ALEXANDER AUGUSTO DE LIMA JORGE
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
2 resultados
Resultados de Busca
Agora exibindo 1 - 2 de 2
- A Genome-Wide Pharmacogenetic Study of Growth Hormone Responsiveness(2020) DAUBER, Andrew; MENG, Yan; AUDI, Laura; VEDANTAM, Sailaja; WEAVER, Benjamin; CARRASCOSA, Antonio; ALBERTSSON-WIKLAND, Kerstin; RANKE, Michael B.; JORGE, Alexander A. L.; CARA, Jose; WAJNRAJCH, Michael P.; LINDBERG, Anders; CAMACHO-HUBNER, Cecilia; HIRSCHHORN, Joel N.Context: Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness. Objective: To identify genetic variants associated with GH responsiveness. Design: Genome-wide association study (GWAS). Setting: Cohorts from multiple academic centers and a clinical trial. Patients: A total of 614 individuals from 5 short stature cohorts receiving GH: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age. Intervention: Association of more than 2 million variants was tested. Main Outcome Measures: Primary analysis: individual single nucleotide polymorphism (SNP) association with first-year change in height standard deviation scores. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genome-wide significant height SNPs with GH responsiveness. Results: No common variant associations reached genome-wide significance in the primary analysis. The strongest suggestive signals were found near the B4GALT4 and TBCE genes. After meta-analysis including replication data, signals at several loci reached or retained genomewide significance in secondary analyses, including variants near ST3GAL6. There was no significant association with variants previously reported to be associated with GH response nor with a polygenic predicted height score. Conclusions: We performed the largest GWAS of GH responsiveness to date. We identified 2 loci with a suggestive effect on GH responsiveness in our primary analysis and several genomewide significant associations in secondary analyses that require further replication. Our results are consistent with a polygenic component to GH responsiveness, likely distinct from the genetic regulators of adult height.
- Clinical and Molecular Description of 16 Families With Heterozygous IHH Variants(2020) SENTCHORDI-MONTANE, Lucia; BENITO-SANZ, Sara; AZA-CARMONA, Miriam; PEREDA, Arrate; PARRON-PAJARES, Manuel; TORRE, Carolina de la; VASQUES, Gabriela A.; FUNARI, Mariana F. A.; TRAVESSA, Andre M.; DIAS, Patricia; SUAREZ-ORTEGA, Larisa; GONZALEZ-BUITRAGO, Jesus; PORTILLO-NAJERA, Nancy Elizabeth; LLANO-RIVAS, Isabel; MARTIN-FRIAS, Maria; RAMIREZ-FERNANDEZ, Joaquin; POZO, Jaime Sanchez del; GARZON-LORENZO, Lucia; MARTOS-MORENO, Gabriel A.; ALFARO-IZNAOLA, Cristina; MULERO-COLLANTES, Ines; RUIZ-OCANA, Pablo; CASANO-SANCHO, Paula; PORTELA, Ana; RUIZ-PEREZ, Lorea; POZO, Angela del; VALLESPIN, Elena; SOLIS, Mario; LERARIO, Antonio M.; GONZALEZ-CASADO, Isabel; ROS-PEREZ, Purificacion; NANCLARES, Guiomar Perez de; JORGE, Alexander A. L.; HEATH, Karen E.Context: Heterozygous variants in the Indian hedgehog gene (IHH) have been reported to cause brachydactyly type A1 and mild hand and feet skeletal anomalies with short stature. Genetic screening in individuals with short stature and mild skeletal anomalies has been increasing over recent years, allowing us to broaden the clinical spectrum of skeletal dysplasias. Objective: The objective of this article is to describe the genotype and phenotype of 16 probands with heterozygous variants in IHH. Patients and Methods: Targeted next-generation sequencing or Sanger sequencing was performed in patients with short stature and/or brachydactyly for which the genetic cause was unknown. Results: Fifteen different heterozygous IHH variants were detected, one of which is the first reported complete deletion of IHH. None of the patients showed the classical phenotype of brachydactyly type A1. The most frequently observed clinical characteristics were mild to moderate short stature as well as shortening of the middle phalanx on the fifth finger. The identified IHH variants were demonstrated to cosegregate with the short stature and/or brachydactyly in the 13 probands whose family members were available. However, clinical heterogeneity was observed: Two short-statured probands showed no hand radiological anomalies, whereas another 5 were of normal height but had brachydactyly. Conclusions: Short stature and/or mild skeletal hand defects can be caused by IHH variants. Defects in this gene should be considered in individuals with these findings, especially when there is an autosomal dominant pattern of inheritance. Although no genotype-phenotype correlation was observed, cosegregation studies should be performed and where possible functional characterization before concluding that a variant is causative.