ABSTRACT
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.
Subject(s)
Angiotensinogen/genetics , Pre-Eclampsia/genetics , Renin/genetics , Angiotensinogen/metabolism , Child , Female , Fetus/metabolism , Gene Expression , Genes , Genotype , Haplotypes , Heterozygote , Homozygote , Humans , Hypertension/genetics , Polymorphism, Single Nucleotide , Pregnancy , Regression Analysis , Renin-Angiotensin System/genetics , Risk FactorsABSTRACT
Preeclampsia is a serious disorder affecting nearly 3% of all in the Western world. It is associated with hypertension and proteinuria, and several lines of evidence suggest that the renin-angiotensin system (RAS) may be involved in the development of hypertension at different stages of a preeclamptic pregnancy. In this study, we developed rapid genotyping assays on the LightCycler® instrument to allow the detection of genetic variants in the renin gene (REN) that may predispose to preeclampsia. The method is based on real-time PCR and allele-specific hybridization probes, followed by fluorescent melting curve analysis to expose a change in melting temperature (Tm). Ninety-two mother-father-child triads (n=276) from preeclamptic pregnancies were genotyped for three haplotype-tagging single nucleotide polymorphisms (htSNPs) in REN. All three htSNPs (rs5705, rs1464816 and rs3795575) were successfully genotyped. Furthermore, two unexpected nucleotide substitutions (rs11571084 and rs61757041) were identified within the selected hybridization probe area of rs1464816 and rs3795575 due to aberrant melting peaks. In conclusion, genotyping on the LightCycler® instrument proved to be rapid and highly reproducible. The ability to uncover additional nucleotide substitutions is particularly important in that it allows the identification of potentially etiological variants that might otherwise be overlooked by other genotyping methods.
Subject(s)
Genetic Testing/methods , Pre-Eclampsia/genetics , Renin/genetics , Base Sequence , Case-Control Studies , DNA Probes , Female , Haplotypes , Humans , Male , Polymorphism, Single Nucleotide , Pre-Eclampsia/diagnosis , Pregnancy , Transition TemperatureABSTRACT
The BCR-ABL fusion gene represents the hallmark of chronic myelogenous leukemia (CML) and is derived from a translocation between chromosome 9 and 22. The majority of CML patients have a breakpoint in the major BCR region of the BCR gene giving rise to e13a2 or e14a2 BCR-ABL transcripts. Occasionally, other BCR breakpoints occur. The current report describes two e6a2 CML patients with imatinib treatment failure and unusual disease progression. One patient was Philadelphia chromosome positive and one was Philadelphia chromosome negative with an atypical BCR-ABL rearrangement, ins (22;9).
