Search

Lumacaftor/ivacaftor (LUMA-IVA) therapy is prescribed to people with cystic fibrosis (pwCF) homozygous for the Phe508del-CFTR variant to restore CFTR protein function. There is, however, large inter-individual variability in treatment response. Here, we seek to identify clinical and/or genetic factors that may modulate the response to this CFTR modulator therapy. A total of 765 pwCF older than 12 years under LUMA-IVA therapy and with lung function and nutritional measurements available before and after treatment initiation were included. Response to treatment was determined by the change in lung function and nutritional status, from baseline and over the first two years after initiation, and it was assessed by weighted generalized estimating equation models. Gains in lung function and nutritional status were observed after 6 months of treatment (on average 2.11 ± 7.81% for percent predicted FEV1 and 0.44 ± 0.77 kg/m2 for BMI) and sustained over the 2 years. We observed that the more severe patients gained the most in lung function and nutritional status. While females started with a nutritional status more impaired than males, they had a larger response and regained BMI Z-score values similar to men after 2 years of treatment. We observed no association between variants in solute carrier (SLC) genes and the respiratory function response to LUMA-IVA, but the SLC6A14 rs12839137 variant was associated with the nutritional response. Further investigations, including other genomic regions, will be needed to fully explore the inter-individual variability of the response to LUMA-IVA.

ResumenPara evitar la endogamia muchas plantas con flores hermafroditas evolucionaron con un mecanismo para reconocer y rechazar su propio polen y que se conoce como sistema de autoincompatibilidad (AI). En muchos casos la AI está controlada genéticamente por un solo locus altamente polimórfico, conocido como locus S. Esta región del DNA incluye dos unidades transcripcionales fuertemente ligadas. Una de ellas codifica la determinante femenina (expresada en el pistilo) y la otra a la determinante masculina (expresada en el polen). En esta revisión se discuten los principales avances en el mecanismo de AI gametofítica dependiente de S-RNasas, el cual está presente en Solanaceae, Rosaceae y Plantaginaceae. En estas familias, la determinante femenina codifica una ribonucleasa (S-RNasa) y la determinante masculina una proteína con caja F (SLF/SFB). Además, se describe la participación de genes modificadores no codificados en el locus S y que son esenciales en la AI, así como la posible función de sus productos en el mecanismo de rechazo del polen. Finalmente, proponemos un modelo que incluye los principales sucesos descritos a la fecha.AbstractTo avoid endogamy many flowering plants evolved a mechanism to recognize and reject their self-pollen, which is known as self-incompatibility (SI) system. In many cases the SI is genetically controlled by a single and highly polymorphic locus known as the S-locus. This DNA region carries two tightly linked transcriptional units. One of them encodes the female determinant (pistil expressed) and the second one the male determinant (pollen expressed). In this review, we discuss the most relevant advances in the SI mechanism in S-RNase based systems, which are present in Solanaceae, Rosaceae and Plantaginaceae. In these families, the female determinant encodes a ribonuclease named S-RNase and the male determinant encodes a protein called SLF/SFB (S-locus F-Box). We finally describe the role of the role of modifier genes, not coded by S-locus, in the pollen rejection response and propose a model including the main events so far described.