking this high risk for Alzheimer's in the African-American population, with DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM, could pave the way for novel, targeted pro-dopamine homeostatic treatment.

Necrotizing enterocolitis and high intestinal iron uptake due to genetic variants.

BackgroundIntestinal iron is a nutritional compound, which is essential for enteric microbiota. We evaluated the hypothesis that polymorphisms, which are known modifiers of intestinal iron uptake in adults, are associated with necrotizing enterocolitis (NEC) in preterm infants.MethodsPreterm infants (birth weight below 1,500 g) were studied. Single-nucleotide polymorphisms with known effects on serum iron levels (rs1800562, rs1799945, and rs855791) were determined using PCR. The effects of polymorphisms on NEC surgery were tested by Mendelian randomization. Outcome data were compared with χ2-test, Fisher's exact test, t-test, and Cochran-Armitage test for trend and multiple logistic regression analysis.ResultsComplete genotyping data were available for 11,166 infants. High serum iron levels due to rs855791 genotype were associated with a significantly reduced risk of NEC surgery (odds ratio (OR) 0.265; 95% confidence interval (CI) 0.11-0.65; adjusted P=0.011). Carriers of the rs855791 A-allele not receiving prophylactic probiotics had a higher risk of NEC surgery (OR 1.12, 95% CI 1.08-1.70, nominal P=0.002). Prophylactic treatment with probiotics was associated with a reduced risk of NEC surgery in carriers of the rs855791 A-Allele. No differences were found with regard to other short- or long-term outcome data.ConclusionPolymorphisms inducing lower intestinal iron uptake like the rs855791 A-allele might be an underestimated risk factor for NEC.

Depression in early adolescence: Contributions from relational aggression and variation in the oxytocin receptor gene.

Interpersonal stress arising from relational aggression (RA)-the intentional effort to harm others via rejection and exclusion-may increase risk for depression in youth. Biological vulnerabilities related to the hormone oxytocin, which affects social behavior and stress responses, may exacerbate this risk. In a community sample of 307 youth (52% female; age range = 10-14 years), we tested whether (1) the association between RA and subsequent depressive symptoms was mediated through social problems and (2) a single nucleotide polymorphism (rs53576) in the oxytocin receptor gene (OXTR) moderated this indirect association between RA and depression, where GG homozygotes are predicted to be more sensitive to the effects of social problems than A-allele carriers. Youth-reported RA and depressive symptoms were measured using a structured interview and a questionnaire, respectively. DNA was extracted from saliva collected with Oragene kits. Consistent with the interpersonal theory of depression, the association between relational aggression and subsequent depressive symptoms was mediated by social problems. This indirect effect was further moderated by rs53576 genotype, such that GG homozygotes showed a stronger mediation effect than A-carriers. These results suggest that rs53576 variants confer vulnerability for depression within the context of interpersonal risk factors, such that youth with the GG genotype may be particularly sensitive to the social consequences resulting from RA.

Polymorphism rs3123554 in the cannabinoid receptor gene type 2 (CNR2) reveals effects on body weight and insulin resistance in obese subjects

BackgroundFew studies assessing the relationship between single nucleotide polymorphisms in CNR2 and obesity or its related metabolic parameters are available. ObjectiveTo investigate the influence of polymorphism rs3123554 in the CNR2 receptor gene on obesity anthropometric parameters, insulin resistance, and adipokines in subjects with obesity. DesignThe study population consisted of 1027 obese subjects, who were performed bioelectrical impedance analyses, blood pressure measurements, serial assessments of dietary intake during three days, and biochemical tests. ResultsGenotypes GG, GA, and AA were found in 339 (33.0%), 467 (45.5%), and 221 (21.5%) respectively. Body mass index, weight, fat mass, waist circumference, insulin, HOMA-IR, and triglyceride and leptin levels were higher in A-allele carriers as compared to non A-allele carriers. No differences were seen in these parameters between the GA and AA genotypes. There were no statistical differences in dietary intake. ConclusionThe main study finding was the association of the minor allele of the SNP rs3123554 in the CNR2 gene with body weight and triglyceride, HOMA-IR, insulin, and leptin levels.