RNASEL and MIR146A SNP-SNP interaction as a susceptibility factor for non-melanoma skin cancer.
Immunity and inflammatory pathways are important in the genesis of non-melanoma skin cancers (NMSC). Functional genetic variation in immune modulators has the potential to affect disease etiology. We investigated associations between common variants in two key regulators, MIR146A and RNASEL, and their relation to NMSCs. Using a large population-based case-control study of basal cell (BCC) and squamous cell carcinoma (SCC), we investigated the impact of MIR146A SNP rs2910164 on cancer risk, and interaction with a SNP in one of its putative targets (RNASEL, rs486907). To examine associations between genotype and BCC and SCC, occurrence odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using unconditional logistic regression, accounting for multiple confounding factors. We did not observe an overall change in the odds ratios for SCC or BCC among individuals carrying either of the RNASEL or MIR146A variants compared with those who were wild type at these loci. However, there was a sex-specific association between BCC and MIR146A in women (ORGC = 0.73, [95%CI = 0.52-1.03]; ORCC = 0.29, [95% CI = 0.14-0.61], p-trend<0.001), and a reduction in risk, albeit not statistically significant, associated with RNASEL and SCC in men (ORAG = 0.88, [95%CI = 0.65-1.19]; ORAA = 0.68, [95%CI = 0.43-1.08], p-trend = 0.10). Most striking was the strong interaction between the two genes. Among individuals carrying variant alleles of both rs2910164 and rs486907, we observed inverse relationships with SCC (ORSCC = 0.56, [95%CI = 0.38-0.81], p-interaction = 0.012) and BCC (ORBCC = 0.57, [95%CI = 0.40-0.80], p-interaction = 0.005). Our results suggest that genetic variation in immune and inflammatory regulators may influence susceptibility to NMSC, and novel SNP-SNP interaction for a microRNA and its target. These data suggest that RNASEL, an enzyme involved in RNA turnover, is controlled by miR-146a and may be important in NMSC etiology.
Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.
Shohreh F
SF
Farzan
Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.
Margaret R
MR
Karagas
Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America; Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
Brock C
BC
Christensen
Department of Community and Family Medicine, Section of Biostatistics and Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.
Zhongze
Z
Li
Division of Epidemiology and Community Health, The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
Jacquelyn K
JK
Kuriger
Division of Epidemiology and Community Health, The Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
Heather H
HH
Nelson
D000328:Adult; D000368:Aged; D002280:Basal Cell Carcinoma / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D016022:Case-Control Studies; D004722:Endoribonucleases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012878:Skin Neoplasms / Q000235:genetics*
C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease