ABSTRACT
Non-Hodgkin lymphoma (NHL) has been associated with immunological defects, chronic inflammatory and autoimmune conditions. Given the link between immune dysfunction and NHL, genetic variants in toll-like receptors (TLRs) have been regarded as potential predictive factors of susceptibility to NHL. Adequate anti-tumoral responses are known to depend on TLR9 function, such that the use of its synthetic ligand is being targeted as a therapeutic strategy. We investigated the association between the functional rs5743836 polymorphism in the TLR9 promoter and risk for B-cell NHL and its major subtypes in three independent case-control association studies from Portugal (1160 controls, 797 patients), Italy (468 controls, 494 patients) and the US (972 controls, 868 patients). We found that the rs5743836 polymorphism was significantly overtransmitted in both Portuguese (odds ratio (OR), 1.85; P=7.3E-9) and Italian (OR, 1.84; P=6.0E-5) and not in the US cohort of NHL patients. Moreover, the increased transcriptional activity of TLR9 in mononuclear cells from patients harboring rs5743836 further supports a functional effect of this polymorphism on NHL susceptibility in a population-dependent manner.
Subject(s)
Lymphoma, Non-Hodgkin/genetics , Polymorphism, Genetic , Toll-Like Receptor 9/genetics , Female , Genetics, Population , Humans , Lymphoma, Non-Hodgkin/epidemiology , Male , Middle Aged , Risk FactorsABSTRACT
El seudohipoparatiroidismo tipo Ia (PHP-Ia) resulta de un déficit específico de la proteína Gsα, que se manifiesta por la resistencia a la parathormona y un fenotipo característico, denominado osteodistrofia hereditaria de Albright. Fueron identificadas varias mutaciones en el gen GNAS1 en los individuos con PHP-Ia y seudoseudohipoparatiroidismo. Una sola mutación del gen GNAS1 puede ser responsable de ambas enfermedades. Cuando la anomalía es transmitida por el padre dará lugar a un fenotipo de seudoseudohipoparatiroidismo y cuando lo es por la madre, se manifestará como un PHP-Ia. Los autores presentan el caso de un varón adolescente con PHP-Ia. El estudio del gen GNAS1 reveló la mutación c.899A >.Lys300Ile en el exón 11. Hemos identificado la misma mutación en la madre, que solo presentaba alteraciones somáticas no asociadas a resistencia a la hormona seudoseudohipoparatiroidismo. Esta es una mutación original, aún no descrita en la literatura (AU)
Pseudohypoparathyroidism Ia (PHP-Ia) results from a specific deficiency of the α subunit of stimulatory G protein, manifested by resistance to parathormone and a characteristic phenotype, referred to as Albright hereditary osteodystrophy (AHO). Several mutations were identified in the GNAS1 gene in individuals with PHP-Ia and pseudopseudohypoparathyroidism (PPHP). A single GNAS1 mutation may be responsible for both PHP-Ia e PPHP in the same family, when inherited from the maternal and the paternal allele, respectively. The authors present the case of a teenage boy with PHP- Ia. The study revealed the GNAS1 mutation c.899A>T (p.Lys300Ile) in exon 11. After the genetic study of his parents, we have identified the same mutation in the mother, who had only somatic alterations (AHO), not associated with hormone resistance (PPHP). This is an original mutation, not yet described in the literature (AU)
Subject(s)
Humans , Male , Adolescent , Pseudohypoparathyroidism/diagnosis , Fibrous Dysplasia, Polyostotic/diagnosis , Mutation , Genetic Predisposition to DiseaseABSTRACT
Pseudohypoparathyroidism Ia (PHP-Ia) results from a specific deficiency of the alpha subunit of stimulatory G protein, manifested by resistance to parathormone and a characteristic phenotype, referred to as Albright hereditary osteodystrophy (AHO). Several mutations were identified in the GNAS1 gene in individuals with PHP-Ia and pseudopseudohypoparathyroidism (PPHP). A single GNAS1 mutation may be responsible for both PHP-Ia e PPHP in the same family, when inherited from the maternal and the paternal allele, respectively. The authors present the case of a teenage boy with PHP- Ia. The study revealed the GNAS1 mutation c.899A >T (p.Lys300Ile) in exon 11. After the genetic study of his parents, we have identified the same mutation in the mother, who had only somatic alterations (AHO), not associated with hormone resistance (PPHP). This is an original mutation, not yet described in the literature.
Subject(s)
Mutation , Pseudohypoparathyroidism/classification , Pseudohypoparathyroidism/genetics , Adolescent , Humans , Male , PhenotypeABSTRACT
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