Association Between RET (rs1800860) and GFRA1 (rs45568534, rs8192663, rs181595401, rs7090693, and rs2694770) Variants and Kidney Size in Healthy Newborns.

BACKGROUND: Abnormal congenital nephron number has been implicated in the pathogenesis of hypertension and renal disease. The RET receptor complex propagates signals essential for nephrogenesis and the RET c.1296G>A polymorphism, leading to aberrant splicing of exon 7, is associated with reduced kidney volume, a surrogate for nephron endowment. The glial cell-derived neurotrophic factor (GDNF) family receptor alpha 1 (GFRA1) is a component of the RET receptor complex, and three alternatively spliced GFRA1 transcripts (with or without exon 5) have been identified. In rats, exclusion of exon 5 results in stronger GDNF binding affinity and RET activation. The aims of this study were to investigate further the relationship between RET c.1296G>A and kidney volume, and also to investigate the association between the GFRA1 polymorphisms near and within the alternatively spliced exon 5, as well as the functional 5'-UTR c.-193C>G with kidney volume. MATERIALS AND METHODS: The study included 188 healthy full-term newborns. Genotyping of the RET (NM_020975.4:c.1296G>A, rs1800860) and GFRA1 (NM_005264.5:c.-193C>G, rs45568534; c.419-87A>G, rs8192663; c.429G>A, rs181595401; c.433+127A>G, rs7090693; c.433+245A>G, rs2694770) polymorphisms was performed using polymerase chain reaction-restriction fragment length polymorphism, minisequencing, or sequencing. Total kidney volume (TKV) was determined by ultrasound and normalized to body surface area (TKV/BSA). Both marker-by-marker and haplotype-based methods were used to test for associations between polymorphisms and TKV/BSA. RESULTS: TKV/BSA in RET c.1296A allele carriers was significantly lower compared with GG homozygotes (103 ± 23 vs. 110 ± 19 mL/m2, p = 0.034). c.429G>A was invariant in our sample. There was no association between any of the GFRA1 polymorphisms and renal volume. CONCLUSIONS: RET c.1296A may be a common susceptibility allele for nephron underdosing-related diseases. The 5'-UTR and intronic variants near exon 5 of GFRA1 are not associated with nephron endowment.

Epistatic interaction between common AGT G(-6)A (rs5051) and AGTR1 A1166C (rs5186) variants contributes to variation in kidney size at birth.

Low nephron number has been recognised as an important cardiovascular risk factor and recently a strong correlation between renal mass and nephron number has been demonstrated in newborns. The aim of this study was to investigate individual, as well as combined, effects of common variants of genes which encode for major components of the renin-angiotensin system (REN G10601A, AGT G(-6)A, ACE I/D, AGTR1 A1166C) on kidney size in healthy, full-term newborns. A significant additive main effect of the ACE I/D polymorphism, as well as an additive-by-additive interaction between AGT G(-6)A and AGTR1 A1166C variants, were found. The variance attributed to the epistatic effect was 27.9 ml(2)/m(4), which accounted for 73.8% of the interaction variance (37.8 ml(2)/m(4)), 66.4% of the genetic variance (42.0 ml(2)/m(4)) and 4.4% to the total phenotypic variance (628 ml(2)/m(4)). No other statistically significant main or epistatic effects were detected. Our results highlight the importance of considering gene-gene interactions as part of the genetic architecture of congenital nephron number, even when the loci do not show significant single locus effects. Unravelling the genetic determinants of low nephron number, along with early molecular screening, may well help to identify children at risk for cardiovascular disease.

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 cm(3)/m(2), 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 BMPR1A polymorphism, but not BMP4, with kidney size in full-term newborns.

BACKGROUND: A correlation between renal mass and nephron number in newborns allows the use of total kidney volume at birth as a surrogate for congenital nephron number. As the bone morphogenetic protein type 4 (BMP4), and its receptor type 1A (BMPR1A, ALK3), play an important role in renal development, we hypothesized that common, functional polymorphisms in their genes might be responsible for variation in kidney size among healthy individuals. METHODS: We recruited 179 healthy full-term newborns born to healthy women. Kidney volume was measured sonographically. Total kidney volume (TKV) was calculated as the sum of left and right kidneys, and normalized for body surface area (TKV/BSA). Genomic DNA was extracted from umbilical cord blood leukocytes, and c.455T > C (rs17563) BMP4 and c.67 + 5659A > T (rs7922846) BMPR1A genotypes were identified by PCR-RFLP. RESULTS: TKV/BSA in newborns carrying at least one A BMPR1A allele (AA + AT) was significantly reduced by approximately 13 % as compared with TT homozygous newborns (106.7 ± 21.5 ml/m(2) vs. 122.7 ± 43.8 ml/m(2), p < 0.02). No significant differences in TKV/BSA were found among newborns with different BMP4 genotypes. CONCLUSIONS: Results suggest that rs7922846 BMPR1A polymorphism may account for subtle variation in kidney size at birth, reflecting congenital nephron endowment.

[Clinical and radiological evaluation of malignant metaplasia of benign primary bone tumors on the material of University Orthopaedic Department of Szczecin between 2002-2007]. / Ocena kliniczna i radiologiczna metaplazji zlosliwej pierwotnych lagodnych nowotworów kosci oraz zmian pseudonowotworowych w materiale Kliniki Ortopedii PAM w Szczecinie w latach 2002-2007.

The study presents clinical and diagnostic problems in patients with malignant bone metaplasia. Material is composed of 13 patients treated surgically between april 2002 and august 2007. In three cases tumors were localised in tibia, in 5 patients around distal femur, in 2 in pelvis, in 2 in humerus and in 1 in lumbar spine. None of the patients has had recurrence by february 2006 r, 12 patients have been free of the disease so far. However, one individual diagnosed with giant cell tumor metaplasia to osteosarcoma did not accept proposed therapy. The authors have particularly emphasized thorough clinical and radiological evaluation and the need of team work before surgical procedure.