京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19399号 / 医博第4050号 / 新制||医||1012(附属図書館) / 32424 / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 川口 義弥, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Thesis (M. Sc. Agriculture (Animal Production)) -- University of Limpopo, 2022 / Weighing scales are typically out of reach for small-scale farmers due to expensive cost and a lack of operational expertise. However, understanding body weight and its relationship to linear body measures are critical for farmers making management decisions. Single nucleotide polymorphisms (SNPs) are significant because they influence the coding area of the DNA, leading to changes to the amino acid sequences, which might affect the animal's phenotype. The current study sought to find genetic indicators of the insulin-like growth factor 1 gene that may be exploited for breeding selection in order to improve the growth traits of Kalahari Red goats. The research was carried out at the Zuurfontein farm in Polokwane. As experimental animals, fifty (n = 50) Kalahari Red goats (8 males and 42 females) aged 2 to 3 years were used. A balance weighing scale was used to record body weight, and a measuring tape was used to capture linear body measures. Blood samples were obtained from the jugular vein once per animal using vacutainer blood collecting tubes. The deoxyribonucleic acid (DNA) was extracted and purified according to the methodology provided by Noegen's Genomic DNA isolation kit. Pearson’s correlation was used to achieve the correlation between the growth traits, Simple linear regression was performed to predict body weight from linear body measurements, Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) was utilized to discover the single nucleotide polymorphism, Chi-square test (χ2) was performed to assess the allele frequencies for Hardy-Weinberg equilibrium and General Linear Model (GLM) was performed for marker-trait association analysis. The mean square error (MSE) and coefficient of determination (R2) were exercised to choose the best regression model. Correlation results indicated a high positive significant correlation (P < 0.01) among BW and RH (r = 0.69), BL (r = 0.92), HG (r = 0.91), WH (r = 0.85) in bucks. While it does, all the linear body measurements indicated a high positive significant correlation (P < 0.01) expect SH (r = 0.41) which had a positive significant correlation (P < 0.05). Simple linear regression findings highlighted that BL had minimum MSE and highest R2 in bucks while in does HG had minimum MSE and highest R2. PCR-RFLP results indicated that two fragment patterns (two fragments and one fragment) were identified. Two genotypes were identified, KK with one fragment and KM with two fragments. The genotype frequency of KK was higher than that of KM and K allele had a higher allelic frequency than the M allele. The χ2 results showed that the Kalahari Red goats population used was not in Hardy Weinberg equilibrium (HWE) (χ2 = 0.39*). Marker-trait association findings by GLM indicated that the genotypes (KK and KM) had no association with the growth traits measured. In conclusion, correlation findings suggest that BW had a higher relationship with BL and HG in Kalahari Red goats. The regression results suggest that in bucks, an increase of 1 cm of BL might increase body weight by 1.24 kg, whereas it does, a 1 cm increase of HG might increase the body weight by 0.73 kg. The χ2 results suggest that the studied population gene and genotypic frequencies keep on changing from generation to generation and the marker-traits association results suggest that the genotypes identified had no relationship with growth traits in Kalahari Red goats. Further studies need to be conducted on single nucleotide polymorphism of IGF-1 and their relationship with growth traits using a larger sample, more growth traits and targeting more exons. / National Research Foundation (NRF)

Mutations in the insulin-like growth factor-I (IGF-I) receptor (IGF1R) have been associated with prenatal and postnatal growth retardation. However, little is known about potential effects of mutations in the IGF1R on carbohydrate homeostasis. Methods: We investigated clinical, endocrine and metabolic parameters in four family members carrying a novel IGF1R mutation (p.Tyr387X): an 18-year-old male (index case), his sister and two paternal aunts. Results: All family members showed a variable degree of impairment in prenatal growth, with birth weight standard deviation scores (SDS) between –1.65 and –2.37 and birth length SDS between –1.78 and –3.08. Their postnatal growth was also impaired, with height SDS between –1.75 and –4.86. The index case presented high IGF-I levels during childhood and adolescence and delayed bone age. The index case and his two paternal aunts had impaired glucose tolerance (IGT) associated with a variable degree of alterations in insulin sensitivity and secretion. In contrast, the index case’s sister, who had had IGT during pregnancy, showed normal glucose metabolism but reduced insulin sensitivity. Conclusion: This is the first study showing an association between a novel IGF1R mutation and a variable degree of alterations in prenatal and postnatal growth and in carbohydrate metabolism.

Endothelial cells separate the bloodstream from the underlying tissue and play a crucial role in vascular homeostasis. They also form an important barrier for vascular drug delivery. This thesis contains preliminary studies targeted at understanding the mechanisms of binding and transport across endothelial cells cultured in vitro. Specifically, the first study investigates how the recombinant source of Factor IX (FIX), a blood coagulant protein used in the treatment of Hemophilia B, impacts surface ligand binding (FIX to its specific receptors) to bovine aortic endothelial cells (BAECs). Competitive binding experiments between 125I-FIX and FIX were undertaken to quantify the interaction of recombinant and transgenic FIX with BAECs and human collagen IV and determine if there was a measurable difference in binding affinity. Results indicate limited specific binding of 125I-FIX to BAECs and no binding to human collagen IV. Concrete conclusions were not drawn from this data due to technical issues during the experimental process. The second study investigates insulin-like growth factor-I (IGF-I) transport across both BAEC and MAC-T cells, a mammary epithelial cell line, cultured on tissue culture inserts. IGF-I is a circulatory growth factor implicated in the regulation of cell division and tissue proliferation. Competitive binding experiments between 125I-IGF-I and unlabeled protein (IGF-I, Y60L-IGF-I, a mutant of IGF-I, and IGF Binding Protein-3 (IGFBP-3)) were undertaken to quantify the binding and transport of IGF-I under various experimental conditions. Results confirmed earlier work from the Williams' laboratory indicating that 125I-IGF-I transport was enhanced by incubation with its non-receptor-binding analog, Y60L-IGF-I, but cell surface associated 125I-IGF-I was decreased by its presence. Other studies were undertaken but conclusive results could not be drawn. / Master of Science

IGF-1 e IGFBP-3 são medidas indiretas da secreção de GH e ferramentas úteis na avaliação do eixo GH/IGF-1. No diagnóstico de deficiência de GH (DGH) estes peptídeos são avaliados pela idade cronológica. Nosso estudo avaliou a capacidade discriminativa desses peptídeos na identificação de pacientes com DGH e comparou a performance dos escores de desvio padrão do IGF-1 e do IGFBP-3 avaliados para idade cronológica (escore-ZIC), idade óssea (escore-ZIO) e estadio puberal (escore-ZIP) no diagnóstico de DGH. Trata-se de um estudo retrospectivo, transversal, com levantamento de dados de prontuário de pacientes pediátricos com distúrbios de crescimento acompanhados em nosso serviço. Os pacientes foram classificados como DGH ou suficientes de GH (não-DGH). O IGF-1 e o IGFBP-3 foram dosados pelo ensaio quimioluminescência - IMMULITE® e foram calculados o escore-ZIC, escore-ZIO e escore-ZIP. Foram avaliados 50 pacientes classificados como DGH e 187 como não-DGH. Os escores-ZIC, escores-ZIO e escores-ZIP do IGF-1 e do IGFBP-3 foram significativamente menores no grupo DGH em comparação com o grupo não-DGH (p < 0,001). O escore-ZIC do IGF-1 apresentou desempenho discriminativo superior ao escore-ZIC do IGFBP-3 na identificação de pacientes com DGH [área sob a curva ROC (AUC) 0,877 e 0,766, respectivamente, p = 0,001], em que o IGF-1 apresentou melhor sensibilidade (92% vs 45,2%) e o IGFBP-3 melhor especificidade (93,8% vs 69%). Entretanto, o valor preditivo positivo, considerando uma prevalência estimada de DGH de 2% entre crianças com baixa estatura, foi de 5,7% para o escore-ZIC do IGF-1 e de 13,1% para o do IGFBP-3, com valores preditivos negativos semelhantes. O escore-ZIO do IGF-1 demonstrou melhor desempenho discriminativo que o escore-ZIC sem atingir significância estatística (AUCs de 0,902 e 0,877, respectivamente, p=0,29). Mas essa superioridade não foi observada com o escore-ZIO do IGFBP-3. Nos pacientes em idade pré-púbere, não houve diferença estatisticamente significante entre o desempenho do escore-ZIC e escore-ZIO das concentrações séricas do IGF-1 e do IGFBP-3. Já nos pacientes em idade puberal houve uma melhora significativa da especificidade dos escore-ZIO e escore-ZIP do IGF-1 em relação ao escore-ZIC (de 65,6% para 92,7% e 98,4%), apesar da redução da sensibilidade (de 91,3% para 72,2% e 63,6%, respectivamente). Além disso, os valores preditivos positivos (VPP) do escore-ZIO e do escore-ZIP apresentaram uma melhora significativa em relação ao escore-ZIC do IGF-1 (16,8%, 44,8% e 5,1%, respectivamente), sem prejuízo nos valores preditivos negativos. A avaliação combinada de IGF-1 e IGFBP-3 em comparação com o escore-Z do IGF-1 isolado apresentou melhor sensibilidade (de 92% para 94,4%) quando somente um escore-Z desses peptídeos está baixo e melhor especificidade (de 69% para 95,7%) quando os escores-Z de ambos os peptídeos estão baixos / IGF-1 and IGFBP-3 are an indirect measure of the GH secretion and are a useful tool in the evaluation of the GH/IGF-1 axis. These peptides are usually evaluated according to the chronological age in the diagnosis of GH deficiency (GHD). Our study evaluated the diagnostic value of IGF-1 and IGFBP-3 in the diagnosis of GHD and compared their performance assessed by chronological age, bone age and pubertal status. This is a retrospective, cross-sectional study; data of pediatric patients with growth disorders evaluated in our tertiary outpatient clinic were retrieved from medical records. The patients were classified as GHD or GH sufficient (non-GHD). The IGF-1 and IGFBP-3 were measured by a chemiluminescent immunometric assay (IMMULITE®) and these values were transformed into standard deviation scores according to chronological age (SDSCA), bone age (SDS-BA) and pubertal status (SDS-PS). 50 patients were classified as GHD and 187 patients as non-GHD. The IGF-1 and IGFBP-3 SDSCA, SDS-BA and SDS-PS were significantly lower in the GHD group in comparison to the non-GHD group (p < 0.001). The IGF-1 SDS-CA had a superior discriminatory performance than the IGFBP-3 SDS-CA in the diagnosis of GHD [area under the ROC curve (AUC) 0.877 and 0.766, respectively, p = 0.001]. The IGF-1 SDS-CA had a higher sensitivity (92% vs 45.2%) and the IGFBP-3 SDSCA had a higher specificity (93.8% vs 69%). However, the predictive value of a positive result, considering an estimated GHD prevalence of 2% among children with short stature was 5.7% for the IGF-1 SDS-CA and 13.1% for the IGFBP-3 SDS-CA, with similar predictive values of a negative result. The IGF-1 SDS-BA had a better discriminatory performance than the IGF-1 SDS-CA, though not statistically significant (AUCs 0.902 and 0.877, respectively, p=0.29). There was no difference in the performance of the IGFBP-3 SDS-CA and SDS-BA. The diagnostic value of the IGF-1 and IGFBP-3 SDS-CA and SDS-BA of patients of pre-pubertal age was similar. On the other hand, in patients of pubertal age, there was a significant improvement of the specificity of the IGF-1 SDS-BA and SDSPS in comparison to the IGF-1 SDS-CA (from 65.5% to 92.7% and 98,4%), albeit the decay on the sensitivity (from 91.3% to 72.2% and 63.6%, respectively). Furthermore, the positive predictive values of the IGF-1 SDS-BA and SDS-PS were higher than the IGF-1 SDS-CA (16.8%, 44.8% and 5.1%, respectively), with similar negative predictive values. The evaluation of IGF-1 and IGFBP-3 assessed simultaneously in comparison to IGF-1 had a better sensitivity (from 92% to 94.4%) when either one of these peptides is low, and a better specificity (from 69 to 95.7%) when both the peptides are low

A resposta individual ao tratamento com hormônio de crescimento recombinante humano (rhGH) na síndrome de Turner (ST) é muito variável. A falta de individualização da dose pode justificar a variabilidade de respostas e os resultados insatisfatórios de algumas pacientes mesmo quando diagnosticadas e tratadas em condições ideais. Como a resposta ao tratamento com rhGH reflete fatores genéticos e não genéticos, o objetivo do presente estudo é avaliar a influência de fatores genéticos no tratamento com rhGH das portadoras de ST. Foram estudadas 112 pacientes com ST, em tratamento ou que interromperam a terapia, após atingir a altura final. O DNA genômico de todas as pacientes foi obtido para estudo de três polimorfismos em genes envolvidos na ação do GH: a presença ou ausência do éxon 3 do receptor do GH (GHR), VNTR presente na região promotora do gene do fator de crescimento insulina-símile-1(IGF1) e polimorfismo de único nucleotídeo (SNP) presente na região promotora do gene da Proteína 3 de Ligação a Fator de Crescimento Insulina-símile (IGFBP3). Os achados moleculares foram correlacionados com a velocidade de crescimento no primeiro ano de tratamento (n=112) e com altura adulta (n=65)) após uso de rhGH por meio de análises de regressão linear simples e múltipla, ajustadas para as demais variáveis clínicas relacionadas à resposta ao tratamento com rhGH em ST. Dois desses polimorfismos - a presença (GHR-fl) ou ausência (GHR-d3) do éxon 3 do GHR e o polimorfismo - 202 A/C IGFBP-3- influenciaram de forma independente e interativa a capacidade de resposta ao tratamento com rhGH em pacientes com ST; e o VNTR de repetições (CA)n da região promotora do IGF1 não demonstrou influência sobre nenhum dos parâmetros analisados. Pacientes carreadoras de, pelo menos, um alelo GHR-d3 apresentaram melhor velocidade de crescimento e maior altura final após tratamento com rhGH do que as homozigotas para o alelo GHR-fl. Similarmente, as carreadoras de, pelo menos, um alelo -202 A-IGFBP3 apresentaram melhor velocidade de crescimento e maior altura final após tratamento com rhGH, além de maiores concentrações séricas de IGFBP-3, do que as homozigotas para o alelo -202 CIGFBP3. Finalmente, a análise conjunta dos genótipos GHR-éxon 3 e -202 A/C IGFBP3 mostrou uma clara influência epistática, parcialmente aditiva, desses dois polimorfismos comuns na altura adulta de pacientes com ST tratadas com rhGH (efeito isolado do GHR-éxon 3, R2 = 0,27; efeito isolado do -202 A/C IGFBP3, R2 = 0,24; influência combinada desses polimorfismos, R2 = 0,37). Em conjunto com as variáveis clinicas, altura ao início do tratamento (p<0,001) e idade cronológica ao início da puberdade (p<0,001), estes dois polimorfismos são capazes de predizer 61% da variabilidade da altura adulta, após uso de rhGH. Embora estudos de validação sejam ainda necessários, acredita-se que as informações geradas por este e outros estudos - direcionados a um melhor entendimento das bases moleculares envolvidas na capacidade de resposta ao tratamento com rhGH - possam servir no futuro como importante ferramenta de individualização do tratamento com rhGH / Individual response to treatment with recombinant human growth hormone (rhGH) in Turner syndrome (TS) is very variable. The lack of individualization of rhGH dosing may explain the variability of response and the unsatisfactory results for some patients even when diagnosed and treated in ideal conditions. As the response to treatment with rhGH reflects genetic and nongenetic factors, the objective of this study is to evaluate the influence of genetic factors on rhGH treatment of patients with TS. We studied 112 patients with TS in rhGH therapy or who have discontinued therapy after adult height. Genomic DNA from all patients was obtained for the study of three polymorphisms in genes involved in GH action: the presence or absence of éxon 3 of the GH receptor (GHR), VNTR in the promoter region of the gene for insulin-like growth factor- 1 (IGF1) and a single nucleotide polymorphism (SNP) in the promoter region of the gene insulin-like growth factor-binding protein 3 (IGFBP3). Molecular findings were correlated with the first-year growth velocity (n = 112) and adult height (n = 65)) after rhGH therapy using simple and multiple linear regressions analysis adjusting for other clinical variables related to the response to rhGH treatment on TS. Two of these polymorphisms - the presence (GHR-fl) or absence (GHR-d3) of the GHR éxon 3 polymorphism and -202 A / C IGFBP-3 independently and interactively influenced the response to rhGH treatment in patients with TS, whereas the VNTR in the promoter region of the gene for IGF1 showed no influence on any of the parameters analyzed. Patients carrying at least one d3-GHR allele have better first-year growth velocity and greater adult height after rhGH treatment than those homozygous for GHR-fl allele. Similarly, the carriers of at least one -202 A-IGFBP3 allele showed better first-year growth velocity and greater adult height after rhGH treatment, besides higher serum IGFBP-3 levels, than those homozygous for -202 C-IGFBP3 allele. Finally, the combined analysis of GHR-éxon 3 and -202 A / C IGFBP3 genotypes have demonstrated a clear epistatic influence, partially additive, of these two common polymorphisms on adult height of patients with TS treated with rhGH (isolated effect of GHR-éxon 3, R2 = 0.27; isolated effect of the -202 A / C IGFBP3, R2 = 0.24; combined influence of these polymorphisms, R2 = 0.37). In conjunction with the clinical variables, baseline height (SDS) (p <0.001) and chronological age at onset of puberty (p <0.001), these two polymorphisms are able to predict 61% of the variability in adult height after rhGH therapy. Although validation studies are still needed, we believe that the information brought by this and other studies whose efforts are to understand the molecular basis involved in responsiveness to rhGH treatment can serve as an important tool in the future individualization of treatment with rhGH

Introdução: Polimorfismos na região promotora dos genes da insulina, IGF2 e IGF1 podem estar relacionados a uma diminuição da expressão desses genes na vida fetal que, por sua vez, pode causar restrição do crescimento intra-uterino e maior risco de hipospádia. Na vida pós-natal, perda completa ou parcial da expressão desses genes pode resultar em ausência de recuperação estatural e menores concentrações séricas de IGF1 na criança, além de um maior risco de diabetes melito tipo 2 e síndrome de resistência à insulina no adulto. Objetivos: Analisar em crianças nascidas pequenas para idade gestacional (PIG) com ou sem recuperação estatural (RE): 1) a freqüência alélica e genotípica dos polimorfismos VNTR-INS e das repetições CA do gene IGF1; 2) a região promotora P4 do gene IGF2; 3) a influência do VNTR INS e das repetições CA do gene IGF1 na sensibilidade à insulina e nas concentrações séricas de IGF1, respectivamente. Pacientes: Foram estudados 142 indivíduos nascidos PIG com (n= 66) e sem recuperação (n= 76) estatural selecionados de três diferentes centros (HC-FMUSP, Santa Casa de São Paulo e HC-UFPR) e um grupo controle constituído de 297 indivíduos nascidos adequados para idade gestacional (AIG). Métodos: Extração de DNA genômico; amplificação por PCR das regiões contendo os polimorfismos VNTR INS e repetições CA do IGF1 e da região promotora P4; digestão por enzima de restrição; software Genescan; seqüenciamento automático; avaliação bioquímica e hormonal da glicemia, insulina e IGF1, extração de RNA, PCR em tempo real e análise estatística com SPSS 13.0 (Statistical Package fo Social Sciences). Resultados: A média do Z-altura, Z-IMC (índice de massa corpórea), Z-altura paterno e ZEA (estatura alvo) foram maiores nas crianças PIG que tiveram recuperação estatural, com o Z-PC (perímetro cefálico) maior nas crianças sem recuperação estatural. O Z-IGF1 sérico foi significantemente mais elevado em crianças que apresentaram RE (p<0,05). A distribuição e genotipica das repetições CA do gene IGF1 e do VNTR INS foi semelhante estatisticamente entre os grupos AIG e PIG, e entre os PIG com e sem RE; não foi observada associação entre esse polimorfismo e as variáveis clínicas e laboratoriais do estudo. O estudo da região promotora P4 do gene IGF2 identificou um novo polimorfismo de 9-12 repetições C na posição -1982, antes do sítio de início de transcrição do exon 2, e este apresentou distribuição semelhante entre os grupos PIG e AIG. Foi identificada também uma troca C/T em heterozigose no nono nucleotídeo do alelo 11C em quatro crianças nascidas PIG. Contudo, a quantificação da expressão do gene IGF2 em duas dessas crianças não demonstrou perda da expressão desse gene. Conclusões: Não observamos influência dos polimorfismos acima descritos no crescimento pré e pós-natal, na presença de resistência à insulina, nem em concentrações séricas de IGF1 dos indivíduos nascidos PIG. Identificamos uma nova variante na região promotora P4 do gene IGF2, contudo estudos preliminares não demonstraram influência desse polimorfismo sobre o crescimento intra-uterino. / Introduction: Polymorphisms in the promoter region of insulin (INS), IGF2 and IGF1 genes may decrease their expression during fetal life and afterward could be related to intra-uterine fetal growth retardation and greater risk of hypospadia development. In post-natal life, decreased expression of these genes can result in lack of stature recovery and in lower IGF1 serum levels in children, as well as in higher risk for type 2 diabetes mellitus and metabolic syndrome in adults. Objectives: The aims of the present study were: (1) to analyze the allelic and the genotypic frequency of the insulin (INS) gene variable number of tandem repeats (VNTR) and the IGF1 gene CA repeats; (2) to analyze the P4 promoter region of IGF2 gene (3) to test the contribution of INS VNTR, IGF1 gene CA repeats on insulin sensitivity and IGF1 serum levels in children born SGA with and without catch up, respectively. Patients: We studied 142 individuals born SGA with catch up (n = 66) and without catch up (n = 76) selected from three different centers (HCFMUSP, Santa Casa de Sao Paulo and HC-UFPR). The control group consisted of 297 children born appropriate for gestational age (AGA). Methods: Extraction of genomic DNA, PCR-amplification of the VNTR of insulin gene, CA repeats of IGF1 and IGF2 gene P4 promoter region; restriction analysis; Genescan software; automatic sequencing. Blood measurements of serum level of glucose, insulin and IGF1. Statistical analysis (Statistical Package for Social Sciences software). Results: Regarding birth parameters, the average of Z-height, Z-BMI (body mass index) and Z-height paternal and Z- EA (target height) were higher in children born SGA who had catch up. Interestingly, we observed that the Z-PC was higher in children born SGA without catch up. In addition, the Z-IGF1 serum levels were significantly higher in children who had catch up (p <0.05). The molecular analysis of IGF1 gene CA repeats and of INS gene VNTR locus did not show a statistically significant difference in the allelic and genotypic distribution of these polymorphisms between adequate for gestational age (AGA) and SGA groups nor between SGA with and without catch up. Similarly, we have not found an association of these polymorphisms with clinical or laboratory variables of this study. A novel polymorphism in the P4 promoter region of the IGF2 gene was identified. It was characterized by cytosine repeats (9-12) at position -1982 before transcription initiation site of exon 2 of IGF2 gene. Yet, we have identified a heterozygous substitution of cytosine for thymine at the nucleotide position 9 in the allele 11C in four children born SGA. This change was also absent in the control population. Quantization of IGF2 gene expression in two of these children did show loss of expression of this gene in patients carrying the variant 9C/T. Conclusions: We have not observed an association of the above described polymorphisms with pre and post natal growth, or with the occurrence of insulin resistance in individuals born SGA. IGF-1 levels did not seem to be associated with the polymorphisms either. A new variant in the P4 promoter region of IGF2 gene was identified, however preliminary studies showed no influence on intra-uterine growth.

O hormônio de crescimento (GH) recombinante humano (rhGH) é o único tratamento disponível para crianças com deficiência de GH (DGH). Embora os resultados sejam em média satisfatórios, existe uma ampla variabilidade individual, de forma que alguns indivíduos ainda falham em atingir uma estatura normal ou dentro do seu potencial genético, mesmo quando diagnosticados e tratados sob as mesmas recomendações. Parte dessa variabilidade tem sido atribuída à falta de individualização da dose, uma vez que a terapia é baseada em doses fixas de rhGH ajustadas somente pelo peso. As variáveis clínicas preditivas de resposta ao tratamento com rhGH conhecidas até o momento explicam apenas 50% da variabilidade observada, sugerindo que outros parâmetros preditivos ainda estejam por ser reconhecidos. Apesar do intenso progresso de estudos moleculares, variáveis genéticas envolvidas na modulação da capacidade de resposta ao tratamento com rhGH permanecem amplamente desconhecidas. Sendo assim, o objetivo do presente estudo foi avaliar a influência de variantes gênicas comuns, presentes em genes envolvidos nos mecanismos de ação do GH, sobre a capacidade de resposta de crescimento de crianças com DGH tratadas com rhGH, de forma a fornecer ferramentas para a individualização do tratamento. Quatro polimorfismos de importância funcional presentes em três genes envolvidos nos mecanismos de ação do GH foram correlacionados à capacidade de resposta ao tratamento com rhGH em 84 crianças pré-púberes com DGH. Os achados moleculares foram correlacionados com a velocidade de crescimento no primeiro ano (n=84) e com a altura ao final (n=37) após tratamento com rhGH. As análises estatísticas foram ajustadas para as demais variáveis clínicas relacionadas à resposta ao tratamento com rhGH. Três desses polimorfismos a presença (GHRfl) ou ausência (GHRd3) do exon 3 do gene do receptor de GH (GHR); as repetições (CA)n, da região promotora do gene do fator de crescimento insulina-símile -1 (IGF1); e o polimorfismo -202 A/C, da região promotora do gene da proteina transpostadora de IGF-3 (IGFBP3) - influenciaram de forma independente e interativa a capacidade de reposta ao tratamento com rhGH em crianças com DGH; enquanto que o polimorfismo p.Leu544Ile do GHR não demonstrou influência sobre nenhum dos parâmetros analisados. Indivíduos portadores de pelo menos um alelo GHRd3 apresentaram maior altura final após tratamento com rhGH do que indivíduos homozigotos para o alelo GHRfl. Indivíduos homozigotos para o alelo de 19 repetições CA na região promotora do IGF1 demonstraram velocidade de crescimento no primeiro ano e altura final inferiores em relação aos indivíduos portadores de pelo menos um alelo alternativo. Finalmente, os homozigotos para o alelo IGFBP3 -202 A apresentaram maiores concentrações de IGFBP-3 sérica e maior velocidade de crescimento no primeiro ano de tratamento com rhGH do que indivíduos carreadores de pelo menos um alelo C nesse mesmo locus. Embora estudos de validação sejam ainda necessários, acreditamos que as informações geradas por este e outros estudos - direcionados a um melhor entendimento das bases moleculares envolvidas na capacidade de resposta ao tratamento com rhGH - possam servir no futuro como importante ferramenta de individualização do tratamento com rhGH / Recombinant human growth hormone (rhGH) is the standard treatment for children with growth hormone deficiency (GHD). Although growth outcomes are usually satisfactory, there is a wide range of individual variability, so that some children do not achieve normal adult height or fail to reach final heights near their genetic potential, even when diagnosed and treated according to the same recommendation. Part of this variability has been attributed to the lack of treatment individualization, since therapy is based on fixed rhGH doses adjusted only by body weight. Clinical variables which predict growth responses to rhGH so far explain only 50% of the variability observed, suggesting that other influential factors may be missing from current prediction models. Despite the striking progress of molecular studies, genetic variables which are involved in modulation of rhGH responsiveness remain largely unknown. Thus, the aim of the present study was to evaluate the influence of common genetic variants present in genes involved in GH actions on the rhGH responsiveness of children with GHD. We assessed the influence of four functional polymorphisms in three genes involved in GH actions on treatment outcomes after rhGH treatment in 84 prepubertal children with GHD. Genotypes were correlated to first year growth velocity (n = 84) and final height after treatment (n = 37). Statistical analyses were adjusted for other clinical influential factors. Our results demonstrated that three of these polymorphisms the presence (GHRd3) or absence (GHRfl) of GH receptor (GHR) gene exon 3; the (CA)n repeats, in the insulin-like growth factor-1 (IGF1) promoter region; and the -202 A/C polymorphism, in the promoter region of insulin-like growth factor binding protein -3 (IGFBP3) gene can independently and interactively influence the rhGH responsiveness of children with GHD. On the other hand, the p.Leu544Ile variant of the GHR did not show any detectable influence. Individuals with at least one GHRd3 alelle had higher final height after rhGH treatment than individuals homozygous for the GHRfl allele. Homozygous for the IGF1 19 CA repeats allele presented lower first year growth velocity and lower final heights than those with at least one alternative IGF1 allele. Moreover, patients homozygous for the IGFBP3 -202 A allele presented higher IGFBP-3 serum levels and higher first year growth velocity than patients with at least one IGFBP3 C allele. Despite further validation studies are required, we believe that the results of this and other studies - directed to a better understanding of genetic basis of rhGH responsiveness - can be used, in the future, as important tools for rhGH treatment individualization