Glucocorticoid receptor gene polymorphisms and glucocorticoid sensitivity of subdermal blood vessels and leukocytes

A considerable variability in the sensitivity to glucocorticoids (GCs) exists between individuals and these differences have been implicated in the etiology of psychiatric diseases such as depression. Glucocorticoid receptor (GR) gene polymorphisms might account in part for variability in GC responsiveness. We assessed the association between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9beta) and markers of glucocorticoid sensitivity in two target tissues (subdermal blood vessels, peripheral leukocytes) in 206 healthy individuals. The BclI GG genotype group showed the least degree of skin blanching, reflecting a lower GC sensitivity of subdermal blood vessels (p=.01). No association between GR genotype and GC sensitivity of peripheral leukocytes was observed. In the same subjects we previously observed an association between GR genotype and GC sensitivity of the pituitary. Polymorphism of the GR gene might constitute a vulnerability or protection factor for stress related disorders and altered GC sensitivity.     

Common studied polymorphisms do not affect plasma cytokine levels upon endotoxin exposure in humans

The aim of this study was to investigate to what extent single nucleotide polymorphisms (SNPs) in promoter regions of genes of Toll-like receptor (TLR)-4, tumour necrosis factor (TNF)-alpha, interleukin (IL)-18, interferon (IFN)-gamma, IL-6 and IL-10 affect the cytokine response during a controlled low-grade inflammatory response in vivo. Two hundred healthy young male volunteers were genotyped, and cytokine levels were measured in response to a low-dose intravenous bolus of Escherichia coli endotoxin. No association was detected between SNPs (TLR-4299, TLR-4399, TNF-308, IL-18-137, IL-18-607, IFN-gamma+874, IL-6-174, IL-10-592 and IL-10-1082) and endotoxin-induced changes in plasma levels of TNF-alpha, IL-6 and IL-10. IL-18 levels were unaffected by endotoxin. In conclusion, the investigated SNPs did not affect endotoxin-induced low-grade cytokine production of TNF-alpha, IL-6, IL-18 or IL-10 in healthy young men. Previous reports of a major heritability factor in the inflammatory response may be due to other target genes or effects in older age groups or women.     

CYP gene polymorphisms and early menarche.

Early age at menarche is a risk factor for breast cancer. A previous study reported a significant positive association between the CYP3A4*1B variant allele and early puberty. We investigated whether polymorphisms of the CYP3A4, CYP17, CYP1B1, and CYP1A2 genes predict the age at onset of menarche. Five hundred eighty-three nulliparous women between ages 17 and 35, of various ethnic backgrounds, completed a questionnaire that included information about menstrual history. Samples of DNA were provided and used to genotype these women for polymorphic variants in the four genes. There was no significant difference in mean age at menarche between women who carried two variant CYP17 A2 alleles (12.5 years) and women who carried one or no variant allele (12.5 years) (P = 0.8, adjusted for ethnic group and year of birth). Similar results were found for the CYP1B1*3 variant allele and for the CYP1A2*1F variant allele. Women who carried two variant CYP3A4*1B alleles had an earlier mean age at menarche (12.0 years) than women who carried one or no variant allele (12.6 years) (P = 0.02). However, after adjusting for ethnic group and year of birth, no significant differences in mean age at menarche were found. The polymorphic variants of the CYP3A4, CYP17, CYP1B1, and CYP1A2 genes are unlikely to influence age of menarche.     

Common polymorphisms in LRP and A2M do not affect genetic risk for Alzheimer disease in Northern Ireland

Genetic variation in one of the major APOE receptors in the brain has been associated with increased risk for Alzheimer disease (AD). A C/T polymorphism in exon 3 and a tetranucleotide repeat polymorphism in the 5' region of the low-density lipoprotein receptor-related protein gene have been reported to increase risk in some studies but these reports have not been universally replicated. In addition, genetic variation in another ligand of LRP, alpha-2 macroglobulin (A2M), has also been associated with increased AD risk. However, these reports also remain controversial. We have genotyped both LRP polymorphisms and two polymorphisms in the A2M gene in a large group of clinically well-defined AD cases and controls from the relatively genetically homogeneous Northern Ireland population. Comparison of genotype and allele frequencies for polymorphisms in LRP revealed no significant differences between cases and controls. Multiple logistic regression analysis performed to assess any possible interaction between LRP and APOE revealed little evidence for genetic interaction despite the obvious biological interaction. Genotype and allele comparisons between the groups for the A2M polymorphisms also gave no evidence that either polymorphism increased risk for disease. The results from this study indicate that polymorphisms in LRP and A2M are not associated with increased risk for AD in Northern Ireland.     

Hepatocyte growth factor concentration in the early second-trimester amniotic fluid does not predict fetal growth at birth.

The purpose of this study was to evaluate whether hepatocyte growth factor (HGF) concentrations in the early second-trimester amniotic fluid predict fetal growth at birth. HGF and insulin-like growth factor-I (IGF-I) concentrations in the early second-trimester amniotic fluid were measured in 12 pregnancies with small for gestational age (SGA) infants, 84 pregnancies with appropriate for gestational age (AGA) infants, and eight pregnancies with large for gestational age (LGA) infants. HGF concentrations were measured from the early second-trimester amniotic fluid samples using an enzyme-linked immunosorbent assay. IGF-I concentrations were measured from the early second-trimester amniotic fluid samples using an immunoradiometric assay. Maternal age in AGA group (34.2 +/- 5.5 years) was significantly lower than in SGA (37.9 +/- 3.0 years) and LGA (37.6 +/- 3.3 years) groups (P < 0.05). There were no significant differences for parity or gestational age at amniocentesis among the groups. There were significant differences for birth age, birth weight, neonatal height, and placental weight among the groups (P < 0.05). HGF concentrations in SGA, AGA and LGA groups were 16.9 +/- 6.6, 16.7 +/- 9.0 and 20.2 +/- 14.8 ng/ml respectively (not significant). There was no correlation between amniotic fluid HGF concentrations and birth weight, height or placental weight. There were also no significant differences for amniotic fluid IGF-I concentrations among the three groups. These results suggest that differences in HGF concentrations in the early second-trimester amniotic fluid do not predict fetal growth at birth. Further study is needed to clarify the role of high HGF concentrations in early second-trimester amniotic fluid during pregnancy.     

Neutrophils do not affect clonal growth of granulocyte progenitor cells cultured in vivo in diffuse chambers

The effect of polymorphonuclear leukocytes on the growth of granulocytic progenitors in the diffusion chamber culture (CFU-dG) has been studied. It has been shown that peripheral blood neutrophils do not affect the myeloid colony formation in this culture system. The inhibition of CFU-dG growth, observed in the presence of peripheral blood leukocytes was dependent on prostaglandins release from monocytes.     

Antithyroid antibodies do not affect pregnancy outcome in women undergoing assisted reproduction.

The purpose of this study was to determine the association of antibodies to thyroglobulin and thyroid peroxidase and pregnancy outcome in women undergoing assisted reproductive techniques. The study included three centres and retrospectively evaluated patient sera for antithyroid antibodies, then related the results to pregnancy outcome. Enzyme-linked immunosorbant assays for thyroglobulin and thyroid peroxidase antibodies were performed using two different commercially available kits. Controls included 200 healthy women of reproductive age. Women (n = 873) who were undergoing assisted reproductive techniques for pelvic adhesions, endometriosis, ovarian dysfunction, or unexplained/other were included. All women utilized a standard regimen of gonadotrophin releasing hormone agonist down-regulation followed by ovulation induction. Embryos were cultured for 3 days, at which time embryo transfer occurred. Statistical analysis utilized the two-tailed Fisher's exact test. Antithyroid antibodies were positive in 143 of 873 (16.4%) women undergoing assisted reproductive techniques while 29 of 200 (14.5%) normal controls were positive (not significant). Deliveries were achieved in 396 of 730 (54.2%) of women who had no thyroid antibodies versus 78 of 143 (54.5%) of women who had thyroid antibodies (not significant). No difference in biochemical pregnancies (not significant) or clinical pregnancy losses (not significant) were detected. Antithyroid antibodies were found no more frequently in women undergoing assisted reproductive techniques than in normal controls. There were no differences in pregnancy outcome based on antithyroid antibody positivity in women undergoing assisted reproductive techniques. These data do not support the testing or treatment for antithyroid antibodies of women undergoing assisted reproductive techniques.     

The relationship between ghrelin and adiponectin levels in breast milk and infant serum and growth of infants during early postnatal life

Ghrelin and adiponectin have been found in breast milk and are considered to take part in the regulation of growth and energy metabolism of infants. Our aims were to determine ghrelin and adiponectin levels in breast milk and serum samples of mothers and their infants, and to investigate the relationship between their levels and anthropometry of newborn infants during early postnatal life. Total and active ghrelin and adiponectin levels were studied in breast milk, and the serum samples of 25 healthy lactating women and their healthy fullterm infants were taken at the 1st and 4th months of life. Anthropometric measurements of infants were also performed during the study period. Breast milk and infant serum active ghrelin levels were found to be significantly increased at the 4th month of life compared with 1st month levels (p < 0.05). Maternal serum total ghrelin and infant serum adiponectin levels were found to be significantly reduced at the 4th month of life (p < 0.05). Breast milk active ghrelin levels were higher than the infant and maternal serum active ghrelin at the 1st and 4th months (p < 0.05). There was a negative significant correlation between the level of infant serum active ghrelin levels and BMI of infants at the 1st month. A positive significant correlation was found between the level of 1st month infant serum adiponectin levels and weight gain of infants during the study period. Fourth month infant serum adiponectin were also positively correlated with weight and BMI of infants at the 4th month and the weight gain during study period. There was a positive significant correlation between the level of 4th month breast milk active ghrelin and weight gain of infants during the study period. Ghrelin and adiponectin are involved in postnatal growth of infants. Ghrelin in breast milk also seems to be related to the growth of infants during early postnatal life. The sources of these peptides in breast milk are probably both maternal serum and breast tissue itself.     

Supraphysiological estradiol levels do not affect oocyte and embryo quality in oocyte donation cycles.

BACKGROUND: The study aim was to determine whether supraphysiological estradiol (E(2)) levels reduce oocyte/embryo quality in oocyte donation cycles. METHODS: A retrospective analysis of 330 consecutive fresh oocyte donation cycles was performed in an assisted reproductive treatment programme between January 1996 and December 2000. Throughout the study period, oocyte donors and recipients followed a standard synchronization regimen that did not vary. A serum E(2) level (peak E(2)) was obtained from all oocyte donors on the morning of HCG administration. Peak E(2) values were grouped by 33rd percentile (group I, <1500 pg/ml; group II, 1500-3000 pg/ml; and group III, >3000 pg/ml). All embryo transfers were performed on day 3 after oocyte recovery. RESULTS: Comparisons between groups revealed no significant differences in the quality of oocytes retrieved, and in fertilization rates. Higher peak E(2) levels were directly correlated with a greater number of oocytes retrieved, embryos available for transfer and cryopreservation, and higher average embryo quality scores (P < 0.005). Compared with group I, group III had significantly higher embryo implantation rates (P < 0.05). CONCLUSIONS: Sustained supraphysiological E(2) levels do not adversely affect the quality of developing oocytes and embryos. On the contrary, elevated E(2) levels are associated with a larger number of oocytes and embryos and high-grade embryos for transfer/cryopreservation and, consequently, improved implantation rates.     

Type 2 diabetes gene TCF7L2 polymorphism is not associated with fetal and postnatal growth in two birth cohort studies

Background  

An inverse association between birth weight and the risk of developing type 2 diabetes (T2D) in adulthood has been reported. This association may be explained by common genetic variants related to insulin secretion and resistance, since insulin is the most important growth factor in fetal life. The objective of this study was to examine whether T2D gene polymorphism TCF7L2 rs7903146 is associated with growth patterns from fetal life until infancy.     

Novel exonic mu-opioid receptor gene (OPRM1) polymorphisms not associated with opioid dependence.

The mu-opioid receptor (MOR) mediates reward and dependence associated with opioids and other commonly abused substances. Variability in the MOR gene, OPRM1, may influence risk for opioid dependence. In this study, associations between two single nucleotide polymorphisms (SNPs), dbSNP rs540825 and dbSNP rs562859, and opioid dependence were investigated. The two SNPs are located in the protein coding region of the novel exon X of an alternative splice variant of OPRM1, and can be detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Genotyping at the two SNPs was performed for 170 severe opioid dependent individuals and 128 carefully screened controls. Although no differences were found between cases and controls, there were significant prevalence differences between African-American (AA) subjects and European-American (EA) subjects for SNP 540825 allele and genotype frequencies. The 540825 and 562859 polymorphisms were found to be in complete linkage disequilibrium (LD) for both ethnic groups, and LD existed between the 562859 SNP and the A(-1320)G SNP in the promoter region of OPRM1 in AAs, based on genotyping data previously carried out on the same subjects. LD between these two markers, separated by 55 kb, links the entire distance studied in this project. The results indicate that polymorphisms in the novel splice variant are not associated with opioid dependence, but are in LD with other polymorphisms in OPRM1.     

Norplant((R)) implants and progesterone vaginal rings do not affect maternal bone turnover and density during lactation and after weaning.

Bone density and turnover was assessed in a longitudinal study of healthy lactating women who initiated use of Norplant((R)) implants (NOR, n = 29), progesterone vaginal rings (PVR, n = 28) or Copper T 380A intrauterine devices (T-Cu, n = 51, control group) around day 60 postpartum. Bone density, serum calcium, phosphorus, alkaline phosphatases, parathyroid hormone (PTH), follicle stimulating hormone (FSH), oestradiol and prolactin, and urinary hydroxyproline and creatinine were measured at postpartum months 1 (PM1), and 12 (PM12) and 6 or 12 months after weaning; at month 6 postpartum (PM6) serum and urine tests alone were performed. Baseline characteristics and lactation performance were similar between groups. Biochemical markers of bone turnover were higher at PM1, PM6 and PM12 than after weaning, with no differences between groups. Bone density in the lumbar spine (L2-L4) and femoral neck at PM1 and PM12 ( approximately 1.11 g/cm(2)) was similar in three groups. Lumbar spine values were found to be lower in lactating women than those present in non-lactating women, but increased after weaning to similar values. The two progestin-only contraceptives studied appear to have no deleterious effect upon bone density and metabolism in healthy lactating women.