1.
Association of Genetic Variants With Response to Anti-Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration.
Lorés-Motta, L, Riaz, M, Grunin, M, Corominas, J, van Asten, F, Pauper, M, Leenders, M, Richardson, AJ, Muether, P, Cree, AJ, et al
JAMA ophthalmology. 2018;(8):875-884
-
-
Free full text
-
Abstract
IMPORTANCE Visual acuity (VA) outcomes differ considerably among patients with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs. Identification of pharmacogenetic associations may help clinicians understand the mechanisms underlying this variability as well as pave the way for personalized treatment in nAMD. OBJECTIVE To identify genetic factors associated with variability in the response to anti-VEGF therapy for patients with nAMD. DESIGN, SETTING, AND PARTICIPANTS In this multicenter genome-wide association study, 678 patients with nAMD with genome-wide genotyping data were included in the discovery phase; 1380 additional patients with nAMD were genotyped for selected common variants in the replication phase. All participants received 3 monthly injections of bevacizumab or ranibizumab. Clinical data were evaluated for inclusion/exclusion criteria from October 2014 to October 2015, followed by data analysis from October 2015 to February 2016. For replication cohort genotyping, clinical data collection and analysis (including meta-analysis) was performed from March 2016 to April 2017. MAIN OUTCOMES AND MEASURES Change in VA after the loading dose of 3 monthly anti-VEGF injections compared with baseline. RESULTS Of the 2058 included patients, 1210 (58.8%) were women, and the mean (SD) age across all cohorts was 78 (7.4) years. Patients included in the discovery cohort and most of the patients in the replication cohorts were of European descent. The mean (SD) baseline VA was 51.3 (20.3) Early Treatment Diabetic Retinopathy Study (ETDRS) score letters, and the mean (SD) change in VA after the loading dose of 3 monthly injections was a gain of 5.1 (13.9) ETDRS score letters (ie, 1-line gain). Genome-wide single-variant analyses of common variants revealed 5 independent loci that reached a P value less than 10 × 10-5. After replication and meta-analysis of the lead variants, rs12138564 located in the CCT3 gene remained nominally associated with a better treatment outcome (ETDRS letter gain, 1.7; β, 0.034; SE, 0.008; P = 1.38 × 10-5). Genome-wide gene-based optimal unified sequence kernel association test of rare variants showed genome-wide significant associations for the C10orf88 (P = 4.22 × 10-7) and UNC93B1 (P = 6.09 × 10-7) genes, in both cases leading to a worse treatment outcome. Patients carrying rare variants in the C10orf88 and UNC93B1 genes lost a mean (SD) VA of 30.6 (17.4) ETDRS score letters (ie, loss of 6.09 lines) and 26.5 (13.8) ETDRS score letters (ie, loss of 5.29 lines), respectively, after 3 months of anti-VEGF treatment. CONCLUSIONS AND RELEVANCE We propose that there is a limited contribution of common genetic variants to variability in nAMD treatment response. Our results suggest that rare protein-altering variants in the C10orf88 and UNC93B1 genes are associated with a worse response to anti-VEGF therapy in patients with nAMD, but these results require further validation in other cohorts.
2.
Functional SNPs in human C20orf54 gene influence susceptibility to esophageal squamous cell carcinoma.
Ji, A, Wang, J, Yang, J, Wei, Z, Lian, C, Ma, L, Ma, L, Chen, J, Qin, X, Wang, Ld, et al
Asian Pacific journal of cancer prevention : APJCP. 2011;(12):3207-12
Abstract
OBJECTIVES C20orf54, also known as a human riboflavin transporter 2 (RFT2), encodes an open reading frame protein RFT2 newly identified to play an important role in esophageal carcinogenesis by modulating riboflavin uptake. Missense cSNPs on exon 3,1172 C>A (T391M) and 1246A>G (I416V) have been suggested to modulate protein expression. The aim of present study was to explore the association of C20orf54 functional SNPs with susceptibility to esophageal squamous cell carcinoma (ESCC) in a northern Chinese population. METHODS 240 patients with ESCC and 198 healthy individuals without overt cancer were chosen as our experimental subjects. Information about family address, sex, age, BMI, smoking and drinking habits and family history of cancer were collected. Blood samples were taken from all subjects and tumor tissues were freshly sampled from resected specimens. After DNA was extracted and amplified, the C20orf54 SNPs were sequenced by ABI 3730XL in BGI China. Frequencies were then calculated and associated with the collected suspicous risk factors. RESULTS Drinking status, a family history of ESCC, blood type and BMI were found to have great influence on the risk of developing ESCC. Overall genotype frequencies of the RFT2 SNP 1172 C>A (rs3746803) and 1246A>G (rs3746802) in ESCC patients are significantly different from that in healthy controls (x2=13.10, P=0.001 and x2=7.97, P=0.019, respectively). For RFT2 rs3746803, C/T+T/T genotype did not show a relationship with the risk of ESCC (the age and gender adjusted OR=0.66, 95% CI=0.41-1.05) when using C/C genotype as the reference. For RFT2 rs3746802, the A/G +G/G genotype demonstrated a significantly decreased risk to the development of ESCC (the age and sex adjusted OR=0.53, 95% CI=0.34-0.84) with A/A as the reference. CONCLUSIONS The present study suggests that the C20orf54 functional SNPs might be associated with a risk of ESCC development.