Grażyna Dawid

Common Genetic Variants of the BMP4, BMPR1A, BMPR1B, and ACVR1 Genes, Left Ventricular Mass, and Other Parameters of the Heart in Newborns

The members of the family of bone morphogenetic proteins (BMPs) are important regulators in cardiac development. The present study was designed to evaluate the effect of common genetic variants of BMP-4 and its receptors BMPR1A, BMPR1B, and ACVR1 on left ventricular mass (LVM) and other parameters of the heart and blood pressure in newborns. The study included 210 healthy newborns. Two-dimensional M-mode echocardiography was used to assess LVM between days 3 and 4 after birth. Polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism technique. We found lack of associations between LVM, values of blood pressure, and the BMP4, BMPR1A, BMPR1B, and ACVR1 genotypes. A significant association was observed between the 455C allele of BMP4 and increased left ventricular internal diameter systolic (p=0.004) and between 1650T allele of BMPR1B and lower left atrium diameter (p=0.038). Presence of the 455C allele of BMP4 and the 8474T allele of ACVR1 gene was significantly associated with decreased left ventricular ejection fraction (LVEF) (p=0.0004 and p=0.046, respectively). The 455C allele of BMP4 and the 8474T allele of ACVR1 may play a role as significant predictors for decreased LVEF in newborns.

Association of CD36 gene polymorphisms with echo- and electrocardiographic parameters in patients with early onset coronary artery disease.

Introduction CD36 plays an important role in long-chain fatty acid homeostasis in skeletal muscle and the myocardium. CD36 deficiency may lead to reduced myocardial uptake of long-chain fatty acid. Therefore, different mutations of the CD36 gene may contribute to the clinical heterogeneity of cardiac hypertrophy. Material and methods The objective of the study was to investigate whether there is an association between the sequence changes in CD36 and echocardiographic and electrocardiographic parameters in Caucasian patients with early onset coronary artery disease. The study group comprised 100 patients. Electrocardiography and echocardiography were performed in all patients. Amplicons of exons 4 to 6 including fragments of introns were studied using the denaturing high-performance liquid chromatography technique. Results IVS3-6TC (rs3173798) heterozygotes had impaired left ventricle diastolic function. 573GA heterozygotes (rs5956) had higher frequency of pseudonormal left ventricular diastolic function and it was confirmed by the increase in wave A’ in the tissue Doppler. 591AT genotype was associated with borderline higher posterior wall end-diastolic thickness and lower E/A ratio. These results are consistent with electrocardiography parameters which could reflect left ventricular hypertrophy (higher RV5(6) and RV5(6) + SV1(2) parameters, depressed ST segments and tendency to longer Qtc II interval) in 591AT heterozygotes. Conclusions Detected variant alleles of CD36 may be associated with features of left ventricular hypertrophy and impaired diastolic function.

Possible counter effect in newborns of 1936A>G (I646V) polymorphism in the AKAP10 gene encoding A-kinase-anchoring protein 10.

Objective:Cyclic adenosine monophosphate/protein kinase A (PKA) is important in embryonic development. The human AKAP10 gene is polymorphic: 1936A>G results in changes to a PKA-binding domain and increased targeting to mitochondria. Previous studies found G1936 as ‘deleterious’ in adults, and this study investigates whether this holds true in preterm birth.Study Design:Study group consisted of 80 preterm newborns (PTNs) born before the 38th gestation week. Control group consisted of 123 full-term healthy newborns born after the 37th gestation week with uncomplicated pregnancies. Genomic DNA was extracted from umbilical blood and AKAP10 genotypes were identified by PCR/restriction enzyme.Result:Significant differences in frequencies of 1936A>G genotypes/alleles between both groups were found. PTNs had increased frequency (55%) of AA homozygotes (odds ratio, AA versus AG+GG: 2.63 (95% confidence interval: 1.33 to 5.20), P=0.006) after adjustments: mothers with previous PTNs, smoking, first pregnancy, first delivery and Cesarean section.Conclusion:Results suggest G1936 is preventative factor against preterm birth, in contrast with previously asserted negative effects in adults.

Genetics of the renin-angiotensin system with respect to cardiac and blood pressure phenotypes in healthy newborn infants.

Introduction: Left ventricular mass (LVM) is a strong predictor of various heart diseases. We examine the association between the G(-6)A AGT, I/D ACE, A1166C AGTR1, T(-344)C CYP 11β2, A538G MR and A10631G REN polymorphisms and LVM and blood pressure in newborn infants. Material and methods: The study included 211 healthy newborn infants. Two-dimensional M-mode echocardiography was used to assess LVM between days 3–4 after birth. Polymorphisms were determined by polymerase chain reaction - restriction fragment length polymorphism (PCR-RLFP). Results: AGTR1 genotype was significantly associated with neonatal systolic blood pressure (≥90 percentile). LVM indexes (LVMIs) were tested for association with genotypes in multivariate analysis. The carriers of the A allele of the AGT polymorphism had significantly higher LVM/body length (BL) values when compared with newborn infants homozygous for the G allele (padjusted=0.03). The higher LVM/BL values were seen in the carriers of the A alleles of the AGTR1 polymorphism (padjusted=0.046). All examined indexes (LVM/body surface area (BSA), LVM/BL, LVM/bodyweight (BW)) were associated with CYP11B polymorphism. The newborn infants homozygous for the T allele had significantly higher values of LVM/BSA, LVM/BL, and LVB/BW compared to non-TT-homozygous neonates (padjusted=0.003; padjusted=0.003; padjusted=0.004 respectively). Conclusion: The AGT, AGTR1, CYP11β polymorphisms are associated with increased LVMIs in newborns. This observation indicates that genetic factors may be modulating LVM at birth.

Familial distal monosomy 3p26.3-pter with trisomy 4q32.2-qter, presenting with progressive ataxia, intellectual disability, and dysmorphic features.

We present a boy diagnosed with partial 3p monosomy and partial 4q trisomy. The patient was 9 years of age with intellectual disability, dysmorphic features, and ataxia. A family history and medical evaluation showed that the father manifested similar facial dysmorphic features, intellectual disability, quadriparesis, and progressive cerebrospinal ataxia. The chromosomal aberration found in the proband was inherited from his father who was found to have a balanced reciprocal translocation of chromosomes 3p and 4q, which was in turn inherited from the paternal grandfather. The final cytogenetic diagnosis according to microarray was 46,XY,der(3)t(3;4)(p26.1;q32.2)arr 3p26.1(39,066–5,363,502)x1,4q32.2q35.2(162,555,236–191,173,881)x3. We describe the cytogenetic investigations that led to the identification of the breakpoints. In addition, we present an overview of the clinical features found in patients with partial 3p monosomies and partial 4q trisomies as reported in the literature.

An insertion/deletion ACE polymorphism and kidney size in Polish full-term newborns

The number of nephrons is a multifactorial trait controlled by the interaction of environmental factors and genetic variants that influence the extent of branching nephrogenesis during foetal life. A correlation between renal mass and nephron number in newborns allows the use of the total kidney volume at birth as a surrogate for congenital nephron number. Since the renin–angiotensin system plays an important role in renal development we hypothesized that the common, functional insertion/deletion (I/D) polymorphism in the ACE gene might be responsible for the variation in kidney size amongst healthy individuals. We recruited 210 healthy Polish full-term newborns born to healthy women with uncomplicated pregnancies. The kidney volume was measured sonographically. Total kidney volume (TKV) was calculated as the sum of left kidney volume and right kidney volume. TKV was normalized to body surface area (TKV/BSA). The I and D alleles were identified using polymerase chain reaction. TKV/BSA in newborns carrying at least one insertion ACE allele was significantly reduced by approximately 8% as compared with homozygous newborns for the D allele (DD genotype) (105.1±23.6 vs. 114.2±28.2 cm3/m2, p<0.05). The results of this study suggest that I/D ACE polymorphism may account for subtle variation in kidney size at birth, which reflects congenital nephron endowment.

Association of 1936A > G in AKAP10 (A-kinase anchoring protein 10) and blood pressure in Polish full-term newborns

Abstract Objective. The 1936G AKAP10 allele is associated with increased adult basal heart rate (HR) and decreased variability, markers of low cholinergic/vagus sensitivity associated with hypertension. Blood pressure (BP) values in newborns are important measurable markers of cardiovascular risk later in life. The question was whether decreased vagal function-related 1936A > G AKAP10 is associated with newborn BP. Study design. 114 healthy Polish newborns born after 37th gestational week to healthy women with uncomplicated pregnancies. At birth, newborn cord blood obtained for isolation of genomic DNA. BP and HR measured on days 1 and 3 after delivery. Results. Diastolic BP on day 3 and absolute and relative differences between diastolic BP values, as well as between mean BP values on day 3 and on day 1 after birth, in carriers of 1936G AKAP10 allele, were significantly higher as compared with wild-type homozygotes. Conclusion. Results demonstrate possible association between 1936G AKAP10 variant and BP in Polish newborns.

Association of Genetic Variation in Calmodulin and Left Ventricular Mass in Full-Term Newborns

Calmodulin II (CALM2) gene polymorphism might be responsible for the variation in the left ventricular mass amongst healthy individuals. The aim was to evaluate the correlation between left ventricular mass (LVM) and g.474955027G>A (rs7565161) polymorphism adjacent to the CALM2 gene. Healthy Polish newborns (n = 206) were recruited. Two-dimensional M-mode echocardiography was used to assess LVM. Polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism and sequencing analyses. The carriers of the G allele of the CALM2 polymorphism had significantly higher left ventricular mass/weight (LVM/BW) values, when compared with newborns homozygous for the A allele (3.1 g/m2 versus 2.5 g/m2, P adjusted = 0.036). The AG genotype of CALM2 was associated with the highest values of LVM/BW, exhibiting a pattern of overdominance (2.9 g/kg versus 3.1 g/kg versus 2.5 g/kg, P adjusted = 0.037). The results of this study suggest that G>A CALM2 polymorphism may account for subtle variation in LVM at birth.