RESUMEN
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
Asunto(s)
Tejido Adiposo/metabolismo , Distribución de la Grasa Corporal , Estudio de Asociación del Genoma Completo , Insulina/metabolismo , Sitios de Carácter Cuantitativo/genética , Adipocitos/metabolismo , Adipogénesis/genética , Factores de Edad , Índice de Masa Corporal , Epigénesis Genética , Europa (Continente)/etnología , Femenino , Genoma Humano/genética , Humanos , Resistencia a la Insulina/genética , Masculino , Modelos Biológicos , Neovascularización Fisiológica/genética , Obesidad/genética , Polimorfismo de Nucleótido Simple/genética , Grupos Raciales/genética , Caracteres Sexuales , Transcripción Genética/genética , Relación Cintura-CaderaRESUMEN
Many cytokines are currently under investigation as potential target to improve cardiac function and outcome in the setting of acute myocardial infarction (MI) or chronic heart failure (HF). Here we aim to provide a translational overview of cytokine inhibiting therapies tested in experimental models and clinical studies. In various experimental studies, inhibition of interleukin-1 (IL-1), -6 (IL-6), -8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), CC- and CXC chemokines, and tumor necrosis factor-α (TNF-α) had beneficial effects on cardiac function and outcome. On the other hand, neutral or even detrimental results have been reported for some (IL-1, IL-6, IL-8, and MCP-1). Ambivalence of cytokine function, differences in study designs, treatment regimens and chosen endpoints hamper the translation of experimental research into clinical practice. Human studies are currently limited to IL-1ß inhibition, IL-1 receptor antagonists (IL-1RA), IL-6 receptor antagonists (IL-6RA) or TNF inhibition. Despite favorable effects on cardiovascular events observed in retrospective cohort studies of rheumatoid arthritis patients treated with TNF inhibition or IL-1RA, most prospective studies reported disappointing and inconsistent results. Smaller studies (n < 100) generally reported favorable results of anticytokine therapy on cardiac function, but only one of the larger studies (n > 100) evaluating IL-1ß inhibition presented positive results on outcome. In conclusion, of the 10 anticytokine therapies tested in animals models beneficial effects have been reported in at least one setting. In larger clinical studies, findings were unsatisfactory in all but one. Many anticytokine therapies with promising animal experimental data continue to require further evaluation in humans.
Asunto(s)
Antiinflamatorios/uso terapéutico , Fármacos Cardiovasculares/uso terapéutico , Citocinas/antagonistas & inhibidores , Insuficiencia Cardíaca/tratamiento farmacológico , Mediadores de Inflamación/antagonistas & inhibidores , Infarto del Miocardio/tratamiento farmacológico , Animales , Antiinflamatorios/efectos adversos , Fármacos Cardiovasculares/efectos adversos , Citocinas/inmunología , Insuficiencia Cardíaca/inmunología , Insuficiencia Cardíaca/fisiopatología , Humanos , Mediadores de Inflamación/inmunología , Infarto del Miocardio/inmunología , Infarto del Miocardio/fisiopatología , Transducción de Señal/efectos de los fármacos , Investigación Biomédica TraslacionalRESUMEN
We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.