RESUMO
Age-related macular degeneration (AMD) is a multifactorial genetic disease, with at least 52 identifiable associated gene variants at 34 loci, including variants in complement factor H (CFH) and age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase-1 (ARMS2/HTRA1). Genetic factors account for up to 70% of disease variability. However, population-based genetic risk scores are generally more helpful for clinical trial design and stratification of risk groups than for individual patient counseling. There is some evidence of pharmacogenetic influences on various treatment modalities used in AMD patients, including Age-Related Eye Disease Study (AREDS) supplements, photodynamic therapy (PDT), and anti-vascular endothelial growth factor (anti-VEGF) agents. However, there is currently no convincing evidence that genetic information plays a role in routine clinical care.
Assuntos
Degeneração Macular , Proteínas , Humanos , Degeneração Macular/tratamento farmacológico , Degeneração Macular/genética , Suplementos Nutricionais , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Fatores de Crescimento do Endotélio Vascular/genética , Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
BACKGROUND This study was performed to estimate the genetic effects of HtrA1 polymorphisms rs1049331 and rs11200638 on treatment response in stage III colon cancer patients receiving 5-FU-based chemotherapy. MATERIAL AND METHODS A total of 105 stage III colon cancer patients who received postoperative 5-FU based adjuvant chemotherapy were included in our study. Chemotherapy was performed in 3 cycles for the patients. HtrA1 rs1049331 and rs11200638 polymorphisms were genotyped via polymerase chain reaction with sequencing method. The treatment response was estimated according to the RECIST guidelines. RESULTS The response rate of the eligible patients was 53.33%. For rs1049331, the presences of TT genotype and T allele indicted reduced chemotherapy sensitivity (adjusted TT: OR=1.736, 95%CI: 1.001-3.011, P=0.049; T: OR=1.801, 95%CI: 1.054-2.932, P=0.039). The rs11200638 polymorphism had no significant association with chemotherapy sensitivity in the study population (P>0.05 for all). CONCLUSIONS HtrA1 rs1049331 polymorphism, but not rs11200638 polymorphism, can influence individual sensitivity to 5-FU-based treatment in stage III colon cancer patients.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Neoplasias do Colo/terapia , Resistencia a Medicamentos Antineoplásicos/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Adulto , Antimetabólitos Antineoplásicos/uso terapêutico , Povo Asiático , Estudos de Casos e Controles , Quimioterapia Adjuvante , Colectomia , Colo/patologia , Colo/cirurgia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Critérios de Avaliação de Resposta em Tumores SólidosRESUMO
PURPOSE: Age-related macular degeneration (AMD), a multifactorial disease with variable phenotypic presentation, was associated with 52 single nucleotide polymorphisms (SNPs) at 34 loci in a genome-wide association study (GWAS). These genetic variants could modulate different biological pathways involved in AMD, contributing to phenotypic variability. To better understand the effects of these SNPs, we performed a deep phenotype association study (DeePAS) in the Age-Related Eye Disease Study 2 (AREDS2), followed by replication using AREDS participants, to identify genotype associations with AMD and non-AMD ocular and systemic phenotypes. DESIGN: Cohort study. PARTICIPANTS: AREDS and AREDS2 participants. METHODS: AREDS2 participants (discovery cohort) had detailed phenotyping for AMD; other eye conditions; cardiovascular, neurologic, gastrointestinal, and endocrine disease; cognitive function; serum nutrient levels; and others (total of 139 AMD and non-AMD phenotypes). Genotypes of the 52 GWAS SNPs were obtained. The DeePAS was performed by correlating the 52 SNPs to all phenotypes using logistic and linear regression models. Associations that reached Bonferroni-corrected statistical significance were replicated in AREDS. MAIN OUTCOME MEASURES: Genotype-phenotype associations. RESULTS: A total of 1776 AREDS2 participants had 5 years follow-up; 1435 AREDS participants had 10 years. The DeePAS revealed a significant association of the rs3750846 SNP at the ARMS2/HTRA1 locus with subretinal/sub-retinal pigment epithelial (RPE) hemorrhage related to neovascular AMD (odds ratio 1.55 [95% confidence interval 1.31-1.84], P = 2.67 × 10-7). This novel association remained significant after conditioning on participants with neovascular AMD (P = 2.42 × 10-4). Carriers of rs3750846 had poorer visual acuity during follow-up (P = 6.82 × 10-7) and were more likely to have a first-degree relative with AMD (P = 5.38 × 10-6). Two SNPs at the CFH locus, rs10922109 and rs570618, were associated with the drusen area in the Early Treatment Diabetic Retinopathy Study Report (ETDRS) grid (P = 2.29 × 10-11 and P = 3.20 × 10-9, respectively) and the center subfield (P = 1.24 × 10-9 and P = 6.68 × 10-8, respectively). SNP rs570618 was additionally associated with the presence of calcified drusen (P = 5.38 × 10-6). Except for positive family history of AMD with rs3750846, all genotype-phenotype associations were significantly replicated in AREDS. No pleiotropic associations were identified. CONCLUSIONS: The association of the SNP at the ARMS2/HTRA1 locus with subretinal/sub-RPE hemorrhage and poorer visual acuity and of SNPs at the CFH locus with drusen area may provide new insights in pathophysiological pathways underlying different stages of AMD.