Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk

Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, resequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's χ2 = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's χ2 = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (π = 0.0072, Tajima's D= 3.31, 14 SNPs) and the Japanese (π = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer. © 2008 Ding et al

Developmental control of plasma leptin and adipose leptin messenger ribonucleic acid in the ovine fetus during late gestation: role of glucocorticoids and thyroid hormones

In developed countries, the increasing incidence of obesity is a serious health problem. Leptin exposure in the perinatal period affects long-term regulation of appetite and energy expenditure, but control of leptin production in utero is unclear. This study investigated perirenal adipose tissue (PAT) and placental leptin expression in ovine fetuses during late gestation and after manipulation of plasma glucocorticoid and thyroid hormone concentrations. Between 130 and 144 d of gestation (term at 145 ± 2 d), plasma leptin and PAT leptin mRNA levels increased in association with increments in plasma cortisol and T3. Fetal adrenalectomy prevented these developmental changes, and exposure of intact 130 d fetuses to glucocorticoids, by cortisol infusion or maternal dexamethasone treatment, caused premature elevations in plasma leptin and PAT leptin gene expression. Fetal thyroidectomy increased plasma leptin and PAT leptin mRNA abundance, whereas intravenous T3 infusion to intact 130 d fetuses had no effect on circulating or PAT leptin. Leptin mRNA expression was low in the ovine placenta. Therefore, in the sheep fetus, PAT appears to be a primary source of leptin in the circulation, and leptin gene expression is regulated by both glucocorticoids and thyroid hormones. Developmental changes in circulating and PAT leptin may mediate the maturational effects of cortisol in utero and have long-term consequences for appetite regulation and the development of obesity

Developmental Expression and Glucocorticoid Control of the Leptin Receptor in Fetal Ovine Lung

<div><p>The effects of endogenous and synthetic glucocorticoids on fetal lung maturation are well-established, although the role of leptin in lung development before birth is unclear. This study examined mRNA and protein levels of the signalling long-form leptin receptor (Ob-Rb) in fetal ovine lungs towards term, and after experimental manipulation of glucocorticoid levels <i>in utero</i> by fetal cortisol infusion or maternal dexamethasone treatment. In fetal ovine lungs, Ob-Rb protein was localised to bronchiolar epithelium, bronchial cartilage, vascular endothelium, alveolar macrophages and type II pneumocytes. Pulmonary Ob-Rb mRNA abundance increased between 100 (0.69 fractional gestational age) and 144 days (0.99) of gestation, and by 2–4-fold in response to fetal cortisol infusion and maternal dexamethasone treatment. In contrast, pulmonary Ob-Rb protein levels decreased near term and were halved by glucocorticoid treatment, without any significant change in phosphorylated signal transducer and activator of transcription-3 (pSTAT3) at Ser727, total STAT3 or the pulmonary pSTAT3:STAT3 ratio. Leptin mRNA was undetectable in fetal ovine lungs at the gestational ages studied. These findings demonstrate differential control of pulmonary Ob-Rb transcript abundance and protein translation, and/or post-translational processing, by glucocorticoids <i>in utero</i>. Localisation of Ob-Rb in the fetal ovine lungs, including alveolar type II pneumocytes, suggests a role for leptin signalling in the control of lung growth and maturation before birth.</p></div

Cardiac function in adulthood.

<p>Values are mean±S.E.M. for the dP/dt max <i>a</i>, the heart rate-pressure product (RPP) <i>b</i>; and the heart rate responses to 10–6 M Carbachol <i>c</i> and to 10–7 M Isoprenaline <i>d</i>. Groups are: Normoxia, n = 6 (N,□), Hypoxia, n = 6 (H, ▪), Hypoxia+Vitamin C, n = 7 (HC, red histogram) and Normoxic+Vitamin C, n = 7 (NC, blue histogram). Significant (P<0.05) differences are: * vs. all, One-Way ANOVA with Tukey Test.</p