Dataset Information

CYP19A1 single nucleotide polymorphism associations with CYP19A1, NF?B1, and IL6 gene expression in human normal colon and normal liver samples.

ABSTRACT: BACKGROUND:Estrogen is known to decrease the risk of colon cancer in postmenopausal women, and may exert its actions by decreasing interleukin-6 (IL6) production via stabilization of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF?B). Estrogens are biosynthesized by CYP19A1 (aromatase), so it is possible that genetic variations in CYP19A1 influences the risk of colon cancer by altering expression of CYP19A1. Further, studies on gene-gene interactions suggest that single nucleotide polymorphisms in one gene may affect expression of other genes. The current study aims to explore the role of CYP19A1 single nucleotide polymorphisms on CYP19A1, NF?B1 and IL6 gene expression. METHODS:Phenotype-genotype associations, cross-associations between genes, and haplotype analyses were performed in both normal human colon (n=82) and liver (n=238) samples. RESULTS:CYP19A1 rs10459592, rs1961177, and rs6493497 were associated with CYP19A1 expression in colon samples (P=0.042, P=0.041, and P=0.013, respectively). CYP19A1 single nucleotide polymorphisms (rs12908960, rs730154, rs8025191, and rs17523880) were correlated with NF?B1 expression (P=0.047, P=0.04, P=0.05, and P=0.03, respectively), and CYP19A1 rs11856927, rs2470152, and rs2470144 (P=0.049, P=0.025, P=0.047, respectively) were associated with IL6 expression in the colon. While rs730154 and rs17523880 could not be analyzed in the liver samples, none of the other associations with the colon were replicated in the liver samples. Haplotype analysis revealed three separate haplotypes of the CYP19A1 single nucleotide polymorphism that were significantly associated with CYP19A1, NF?B1, and IL6 gene expression. CONCLUSION:CYP19A1 single nucleotide polymorphisms are associated not only with CYP19A1 expression but also with NF?B1 and IL6 expression. These data demonstrate the possible functional consequences of genetic variation within the CYP19A1 gene on other genes in a biologically plausible pathway.

SUBMITTER: Penney RB

PROVIDER: S-EPMC4109316 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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CYP19A1 single nucleotide polymorphism associations with CYP19A1, NFκB1, and IL6 gene expression in human normal colon and normal liver samples.

Penney Rosalind B RB Lundgreen Abbie A Yao-Borengasser Aiwei A Edavana Vineetha K VK Williams Suzanne S Dhakal Ishwori I Wolff Roger K RK Kadlubar Susan S Slattery Martha L ML

Pharmacogenomics and personalized medicine 20140714

<h4>Background</h4>Estrogen is known to decrease the risk of colon cancer in postmenopausal women, and may exert its actions by decreasing interleukin-6 (IL6) production via stabilization of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). Estrogens are biosynthesized by CYP19A1 (aromatase), so it is possible that genetic variations in CYP19A1 influences the risk of colon cancer by altering expression of CYP19A1. Further, studies on gene-gene intera ...[more]

PMID: 25114581

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Project description:BackgroundGenome-wide association studies (GWAS) identify disease-associations for single-nucleotide-polymorphisms (SNPs) from scattered genomic-locations. However, SNPs frequently reside on several different SNP-haplotypes, only some of which may be disease-associated. This circumstance lowers the observed odds-ratio for disease-association.Methodology/principal findingsHere we develop a method to identify the two SNP-haplotypes, which combine to produce each person's SNP-genotype over specified chromosomal segments. Two multiple sclerosis (MS)-associated genetic regions were modeled; DRB1 (a Class II molecule of the major histocompatibility complex) and MMEL1 (an endopeptidase that degrades both neuropeptides and β-amyloid). For each locus, we considered sets of eleven adjacent SNPs, surrounding the putative disease-associated gene and spanning ∼200 kb of DNA. The SNP-information was converted into an ordered-set of eleven-numbers (subject-vectors) based on whether a person had zero, one, or two copies of particular SNP-variant at each sequential SNP-location. SNP-strings were defined as those ordered-combinations of eleven-numbers (0 or 1), representing a haplotype, two of which combined to form the observed subject-vector. Subject-vectors were resolved using probabilistic methods. In both regions, only a small number of SNP-strings were present. We compared our method to the SHAPEIT-2 phasing-algorithm. When the SNP-information spanning 200 kb was used, SHAPEIT-2 was inaccurate. When the SHAPEIT-2 window was increased to 2,000 kb, the concordance between the two methods, in both of these eleven-SNP regions, was over 99%, suggesting that, in these regions, both methods were quite accurate. Nevertheless, correspondence was not uniformly high over the entire DNA-span but, rather, was characterized by alternating peaks and valleys of concordance. Moreover, in the valleys of poor-correspondence, SHAPEIT-2 was also inconsistent with itself, suggesting that the SNP-string method is more accurate across the entire region.Conclusions/significanceAccurate haplotype identification will enhance the detection of genetic-associations. The SNP-string method provides a simple means to accomplish this and can be extended to cover larger genomic regions, thereby improving a GWAS's power, even for those published previously.

Dataset Information

CYP19A1 single nucleotide polymorphism associations with CYP19A1, NF?B1, and IL6 gene expression in human normal colon and normal liver samples.

Publications

CYP19A1 single nucleotide polymorphism associations with CYP19A1, NFκB1, and IL6 gene expression in human normal colon and normal liver samples.

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