Maternal angiotensinogen (AGT) haplotypes, fetal renin (REN) haplotypes and risk of preeclampsia; estimation of gene-gene interaction from family-triad data

Background Preeclampsia is a debilitating disorder affecting approximately 3% of pregnant women in the Western world. Although inconclusive, current evidence suggests that the renin-angiotensin system may be involved in hypertension. Therefore, our objective was to determine whether the genes for placental renin (REN) and maternal angiotensinogen (AGT) interact to influence the risk of preeclampsia. Methods Three haplotype-tagging SNPs (htSNPs) covering REN (rs5705, rs1464818, and rs3795575) and another three covering AGT (rs2148582, rs2478545 and rs943580) were genotyped in 99 mother-father-child triads of preeclampsia pregnancies. We estimated relative risks (RR) conferred by maternal AGT and fetal REN haplotypes using HAPLIN, a statistical software designed to detect multi-marker transmission distortion among triads. To assess a combined effect of maternal AGT and fetal REN haplotypes, the preeclamptic triads were first stratified by presence/absence of maternal AGT haplotype C-T-A and tested for an effect of fetal REN across these strata. Results We found evidence that mothers carrying the most frequent AGT haplotype, C-T-A, had a reduced risk of preeclampsia (RR of 0.4, 95% CI = 0.2-0.8 for heterozygotes and 0.6, 95% CI = 0.2-1.5 for homozygotes). Mothers homozygous for AGT haplotypes t-c-g and C-c-g appeared to have a higher risk, but only the former was statistically significant. We found only weak evidence of an overall effect of fetal REN haplotypes and no support for our hypothesis that an effect of REN depended on whether the mother carried the C-T-A haplotype of AGT (p = 0.33). Conclusion Our findings indicate that the mother's AGT haplotypes affect her risk for developing preeclampsia. However, this risk is not influenced by fetal REN haplotypes.publishedVersio

N-Palmitoyl Glycine, a Novel Endogenous Lipid That Acts As a Modulator of Calcium Influx and Nitric Oxide Production in Sensory Neurons

N-arachidonoyl glycine is an endogenous arachidonoyl amide that activates the orphan G protein-coupled receptor (GPCR) GPR18 in a pertussis toxin (PTX)-sensitive manner and produces antinociceptive and antiinflammatory effects. It is produced by direct conjugation of arachidonic acid to glycine and by oxidative metabolism of the endocannabinoid anandamide. Based on the presence of enzymes that conjugate fatty acids with glycine and the high abundance of palmitic acid in the brain, we hypothesized the endogenous formation of the saturated N-acyl amide N-palmitoyl glycine (PalGly). PalGly was partially purified from rat lipid extracts and identified using nano-high-performance liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry. Here, we show that PalGly is produced after cellular stimulation and that it occurs in high levels in rat skin and spinal cord. PalGly was up-regulated in fatty acid amide hydrolase knockout mice, suggesting a pathway for enzymatic regulation. PalGly potently inhibited heat-evoked firing of nociceptive neurons in rat dorsal horn. In addition, PalGly induced transient calcium influx in native adult dorsal root ganglion (DRG) cells and a DRG-like cell line (F-11). The effect of PalGly on the latter cells was characterized by strict structural requirements, PTX sensitivity, and dependence on the presence of extracellular calcium. PalGly-induced calcium influx was blocked by the nonselective calcium channel blockers ruthenium red, 1-(beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole (SK&F96365), and La3+. Furthermore, PalGly contributed to the production of NO through calcium-sensitive nitric-oxide synthase enzymes present in F-11 cells and was inhibited by the nitric-oxide synthase inhibitor 7-nitroindazole

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N-Palmitoyl Glycine, a Novel Endogenous Lipid That Acts As a Modulator of Calcium Influx and Nitric Oxide Production in Sensory Neurons

N-arachidonoyl glycine is an endogenous arachidonoyl amide that activates the orphan G protein-coupled receptor (GPCR) GPR18 in a pertussis toxin (PTX)-sensitive manner and produces antinociceptive and antiinflammatory effects. It is produced by direct conjugation of arachidonic acid to glycine and by oxidative metabolism of the endocannabinoid anandamide. Based on the presence of enzymes that conjugate fatty acids with glycine and the high abundance of palmitic acid in the brain, we hypothesized the endogenous formation of the saturated N-acyl amide N-palmitoyl glycine (PalGly). PalGly was partially purified from rat lipid extracts and identified using nano-high-performance liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry. Here, we show that PalGly is produced after cellular stimulation and that it occurs in high levels in rat skin and spinal cord. PalGly was up-regulated in fatty acid amide hydrolase knockout mice, suggesting a pathway for enzymatic regulation. PalGly potently inhibited heat-evoked firing of nociceptive neurons in rat dorsal horn. In addition, PalGly induced transient calcium influx in native adult dorsal root ganglion (DRG) cells and a DRG-like cell line (F-11). The effect of PalGly on the latter cells was characterized by strict structural requirements, PTX sensitivity, and dependence on the presence of extracellular calcium. PalGly-induced calcium influx was blocked by the nonselective calcium channel blockers ruthenium red, 1-(beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole (SK&F96365), and La3+. Furthermore, PalGly contributed to the production of NO through calcium-sensitive nitric-oxide synthase enzymes present in F-11 cells and was inhibited by the nitric-oxide synthase inhibitor 7-nitroindazole