Exploring sex differences: insights into gene expression, neuroanatomy, neurochemistry, cognition, and pathology

Increased knowledge about sex differences is important for development of individualized treatments against many diseases as well as understanding behavioral and pathological differences. This review summarizes sex chromosome effects on gene expression, epigenetics, and hormones in relation to the brain. We explore neuroanatomy, neurochemistry, cognition, and brain pathology aiming to explain the current state of the art. While some domains exhibit strong differences, others reveal subtle differences whose overall significance warrants clarification. We hope that the current review increases awareness and serves as a basis for the planning of future studies that consider both sexes equally regarding similarities and differences

Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy

Background: Tamoxifen is frequently used for the treatment of hormone receptor positive breast cancer (BC). Mainly CYP2D6 is responsible for the transformation to therapeutically active metabolites, but CYP2C19, CYP2C9 and CYP2B6 also are involved. We investigated the impact of polymorphisms within the genes encoding these CYP enzymes on the relapse-free time (RFT) in patients with BC. Methods: Ninety-nine patients with hormone receptor positive BC, who had undergone adjuvant tamoxifen therapy, were genotyped for seventeen common variants within the genes encoding CYP2D6, CYP2C9, CYP2C19 and CYP2B6 using TaqMan and PCR-RFLP technology. Kaplan-Meier and Cox regression analyses were performed to elucidate the impact of genetic variants on RFT. Furthermore, CYP2D6 metabolic activity was determined in a subset of 50 patients by assessing dextromethorphan/dextrorphan urinary excretion ratios. CYP2D6 activity was compared to the CYP2D6 allelic combinations to evaluate the predictive value of the CYP2D6 genotyping results on phenotype. Results: Although a trend toward longer RFTs in carriers of CYP2D6 allele combinations encoding for extensive and ultrafast metabolizer phenotypes was observed, none of the investigated genetic variants had a statistically significant impact on RFT. The combined analysis of five major CYP2D6 variants was useful for the discrimination between poor and non-poor metabolizers. Conclusions: Comprehensive CYP2D6 genotyping has a good predictive value for CYP2D6 activity. Common variants in CYP2C9, CYP2C19, CYP2D6, and CYP2B6 did not have a significant impact on the RFT in this cohort of patients with BC

Migraine, inflammatory bowel disease and celiac disease: A Mendelian randomization study

Objective: To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease. Background: Migraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition. Methods: Linkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed. Results: Migraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99-1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99-1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96-1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79-1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00-1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92-0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02-1.29, p = 0.025). However, the results were not significant after multiple testing correction. Conclusions: We found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes. Keywords: Mendelian randomization; celiac disease; gastrointestinal disease; genetic correlation; inflammatory bowel disease; migraine

CYP2C19 and CYP2C9 : New aspects of pharmacogenetics and transcriptional regulation

Cytochrome P450s (CYPs) are responsible for approximately 75% of the phase I-dependent drug metabolism. Several important polymorphisms in these enzymes are known to significantly affect the individual drug response. CYP2C9 and CYP2C19 are polymorphically expressed CYP family members which are responsible for the metabolism of many different clinically important drugs, e.g. anticoagulants, antidepressants and antiulcer drugs. This thesis focuses on novel aspects with regard to the regulation of CYP2C9 and CYP2C19 gene expression. The influence of the recently found common allele variant CYP2C19*17 on CYP2C19 enzyme activity towards two CYP2C19 substrates was investigated in the frame of two pharmacokinetic in vivo studies. The studies compared the single-dose pharmacokinetics of omeprazole and the steady-state kinetics of escitalopram in healthy CYP2C19*17/*17 carriers with the pharmacokinetic outcome obtained for CYP2C19 wild-type subjects. While no significant differences in the metabolic efficacy were observed for escitalopram, CYP2C19*17/*17 subjects showed significantly lower plasma levels of omeprazole compared to CYP2C19 wild type carriers. This observation suggests that CYP2C19*17/*17 carriers might be at a higher risk for therapy failure during treatment with proton pump inhibitors. The transcriptional regulation of CYP2C9 and CYP2C19 gene expression by GATA transcription factors and by estrogen receptor α (ERα) was investigated in vitro. In the proximal promoter regions of both the CYP2C9 and the CYP2C19 gene, two adjacent putative GATA-binding sites with an ER-binding half-site in their vicinity were predicted in silico and initially studied by luciferase gene reporter assay. HepG2 and Huh-7 hepatoma cells were transfected with CYP2C9 or CYP2C19 promoter fragment carrying pGL3basic-constructs along with expression vectors for the transcription factors GATA-2, GATA-4, or ERα. Luciferase activities driven by wild-type CYP2C19 or CYP2C9 promoter were highly increased by GATA-4 and GATA-2 in both cell lines, whereas mutations introduced into the GATA binding sites or the co-transfection of the GATA-4 antagonist FOG-2 caused a significant loss of luciferase activity. In contrast, treatment with estradiol derivatives of ERα-transfected cells caused a significant inhibition of CYP2C19 and CYP2C9 promoter activity that was antagonized by site-directed mutagenesis of the putative ERα-binding half-sites. Additionally, estradiol derivatives significantly suppressed both CYP2C9 and CYP2C19 mRNA expression in human hepatocytes, as measured by real time PCR. Electrophoretic mobility shift assays revealed sequence-specific binding of GATA-4, GATA-6, and ERα to the two adjacent GATA binding sites and to the predicted ER binding half sites, respectively. ChIP assay in the cultured cells furthermore confirmed the association of both GATA-4 and ERα with CYP2C9 and CYP2C19 gene promoter. In conclusion, we have established novel mechanisms of CYP2C9 and CYP2C19 transcriptional regulation that involve transcription factors from the GATA family and estrogen receptor . The estrogen mediated regulation may explain the clinically observed inhibitory effects of oral contraceptives on CYP2C19 and CYP2C9 activity

Challenges in Analyzing Functional Epigenetic Data in Perspective of Adolescent Psychiatric Health

The formative period of adolescence plays a crucial role in the development of skills and abilities for adulthood. Adolescents who are affected by mental health conditions are at risk of suicide and social and academic impairments. Gene-environment complementary contributions to the molecular mechanisms involved in psychiatric disorders have emphasized the need to analyze epigenetic marks such as DNA methylation (DNAm) and non-coding RNAs. However, the large and diverse bioinformatic and statistical methods, referring to the confounders of the statistical models, application of multiple-testing adjustment methods, questions regarding the correlation of DNAm across tissues, and sex-dependent differences in results, have raised challenges regarding the interpretation of the results. Based on the example of generalized anxiety disorder (GAD) and depressive disorder (MDD), we shed light on the current knowledge and usage of methodological tools in analyzing epigenetics. Statistical robustness is an essential prerequisite for a better understanding and interpretation of epigenetic modifications and helps to find novel targets for personalized therapeutics in psychiatric diseases

Volumetric Differences in Cerebellum and Brainstem in Patients with Migraine: A UK Biobank Study

Background: The cerebellum and the brainstem are two brain structures involved in pain processing and modulation that have also been associated with migraine pathophysiology. The aim of this study was to investigate possible associations between the morphology of the cerebellum and brainstem and migraine, focusing on gray matter differences in these brain areas. Methods: The analyses were based on data from 712 individuals with migraine and 45,681 healthy controls from the UK Biobank study. Generalized linear models were used to estimate the mean gray matter volumetric differences in the brainstem and the cerebellum. The models were adjusted for important biological covariates such as BMI, age, sex, total brain volume, diastolic blood pressure, alcohol intake frequency, current tobacco smoking, assessment center, material deprivation, ethnic background, and a wide variety of health conditions. Secondary analyses investigated volumetric correlation between cerebellar sub-regions. Results: We found larger gray matter volumes in the cerebellar sub-regions V (mean difference: 72 mm3, 95% CI [13, 132]), crus I (mean difference: 259 mm3, 95% CI [9, 510]), VIIIa (mean difference: 120 mm3, 95% CI [0.9, 238]), and X (mean difference: 14 mm3, 95% CI [1, 27]). Conclusions: Individuals with migraine show larger gray matter volumes in several cerebellar sub-regions than controls. These findings support the hypothesis that the cerebellum plays a role in the pathophysiology of migraine