Elevated 17β-Estradiol Protects Females from Influenza A Virus Pathogenesis by Suppressing Inflammatory Responses

Studies of the 1918 H1N1 influenza pandemic, the H5N1 avian influenza outbreak, and the 2009 H1N1 pandemic illustrate that sex and pregnancy contribute to severe outcome from infection, suggesting a role for sex steroids. To test the hypothesis that the sexes respond differently to influenza, the pathogenesis of influenza A virus infection was investigated in adult male and female C57BL/6 mice. Influenza infection reduced reproductive function in females and resulted in greater body mass loss, hypothermia, and mortality in females than males. Whereas lung virus titers were similar between the sexes, females had higher induction of proinflammatory cytokines and chemokines, including TNF-α, IFN-γ, IL-6, and CCL2, in their lungs than males. Removal of the gonads in both sexes eliminated the sex difference in influenza pathogenesis. Manipulation of testosterone or dihydrotestosterone concentrations in males did not significantly impact virus pathogenesis. Conversely, females administered high doses of estradiol had a ≥10-fold lower induction of TNF-α and CCL2 in the lungs and increased rates of survival as compared with females that had either low or no estradiol. The protective effects of estradiol on proinflammatory cytokines and chemokines, morbidity, and mortality were primarily mediated by signaling through estrogen receptor α (ERα). In summary, females suffer a worse outcome from influenza A virus infection than males, which can be reversed by administration of high doses of estradiol to females and reflects differences in the induction of proinflammatory responses and not in virus load

A whole genome association study of neuroticism using DNA pooling.

We describe a multistage approach to identify single nucleotide polymorphisms (SNPs) associated with neuroticism, a personality trait that shares genetic determinants with major depression and anxiety disorders. Whole genome association with 452 574 SNPs was performed on DNA pools from approximately 2000 individuals selected on extremes of neuroticism scores from a cohort of 88 142 people from southwest England. The most significant SNPs were then genotyped on independent samples to replicate findings. We were able to replicate association of one SNP within the PDE4D gene in a second sample collected by our laboratory and in a family-based test in an independent sample; however, the SNP was not significantly associated with neuroticism in two other independent samples. We also observed an enrichment of low P-values in known regions of copy number variations. Simulation indicates that our study had approximately 80% power to identify neuroticism loci in the genome with odds ratio (OR)>2, and approximately 50% power to identify small effects (OR=1.5). Since we failed to find any loci accounting for more than 1% of the variance, the heritability of neuroticism probably arises from many loci each explaining much less than 1%. Our findings argue the need for much larger samples than anticipated in genetic association studies and that the biological basis of emotional disorders is extremely complex

Genome-wide linkage scan for exercise participation in Dutch sibling pairs.

This study was aimed at identifying the genomic loci linked to exercise participation in males and females. Cross-sectional exercise data of twins and siblings (18-50 years) were used from the Netherlands Twin Registry. The sample consisted of 1432 genotyped sibling pairs from 622 families (1120 sibling pairs were genotyped on all chromosomes). Exercise participation (no/yes, based on a cutoff criterion of four metabolic equivalents and 60 min weekly) was assessed by survey. Genotyping was based on 361 markers and an average marker density of 10.6 cM. Identical by descent status was estimated for a 1 cM grid. A variance components-based sex-limited linkage scan was carried out for exercise participation. The heritability of exercise participation in males was 68.5% and in females 46.3%. The genetic overlap was estimated at 0.32, indicating that partly different genes affect exercise in the two sexes. Suggestive linkage was found in all subjects on chromosome 19p13.3 (LOD=2.18). Although sex differences in linkage effect were not significant, mainly females contributed to the suggestive linkage. The 19p13.3-13.2 region harbors a number of genes related to muscle performance and muscle blood flow, which might affect exercise behavior through exercise ability. Most likely, a large number of genes with each small effects affect exercise participation in males and females. Large collaborative samples are needed to detect these effects