RESUMO
OBJECTIVE: Individual sensitivity to recombinant human GH (r-hGH) is variable. Identification of genetic factors contributing to this variability has potential use for individualization of treatment. The objective of this study was to identify genetic markers and gene expression profiles associated with growth response on r-hGH therapy in treatment-naïve, prepubertal children with GH deficiency (GHD) or Turner syndrome (TS). DESIGN: A prospective, multicenter, international, open-label pharmacogenomic study. METHODS: The associations of genotypes in 103 growth- and metabolism-related genes and baseline gene expression profiles with growth response to r-hGH (cm/year) over the first year were evaluated. Genotype associations were assessed with growth response as a continuous variable and as a categorical variable divided into quartiles. RESULTS: Eleven genes in GHD and ten in TS, with two overlapping between conditions, were significantly associated with growth response either as a continuous variable (seven in GHD, two in TS) or as a categorical variable (four more in GHD, eight more in TS). For example, in GHD, GRB10 was associated with high response (≥ Q3; P=0.0012), while SOS2 was associated with low response (≤ Q1; P=0.006), while in TS, LHX4 was associated with high response (P=0.0003) and PTPN1 with low response (P=0.0037). Differences in expression were identified for one of the growth response-associated genes in GHD (AKT1) and for two in TS (KRAS and MYOD1). CONCLUSIONS: Carriage of specific growth-related genetic markers is associated with growth response in GHD and TS. These findings indicate that pharmacogenomics could have a role in individualized management of childhood growth disorders.
Assuntos
Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteínas Son Of Sevenless/genética , Síndrome de Turner/tratamento farmacológico , Síndrome de Turner/genética , Estatura/efeitos dos fármacos , Criança , Desenvolvimento Infantil/efeitos dos fármacos , Resistência a Medicamentos , Feminino , Seguimentos , Proteína Adaptadora GRB10/genética , Proteína Adaptadora GRB10/metabolismo , Estudo de Associação Genômica Ampla , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/prevenção & controle , Terapia de Reposição Hormonal , Humanos , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Masculino , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteínas Recombinantes/uso terapêutico , Proteínas Son Of Sevenless/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Síndrome de Turner/sangue , Síndrome de Turner/metabolismoRESUMO
Endometriosis is a polygenic gynaecological condition affecting 5-15% of women of childbearing age. Major symptoms of the disease are pelvic pain and infertility. No clear link has been established between symptoms and the stage of the disease. Although some aspects have begun to be clarified, clinical understanding of endometriosis remains partial at the molecular level. In this perspective, we targeted isolation of differentially expressed genes in the eutopic endometrial tissue. Our assumption was that the endometrial cells of patients presented an unusual gene expression profile, allowing their implantation and survival in an ectopic site, leading to endometriotic lesions. Here, we report that mRNA steady-state levels of two key transcription factors are modulated in endometriosis. FOXO1 (also known as FKHR) levels were 1.6-fold lower in endometriosis compared to the control group at the onset of the secretory phase (day 15-21), while c-jun mRNA was present at higher amounts in endometriosis (1.5-fold) at the proliferative phase of the menstrual cycle. These results were derived from a large sample composed of 157 control subjects and 209 patients with endometriosis. Gene profiling was conducted by real-time quantitative PCR, and data were quality controlled before statistical analysis. Whether protein levels are affected as well remains to be investigated.
