Previous results from our genetic analyses using pedigrees from a French Canadian population suggested that the interval delimited by markers on chromosome 12, D12S86 and D12S378, was the most probable genomic region to contain a susceptibility gene for affective disorders. Association studies with microsatellite markers using a case/control sample from the same population (n = 427) revealed significant allelic associations between the bipolar phenotype and marker NBG6. Since this marker is located in intron 9 of the P2RX7 gene, we analyzed the surrounding genomic region for the presence of polymorphisms in regulatory, coding and intron/exon junction sequences. Twenty four (24) SNPs were genotyped in a case/control sample and 12 SNPs in all pedigrees used for linkage analysis. Allelic, genotypic or family-based association studies suggest the presence of two susceptibility loci, the P2RX7 and CaMKK2 genes. The strongest association was observed in bipolar families at the non-synonymous SNP P2RX7-E13A (rs2230912, P-value = 0.000708), which results from an over-transmission of the mutant G-allele to affected offspring. This Gln460Arg polymorphism occurs at an amino acid that is conserved between humans and rodents and is located in the C-terminal domain of the P2X7 receptor, known to be essential for normal P2RX7 function.
Sex differences in stress hormone functions are presumed to depend on sex hormones. And yet, surprisingly few psychoneuroendocrine studies actually assess within-sex variations of testosterone, estradiol, and progesterone when investigating sex-specific activities of the hypothalamic-pituitary-adrenal axis. In this methodological study of 204 healthy adults (60 men), we assessed whether cortisol profiles would differ between the sexes when unadjusted or adjusted for basal sex hormones among both sexes. Reactive cortisol was sampled using 6 saliva samples measured every 10-min as part of the Trier Social Stress Test that generally activates cortisol among men more than women. Diurnal cortisol was sampled over two days at (1) awakening, (2) 30-min thereafter, (3) 1400 h, (4) 1600 h, and (5) bedtime. Sex hormones were collected at baseline before the psychosocial stressor and on two occasions during diurnal cortisol assessment. Repeated-measures analysis of covariance controlled for key covariates in analyses unadjusted or adjusted for sex hormones. Results revealed that men had higher reactive cortisol than women in unadjusted analysis, but this sex difference was attenuated when adjusting for sex hormones. While diurnal cortisol showed no sex differences in unadjusted models, adjusting for sex hormones revealed that women have higher morning cortisol. Correlations using area under the curve formulae revealed intriguing sex-specific associations with progesterone in men and testosterone in women that we propose have implications for social and affective neuroscience. In summary, our results reveal that adjusting for sex hormones alters "sex-specific" reactive and diurnal cortisol profiles.
BACKGROUND
Biological sex differences and sociocultural gender diversity influence endocrine stress reactivity. Although numerous studies have shown that men typically activate stronger stress responses than women when exposed to laboratory-based psychosocial stressors, it is unclear whether sexual orientation further modulates stress reactivity. Given that lesbian, gay, and bisexual (LGB) individuals frequently report heightened distress secondary to stigma-related stressors, we investigated whether cortisol stress reactivity differs between LGB individuals and heterosexual individuals in response to a well-validated psychosocial stressor.
METHODS
The study population comprised 87 healthy adults (mean age, 25 years) who were grouped according to their biological sex and their gendered sexual orientation: lesbian/bisexual women (n = 20), heterosexual women (n = 21), gay/bisexual men (n = 26), and heterosexual men (n = 20). Investigators collected 10 salivary cortisol samples throughout a 2-hour afternoon visit involving exposure to the Trier Social Stress Test modified to maximize between-sex differences.
RESULTS
Relative to heterosexual women, lesbian/bisexual women showed higher cortisol stress reactivity 40 min after exposure to the stressor. In contrast, gay/bisexual men displayed lower overall cortisol concentrations throughout testing compared with heterosexual men. Main findings were significant while adjusting for sex hormones (estradiol-to-progesterone ratio in women and testosterone in men), age, self-esteem, and disclosure status (whether LGB participants had completed their “coming out”).
CONCLUSIONS
Our results provide novel evidence for gender-based modulation of cortisol stress reactivity based on sexual orientation that goes beyond well-established between-sex differences. This study raises several important avenues for future research related to the physiologic functioning of LGB populations and gender diversity more broadly.
Peripheral blood mononuclear cells (PBMCs) offer a significant promise for gene expression analyses as a substitute for tissues that are not easily accessible. The objective of this study was to validate the use of PBMCs for gene expression analysis as a marker of nutritional intervention as an alternative to skeletal muscle tissue (SMT) biopsies. We performed a transcriptome comparison of PBMCs versus SMT after an 8-week supplementation with n-3 polyunsaturated fatty acid (PUFA) in 16 obese and insulin-resistant subjects. Expression levels of 48,803 transcripts were assessed by the Human-6 v3 Expression BeadChips (Illumina, San Diego, CA). In SMT, 36,738 (75%) transcripts were detected, whereas 34,182 (70%) transcripts were detected in PBMCs. Further, 88% (32,341) of these transcripts were coexpressed in both tissues. Importantly, a strong correlation (r = 0.84, p < 0.0001) was observed between transcript expression levels of PBMCs and SMT after n-3 PUFA supplementation. In conclusion, PBMCs express the majority of transcripts expressed in SMT subsequent to n-3 PUFA supplementation and their expression levels are comparable. In the interest of practicalities and cost, these results support the use of PBMCs as a surrogate model for SMT gene expression in nutrigenomic studies. Further research on PBMC and SMT gene expression in response to other nutritional exposures is warranted.
Previous results from our genetic analyses using pedigrees from a French Canadian population suggested that the interval delimited by markers D12S86 and D12S378 on chromosome 12 was the most probable genomic region to contain a susceptibility gene for affective disorders. Here we present a more detailed genetic analysis of a 7.7 Mb genomic region located on 12q24.31. This region was saturated with 20 microsatellite markers to refine the candidate region and linkage analysis performed in 41 families from the Saguenay-Lac-St-Jean (SLSJ) region of Quebec. The results of two point parametric analysis using MFLINK supported the presence of a susceptibility locus on chromosome 12q24.31. Association studies with microsatellite markers using a case/control sample from the same population (n = 401) and analyzed with CLUMP revealed significant allelic associations between the bipolar phenotype and markers NBG6 (P = 0.008) and NBG12 (P < 10(-3)). According to these results, we investigated candidate genes in the NBG12 area. We analyzed 32 genes for the presence of polymorphisms in coding sequences and intron/exon junctions and genotyped 22 non-synonymous SNPs in the SLSJ case/control sample. Two uncommon polymorphisms (minor allele frequency < or = 0.03) found in KIAA1595 and FLJ22471 genes, gave P-values below 0.05 with the T1 statistic. Moreover, using haplotype analysis, a nearly significant haplotypic association was observed at the HM74 gene. These results do not give strong support for a role in the susceptibility to bipolar disorder of any of these genes analyzed. However, the significance of rare polymorphisms should be explored by further analyses.
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