Associations between the oxytocin receptor gene (OXTR) and "mind-reading" in humans--an exploratory study.

BACKGROUND/AIMS: The application of intranasal oxytocin enhances facial emotion recognition in normal subjects and in subjects with autism spectrum disorders (ASD). In addition, various features of social cognition have been associated with variants of the oxytocin receptor gene (OXTR). Therefore, we tested for associations between mind-reading, a measure for social recognition and OXTR polymorphisms. METHODS: 76 healthy adolescents and young adults were tested for associations between OXTR rs53576, rs2254298, rs2228485 and mind-reading using the "Reading the Mind in the Eyes Test" (RMET). RESULTS: After Bonferroni correction for multiple comparisons, rs2228485 was associated with the number of incorrect answers when subjects evaluated male faces (P =0.000639). There were also associations between OXTR rs53576, rs2254298 and rs2228485 and other RMET dimensions according to P <0.05 (uncorrected). CONCLUSION: This study adds further evidence to the hypothesis that genetic variations in the OXTR modulate mind-reading and social behaviour.

Associations between the oxytocin receptor gene (OXTR) and affect, loneliness and intelligence in normal subjects.

Associations of oxytocin receptor gene (OXTR) variants and autism spectrum disorders (ASD) have been reported in earlier studies; in one of the studies associations with IQ and daily living skills were found additionally. Variations of the oxytocin receptor gene might also regulate affect, attachment and separation beyond the diagnostic borders of autism. We tested hypotheses of associations between positive and negative affects and social and emotional loneliness (285 adults), IQ (117 adolescents) and polymorphisms of the oxytocin receptor gene (OXTR rs53576, rs2254298 and rs2228485) in normal subjects. Individuals with the oxytocin OXTR rs53576 A/A genotype showed lower positive affect scores (F=5.532, df=1; p=0.019). This effect was restricted to males (F=13.098, df=1; p=0.00047). Haplotypes constructed with the three markers were associated with positive affect (p=0.0012), negative affect (p<0.0001) and emotional loneliness (p<0.0001). Non-verbal intelligence was significantly reduced in rs53576 A/A adolescents (T=2.247, p=0.027). Our findings support a role for the oxytocin receptor haplotypes in the generation of affectivity, emotional loneliness and IQ.

Alcohol consumption is associated with an interaction between DRD2 exon 8 A/A genotype and self-directedness in males.

BACKGROUND: Both reduced postsynaptic dopamine D(2) receptor function and the character variable self-directedness (SDD) are related to the level of alcohol consumption. We examined for interactions between DRD2 exon 8(rs6276), a polymorphism which has been associated with various alcohol-related phenotypes, SDD and alcohol consumption. METHODS: A total of 144 male and 186 female probands with alcohol dependence or abuse diagnoses and without were included in the study. All subjects were assessed with the alcohol section of the Semi-Structured Assessment for the Genetics of Alcoholism and the Temperament and Character Inventory. RESULTS: Male probands with A/A genotype reported significantly higher alcohol consumption in a typical week (ANOVA; p = 0.024); those with A/A genotype and low SDD showed particularly high consumption levels (interaction DRD2 x SDD: p = 0.019). Alcohol dependence/abuse (DSM-IV) but not nicotine dependence was also relevant for higher alcohol consumption (trend: p = 0.052). In the female group, only alcohol disorders predicted alcohol consumption. CONCLUSIONS: Our findings support a role for a gene-personality interaction of DRD2 exon 8 x SDD in alcohol consumption in males.

Analysis of the novel factor X gene mutation Glu51Lys in two families with factor X-Riyadh anomaly.

Two families with 'factor X(FX)-Riyadh' have been identified (one of them related to the originally reported family). Affected members of both families exhibit prolongation in prothrombin time (PT) with normal partial thromboplastin time (PTT) and low assay levels of FX, when measured by PT-based assay. They do not have clinical bleeding diathesis, regardless of the PT prolongation. FX genes of the affected family members were analyzed by sequence analysis. A novel missense mutation in exon 4 of the FX gene, which causes the Glu51Lys substitution in the first epidermal growth factor-like domain of FX was found. The Glu51Lys mutation represents a type II mutation with low FX coagulant activity in the extrinsic pathway and normal FX antigen levels. This mutation may result in disruption of the predicted H-bonding between residue Glu51 of FX and the Asn199 residue of the tissue factor (TF) in the FX/TF/factor VIIa ternary complex, producing the phenotype 'FX deficiency Riyadh', with prolonged PT and normal PTT.

The FXIIIVal34Leu, common and risk factors of venous thrombosis in early middle-age Costa Rican patients.

In this study, eight common polymorphisms associated with venous thrombosis (VT) and thrombophilia factors were analyzed in a Costa Rican case-control study. With the use of polymerase chain reaction (PCR) methods the polymorphisms were detected in 120 patients and 133 controls (mean age <40 years old). It was concluded that a high level of fibrinogen, antiphospholipid antibodies, family history, and the genotype 34LeuLeu of FXIII OR 0.42 (0.20-0.89) showed a significant effect on the risk of VT. Associations between the risk of VT and genetic polymorphisms have been established. Some of these polymorphisms are highly prevalent in Caucasians, but there is a significant geographic variation in their prevalence among different populations. The results of this study support the protective effect of FXIII Val34Leu polymorphism in VT. These findings are consistent with previous reports that included other populations.

Common polymorphisms and cardiovascular factors in patients with myocardial infarction of Costa Rica

Eight common polymorphisms of known myocardial infarction (MI)risk factors (factor V Leiden (FVL), factor V HR2 (FVHR2), factor II 20210G>A (FII), factor VII IVS7 (FVII IVS7), factor VII Arg353Gln (FVII), factor XIII Val34Leu (FXIII), Methylenetetrahydrofolate reductase C677T (MTHFR), Angiotensin Converting Enzyme (ACE))and environmental risk factors were analyzed in a MI patients of Costa Rica.This case-control study included 186 MI subjects,95 of them <45 years and 201 age and sex matched controls.With the use of PCR method the polymorphisms were detected and through interviews additional information was collected.Hypercholesterolemia and smoking were associated with a significant risk in younger patients.High fibrinogen level was an important risk factor and interaction with smoking was detected.Mainly,the genotype 34LeuLeu of FXIII showed significant protective effect,(OR 0.32,95%CI 0.13-0.80)while the other polymor- phisms showed no significant difference between the cases and the controls.Carriers of FVII (OR 2.75,95%CI 1.07-7.02)and FXIII (OR 4.20,95%CI 2.03-8.67)polymorphisms showed interaction with fibrinogen in the sta- tistical analysis.It was concluded that there was an important interaction between the common risk factors and the polymorphisms (FVII;FXIII)in the development of MI.This is one of the first reports in a Latin-American population dealing with these molecular markers and MI.

Se estudiaron ocho polimorfismos comunes asociados como factores de riesgo para el infarto al miocardio (IM):factor V Leiden (FVL),factor VHR2 (FVHR2), factor II 20210G>A (FII),factor VII IVS7 (FVII IVS7), factor VIIArg353Gln (FVII),factor XIIIVal34Leu (FXIII), metilentetrahidrofolato reductase C677T (MTHFR), enzima convertidora de la angiotensina (ACE) y factores ambientales de riesgo,en pacientes costarricenses.Este es un estudio de casos y controles,donde participan 186 pacientes,95 de ellos con edades <45 años y 201 sujetos controles.Se utilizó la técnica de reacción en cadena de la polimerasa (PCR)y por medio de entrevistas personales se recolectó información epidemiológica adicional.Se encontró que la hipercolesterolemia y el fumado estan asociados como factores de riesgo en los pacientes jóvenes.Niveles elevados del fibrinógeno fueron detectados como un factor de riesgo importante y se observo interacción entre fumado y estos valores aumentados de fibrinógeno. El genotipo 34LeuLeu del FXIII presentó un efecto protector significante mientras que los otros polimorfimos estudiados no mostraron diferencia estadísticamente significativa entre los casos y controles. Los polimorfismos del FVII y FXIII demostraron interación con el fibrinógeno,según el análisis estadístico aplicado. Se evidencia, la interación entre factores de riesgo común y ciertos polimorfismos (FVII;FXIII)en la patogénesis del IM.Este es uno de los primeros informes sobre estos marcadores moleculares y su asociación con IM en una población latinoamericana.

Negative perceived paternal parenting is associated with dopamine D2 receptor exon 8 and GABA(A) alpha 6 receptor variants: an explorative study.

Twin studies suggest a genetic influence upon perceived parenting. The D(2) dopaminergic receptor is involved in the modulation of social behaviors, and might influence parenting and its perception. A polymorphism (E8) in exon 8 of the D(2) receptor gene (DRD2) has been previously associated with alcoholism-related phenotypes. Similarly, the Pro385Ser variant of GABRA6, the polymorphic gene for GABA(A) receptor alpha6 subunit, has been associated with alcohol- and depression-related traits; and rat pups maintained a more immature GABAR phenotype after brief separation distress. The relationships among DRD2 (E8) and GABRA6 (Pro385Ser) polymorphisms, and perceived parenting were studied here. The association of DRD2 (E8) and GABRA6 (Pro385Ser) genotypes and perceived parental rearing behavior (short-EMBU; questionnaire concerning own memories concerning upbringing) were determined in 207 unrelated adults using multivariate analysis of variance. Temperaments (Temperament and Character Inventory; TCI) were included as covariates. Probands with DRD2 (E8) A/A genotype showed higher scores for father rejection (P = 0.011), parents overprotection (P = 0.021), and father overprotection (P = 0.016) in the total group. An interaction between DRD2 and GABRA6 genotypes on father rejection (P = 0.010) and parents rejection (P = 0.030) was also observed. Further analyses showed that these associations were restricted to the female subgroup only; however, secondary gender-specific analyses were not corrected for multiple testing. Our findings support a role for DRD2 (E8) and GABRA6 (Pro385Ser) in perceived parenting.

Common polymorphisms and cardiovascular factors in patients with myocardial infarction of Costa Rica.

Eight common polymorphisms of known myocardial infarction (MI) risk factors (factor V Leiden (FVL), factor V HR2 (FVHR2), factor II 20210G > A (FII), factor VII IVS7 (FVII IVS7), factor VII Arg353Gln (FVII), factor XIII Va134Leu (FXIII), Methylenetetrahydrofolate reductase C677T (MTHFR), Angiotensin Converting Enzyme (ACE)) and environmental risk factors were analyzed in a MI patients of Costa Rica. This case-control study included 186 MI subjects, 95 of them < or = 45 years and 201 age and sex matched controls. With the use of PCR method the polymorphisms were detected and through interviews additional information was collected. Hypercholesterolemia and smoking were associated with a significant risk in younger patients. High fibrinogen level was an important risk factor and interaction with smoking was detected. Mainly, the genotype 34LeuLeu of FXIII showed significant protective effect, (OR 0.32, 95% CI 0.13-0.80) while the other polymorphisms showed no significant difference between the cases and the controls. Carriers of FVII (OR 2.75, 95% CI 1.07-7.02) and FXIII (OR 4.20, 95% CI 2.03-8.67) polymorphisms showed interaction with fibrinogen in the statistical analysis. It was concluded that there was an important interaction between the common risk factors and the polymorphisms (FVII; FXIII) in the development of MI. This is one of the first reports in a Latin-American population dealing with these molecular markers and MI.

[Homocysteinemia and its relationship with the methylentetrahydrofolate reductase polymorphism in various ethnic groups from western Venezuela]. / La homocisteinemia y su relación con el polimorfismo de la metilentetrahidrofolato reductasa en varios grupos etnicos del occidente de Venezuela.

The prevalence of hyperhomocysteinemia and C677T MTHFR polymorphism was studied in various ethnic groups from Western Venezuela (60 Wayuu Indians, 42 italian immigrants and 77 Venezuelan mestizos) in relation with the prevalence of hyperhomocysteinemia and the C677T MTHFR polymorphism. Homocysteinemia was determined by polarized fluorescence immunoassay in an IMX system, serum folate was measured by radioimmunoanalysis and the MTHFR genotype was determined by PCR and restriction analysis. Hyperhomocysteinemia was defined as a value over 2 SD above the mean value for normal MTHFR (CC677) in each group. The prevalence of MTHFR variants (C677T and 677TT) was elevated in all ethnic groups (78% among the wayuu, 76% among Italians and 63% among mestizos) with a significant association between the concentrations of homocysteine and the levels of serum folate among the wayuu (p < 0.0001) and the mestizos (p < 0.001) only. Hyperhomocysteinemia was associated with MTHFR variants in 23% of the wayuu (OR: 6.17, CI 95: 0.74-51.36), 9.5% of the Italians (OR: 0.93, CI 95: 0.085-10.10) and 20.7 of the Venezuelans mestizos (OR: 5.2, CI 95: 1.08-24.90, p > 0.03). There was no relationship between hyperhomocysteinemia and folate deficiency in any of the groups studied. In conclusion, despite a high prevalence of C677T MTHFR variants in these ethnic groups of western Venezuela, the lack of no evidence of hyperhomocysteinemia combined with folate deficiency may imply that the nutritional status of these groups plays an important role in the control of hyperhomocysteinemia as a risk factor for cardiovascular disease.

Decrease of carotid intima-media thickness in patients at risk to cerebral ischemia after supplementation with folic acid, Vitamins B6 and B12.

OBJECTIVE: Hyperhomocysteinemia is associated with atherosclerotic risk. Although vitamins can lower homocysteine (Hcy), information about effects on atherosclerosis is scarce. METHODS: We used carotid intima-media thickness (IMT) as an accepted marker of atherosclerotic changes. Fifty patients (60 +/- 8 years) with IMT> or =1 mm were included. In a double blind, randomized trial they received daily 2.5 mg folic acid, 25 mg Vitamin B6, and 0.5mg Vitamin B12 or placebo for 1 year. RESULTS: In the treatment group, Hcy decreased from 10.50 +/- 3.93 to 6.56 +/- 1.53 micromol/l (P < 0.0001), whereas it remained unchanged in the placebo group (10.76 +/- 2.36 versus 10.45+/-3.30 micromol/l). IMT decreased from 1.50 +/- 0.44 to 1.42 +/- 0.48 mm (P = 0.034) in the treatment group, whereas it increased from 1.47 +/- 0.57 to 1.54 +/- 0.71 mm in the placebo group. The mean individual changes of IMT between both groups differed significantly (-0.08 +/- 0.17 versus 0.07 +/- 0.25 mm, P = 0.019). Multiple regression analysis revealed that the observed effect on IMT depended only on medication. CONCLUSIONS: Vitamin supplementation significantly reduces IMT in patients at risk. This effect is independent of Hcy concentration.

Interaction between factor V Leiden and serum LDL cholesterol increases the risk of atherosclerosis.

OBJECTIVES: We investigated the association between the factor V Leiden gene variant and carotid atherosclerosis in a cross-sectional study and explored possible associations between this gene variant and coronary artery disease (CAD) in a case-control study. METHODS: The presence (n=1696) or absence (n=703) of carotid atherosclerosis were sonographically assessed among participants of the population-based Study of Health in Pomerania (SHIP). The case-control study included 1021 patients with severe CAD and 2791 healthy SHIP participants. The factor V Leiden gene variant was determined by PCR and MnlI digestion. RESULTS: Multivariable analyses revealed no independent association between the factor V Leiden gene variant per se and carotid atherosclerosis or CAD. In the cross-sectional study, there was an interaction between the factor V Leiden gene variant and serum LDL cholesterol in non-diabetics with respect to the risk of carotid atherosclerosis. In the case-control study a similar interaction was found for CAD. In both studies the atherosclerotic risk increased with rising serum LDL cholesterol concentrations in carriers of the factor V Leiden gene variant. CONCLUSION: The co-existence between the factor V Leiden gene variant and high serum LDL cholesterol is independently associated with the risk of atherosclerosis.

Clinical phenotypes and factor VII genotype in congenital factor VII deficiency.

To investigate the relationship between clinical phenotype, clotting activity (FVIIc) and FVII genotype, a multi-center study of factor VII (FVII) congenital deficiency with centralized genotyping and specific functional assays was carried out. FVII mutations characterized in patients (n=313) were extremely heterogeneous (103 different, 22 novel). Clinical phenotypes ranged from asymptomatic condition, including 15 homozygotes and 14 double heterozygotes, to patients with a severe disease characterized by life-threatening and disabling symptoms (CNS, GI bleeding and hemarthrosis) strongly associated with an early age of presentation. Based on type and number of symptoms we classified 90 'severe' (median FVIIc 1.4%, IQR [Interquartile Range] 0.9-3.8), 83 'moderate' (FVIIc 3%, IQR 1-21.7), and 140 'mild' bleeders (FVIIc 14%, IQR 3-31). The significantly different FVIIc levels, and the decreasing prevalence of homozygotes or double heterozygotes among severe (98%), moderate (84%) and mild (56%) bleeders, further support our classification. The excess of females among moderate bleeders (female/male ratio = 2.6) is attributable to menorrhagia. There was no evidence for modulation of clinical features by frequent functional polymorphisms. Homozygotes for the same mutation (Ala294Val; 11125delC) with similar FVIIc and FXa generation levels, showed striking differences in clinical phenotypes. Our study depicts the ample clinical picture of this rare disorder, proposes a severity classification and provides arguments for the early management of the disease in the severe cases. Genotype-phenotype relationships indicate the presence of major environmental and/or extragenic components modulating expressivity of FVII deficiency.

Homozygous Factor X gene mutations Gly380Arg and Tyr163delAT are associated with perinatal intracranial hemorrhage.

Intracranial hemorrhage (ICH) is a severe complication of Factor X (FX) deficiency. We report 6 homozygous patients with central nervous system (ICH) bleeds. Five patients are homozygous for the mutation Gly380Arg and one for the novel deletion Tyr163delAT. We describe the association of these mutations with ICH bleeding.

Influence of factor V HR2 on thrombin generation and clinical manifestation in rare bleeding disorders.

In this study we investigated the influence of the presence of the factor V HR2 haplotype, defined by the factor V gene mutation H1299R (FV(HR2)), on thrombin generation. Measurements were performed in platelet-poor plasma of individuals with factor V(HR2) or factor V(Leiden) in comparison to a control group carrying none of these mutations. Coagulation was triggered by low concentrations of recombinant tissue factor in the presence of activated protein C. Thrombin generation was monitored by a fluorogenic substrate. The endogenous thrombin potential was calculated from the obtained curves. As a result we observed an increased thrombin generation both for individuals heterozygous and homozygous for FV(HR2). The level of endogenous thrombin potential is in the same range as in samples of patients heterozygous or homozygous for FV(Leiden). The results indicate that FV(HR2) plays a role as a risk factor for venous thrombosis in homozygous patients through an increased thrombin generation. The association between different clinical manifestations in individuals with FVII deficiency and endogenous thrombin potential and the presence of FV(HR2) was studied.

Prevalence of eight molecular markers associated with thrombotic diseases in six Amerindian tribes and two African groups of Costa Rica.

Individuals belonging to six different Amerindian tribes and two African groups of Costa Rica were genotyped for factor V Leiden (FV), factor V haplotype HR2 (FV HR2), Factor II 20210G>A (FII), the methylenetetrahydrofolate reductase (MTHFR), factor VII polymorphisms (FVII IVS7, FVII R353Q), factor XIII (FXIII V34L), and the insertion/deletion (I/D) polymorphism of the gene of angiotensin converting enzyme (ACE). Clear differences in the prevalence were found and are first reported. The prevalence of some of the established genetic risk factors was low in Amerindians of Costa Rica (ACE) or even absent (FVL, FII), and others (MTHFR, FVHR2) had an extremely high prevalence. People of African origin carried very rare FVL or FII polymorphisms, but the DD genotype of ACE is the highest reported. Concerning the protective factors, the QQ genotype of FVII R353Q was absent in Amerindians, but the protective 7/7 genotype of FVII IVS7 frequently found. Novel alleles of FVII IVS7 (4, 8, and 9 monomers) were found. Intertribal heterogeneity was observed that may reflect the evolutionary history of these tribal groups and their admixture with other populations.

Factor V Leiden and the risk of stillbirth in a German population.

An association between the factor V Leiden variant and an increased risk of pregnancy loss has been reported. Most previous studies were performed with clinically recruited patients and controls. This approach may cause selection bias. The present analysis was performed with the aim to investigate the association between the factor V Leiden mutation and the risk of stillbirth in a population-based sample. The Study of Health in Pomerania (SHIP) is a survey that was carried out in North East Germany. A random sample from the population aged 20 to 79 years was taken. The total SHIP population comprised 4,310 participants. The presence of the factor V Leiden variant was determined by PCR and Mnl I digestion. The presence of the factor V Leiden variant was neither associated with the number of pregnancies nor with the number of children per women. Data from 1,768 females who had at least one pregnancy with known outcome was available for the present analysis. Seventy-three women (4.1%) reported at least one stillbirth. Women with and without the factor V Leiden mutation did not differ with respect to the number of women with at least one stillbirth (OR for factor V Leiden variant 1.57; 95%-CI 0.76 - 3.25). Furthermore, the number of women with two or more stillbirths, the number of stillbirths per affected woman and the number of stillbirths per number of pregnancies per woman was similar between both genotype groups. In conclusion, there is no association between the factor V Leiden mutation and the risk of stillbirth in a representative population sample.

Platelet receptor and clotting factor polymorphisms as genetic risk factors for thromboembolic complications in heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an immune mediated adverse reaction to heparin treatment often associated with limb- and/or life-threatening thromboembolic complications (TECs). Presently, no prognostic marker has been identified that allows differentiation between mildly (isolated thrombocytopenia) and severely (TECs) affected patients. This study assesses the impact of platelet glycoprotein- and clotting factor polymorphisms in HIT-patients with isolated thrombocytopenia compared to HIT-patients with TECs. Sixty-three HIT-patients with isolated thrombocytopenia and 79 HIT-patients with HIT-related TECs were genotyped for GPIIb-IIIa polymorphisms (HPA-1, HPA-3), GPIa-IIa polymorphisms (HPA-5, GPIaC807T), GPIb-IX-V polymorphisms (HPA-2, Kozak-5, VNTR), and clotting factor polymorphisms (FV-Leiden R506Q, prothrombin PT-G20210A and MTHFR C677T). Women more often presented with TECs than men (P = 0.04). No differences in genotype frequencies could be seen on comparing HIT-patients with and without TECs. Analysing men and women separately, the C allele of the Kozak polymorphism was overrepresented in men who developed TECs (P = 0.034). The enhanced risk of women to develop HIT-associated TECs remains unexplained but it is potentially important in view of recent data on sex-hormone related changes of haemostasis. There was no correlation between platelet glycoprotein- and clotting factor polymorphisms and the risk to develop HIT-associated TECs. An association between the development of TECs and the Kozak-5C allele could be seen among male patients. However, this would need to be assessed in further larger studies. Most likely, the high levels of thrombin generation during acute HIT are so procoagulant that less pronounced risk factors such as polymorphisms are overshadowed.