[Associations of circulating leptin levels with colorectal adenoma and colorectal cancer: a case-control and Mendelian randomization study].

OBJECTIVE: To explore the causal association between circulating leptin levels and the risk of colorectal adenoma and colorectal cancer. METHODS: We collected demographic and clinical data and serum samples from 497 patients with colorectal adenoma, 955 patients with colorectal cancer, and 911 healthy individuals from the First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Cancer Hospital, Zhuji People's Hospital, and Lin'an District First People's Hospital. Instrumental variables of leptin were selected and genotyping tests were performed. A logistic regression model and stratified analysis were used to evaluate the association of serum leptin levels with colorectal adenoma, colorectal cancer, and the progression of colorectal adenoma to colorectal cancer. Genetic risk score (GRS) and single nucleotide polymorphisms (SNPs) were further used as instrumental variables in one-sample and two-sample Mendelian randomization analyses leveraging two-stage least squares and inverse-variance weighted methods to estimate the causal association of leptin levels with the risk of colorectal adenoma, colorectal cancer, and progression of colorectal adenoma to colorectal cancer. RESULTS: High levels of leptin, compared with its lowest quartile, were positively correlated with colorectal adenoma (P=0.005) and negatively with colorectal cancer (P < 0.001) and the risk of progression of colorectal adenoma to colorectal cancer (P < 0.001). Mendelian randomization analysis showed that GRS of leptin, either weighted or not, was not significantly correlated with the risk of colorectal adenoma, colorectal cancer, or the progression of colorectal adenoma to colorectal cancer, nor did the two-sample Mendelian randomization study support an association between leptin and the risk of colorectal cancer (P>0.05). CONCLUSION: Although the case-control study suggests probable correlations of leptin with the risk of colorectal adenoma, colorectal cancer, and colorectal adenoma progression to colorectal cancer, Mendelian randomization studies did not support a causal association of leptin with the risks of colorectal adenoma, colorectal cancer, or colorectal adenoma progression to colorectal cancer.

IL-17 and infections

IL-17 immunity has been shown to be essential for mucocutaneous protection against Candida albicans in mice and humans. However, mice with defective IL-17 immunity display broader susceptibility, as they are also prone to infections with diverse infectious agents at various sites. Humans with genetic defects affecting their IL-17 immunity usually suffer from chronic mucocutaneous candidiasis (CMC): recurrent or persistent infections of the skin, nails, and mucosae with C. albicans, with or without other clinical signs. Most patients with autosomal dominant (AD) hyper-IgE syndrome (HIES) due to STAT3 deficiency or AD STAT1 gain-of-function display impaired IL-17-producing T-cell development, and CMC is one of their principal clinical manifestations. Similarly, patients with autosomal recessive (AR) autoimmune polyendocrine syndrome type 1 (APS-1) caused by AIRE deficiency have high levels of neutralizing autoantibodies against IL-17A, IL-17F and/or IL-22 and present CMC as their only infectious disease. Finally, CMC is the main clinical phenotype observed in patients with inborn errors specifically affecting IL-17 immunity. Indeed, patients with AD IL-17F deficiency or AR IL-17RA or ACT1 deficiency display CMC and, to a lesser extent, superficial staphylococcal diseases. Candida infection was recently reported in psoriasis patients treated with anti-IL-17A antibodies. Careful monitoring for CMC is thus important during anti-IL-17 treatment

Se ha demostrado que la inmunidad IL-17 es esencial para la protección mucocutánea contra la Candida albicans en ratones y humanos. Independientemente, los ratones con inmunidad IL-17 defectuosa muestran una susceptibilidad más amplia, de modo que también son propensos a infecciones por diversos agentes infecciosos en varios lugares. Los humanos con defectos genéticos que afectan su inmunidad IL-17 habitualmente padecen candidiasis mucocutánea crónica (CMC): infecciones cutáneas recurrentes o persistentes de uñas y mucosas por C. albicans, con o sin otros signos clínicos. Muchos pacientes con síndrome de hiper IgE autosómico dominante (AD-HIES) debido a deficiencia STAT3 o a aumento de función AD STAT1 muestran un desarrollo dañado de células T productoras de IL-17 y la CMC es una de sus principales manifestaciones. De igual manera, los pacientes con síndrome poliendocrino autoinmune tipo 1 recesivo autosómico (AR-APS-1) causado por deficiencia de AIRE (regulador autoinmune) presentan altos niveles de anticuerpos neutralizantes contra IL-17A, IL-17F y/o IL-22 y padecen CMC como su única enfermedad infecciosa. Finalmente, la CMC es el principal fenotipo clínico observado en pacientes con errores innatos, específicamente aquellos que afectan la inmunidad IL-17. De hecho, los pacientes con deficiencia AD IL-17F o deficiencia IL-17RA o ACT1 presentan CMC y, en menor medida, enfermedades estafilocócicas superficiales. Se ha informado recientemente CMC en pacientes tratados con anticuerpos anti-IL-17A. Es importante el control cuidadoso de la CMC en estos pacientes durante el tratamiento con anti-IL-17ª