Expression quantitative trait loci (eQTL) analysis can provide insights into the genetic regulation of gene expression at a genomic level and this information is proving extremely useful in many ...different areas of research. As a consequence of the role of the liver in drug metabolism and disposition, the study of eQTLs in primary human liver tissue could provide a foundation for pharmacogenomics. Thus far, four genome-wide eQTL studies have been performed using human livers. Many liver eQTLs have been found to be reproducible and a proportion of these may be specific to the liver. Already these data have been used to interpret and inform clinic genome-wide association studies, providing potential mechanistic evidence for clinical associations and identifying genes which may impact clinical phenotypes. However, the utility of liver eQTL data has not yet been fully explored or realized in pharmacogenomics. As further liver eQTL research is undertaken, the genetic regulation of gene expression will become much better characterized and this knowledge will create a rational basis for the prospective pharmacogenomic study of many drugs.
To assess whether polymorphisms in NOD2 and ATG16L1 affect cytokine responses and mycobacterium avium subspecies paratuberculosis (MAP) survival in monocytes from Crohn's disease (CD) patients.
...Monocytes were isolated from peripheral blood of CD patients of known genotype for common single nucleotide polymorphisms of NOD2 and ATG16L1. Monocytes were challenged with MAP and bacterial persistence assessed at subsequent time-points. Cytokine responses were assayed using a Milliplex multi-analyte profiling assay for 13 cytokines.
Monocytes heterozygous for a NOD2 polymorphism (R702W, P268S, or 1007fs) were more permissive for growth of MAP (P = 0.045) than those without. There was no effect of NOD2 genotype on subsequent cytokine expression. The T300A polymorphism of ATG16L1 did not affect growth of MAP in our model (P = 0.175), but did increase expression of cytokines interleukin (IL)-10 (P = 0.047) and IL-6 (P = 0.019).
CD-associated polymorphisms affected the elimination of MAP from ex vivo monocytes (NOD2), or expression of certain cytokines (ATG16L1), implying independent but contributory roles in the pathogenesis of CD.
Human genomics research has produced vast amounts of data that can be applied to or used to inform pharmacogenomic studies. The Internet is an extremely useful resource for pharmacogenomics as many ...Web sites provide access to data from genomic and clinical studies or host tools which can be used to interpret findings or generate hypotheses. Human genetic variation can now easily be explored or visualized through genome browsers and Web-based repositories which store the details of millions of human germ-line and somatic genetic variants. Gene expression data from many different tissue and cell types are available through Web-based repositories, and human genetic variants that associate with mRNA expression can be identified using Web data portals. Pharmacogenetic associations can be explored through publically available data repositories and the functionality of genetic variants predicted through Web-based bioinformatic tools. Furthermore, resources relating to currently used genetic tests are available online. Large clinical and population studies, many linked to medical records, can be queried for the availability of biospecimens or data. In the future, as the amount of genomic and associated clinical data increases, there is little doubt that Web-based resources will continue to evolve and overcome barriers hindering their efficient use, leading to systems-based approaches to pharmacogenomics.
Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight ...risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.
Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent ...associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two‐sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low‐density lipoprotein LDL and high‐density lipoprotein HDL cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10−8) were identified as instrumental variables, and assessed using genome‐wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non‐endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non‐endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non‐endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non‐endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.
What's new?
Some studies have suggested that serum lipids may correlate with endometrial cancer (EC) risk, but results have been inconsistent. In our study, the authors used genetic markers to predict LDL and HDL cholesterol levels and analyze EC risk. They found that when lower LDL or higher HDL levels were predicted, EC risk was increased. These results support a role for LDL and HDL cholesterol in the development of EC, and lipid levels may represent a risk factor for EC. Further studies are required to assess the biological and clinical significance of these associations.
Hes6 is a neurogenic gene which is down-regulated in the hippocampi of rats chronically treated with the antidepressant paroxetine. To assess whether variability in
HES6 associates with mood disorder ...diagnosis or antidepressant response, this gene was sequenced in 24 unrelated New Zealand Caucasians. A total of 12 polymorphisms were identified, six of which were in the promoter region of the gene. Haplotypes encompassing the promoter SNPs were studied by cloning the region upstream of the transcription start site, and examining basal transcription rates in luciferase reporter gene assays. SNPs located at positions −1099, −831, −424 and −267 were shown to significantly alter expression of the reporter gene. These four variants were tested for association with mood disorder diagnosis or antidepressant response in a family study of depression, but no significant associations were observed. However, given the importance of this gene in neural function and development, the promoter variants described here may be of wider relevance.
We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ...ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103T allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.
GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs ...using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.
Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found ...to be associated with outcome at genome-wide levels of significance.
We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy.
We found seven SNPs at 12q24.33 associated with PFS (
< 5 × 10
), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34;
= 1.47 × 10
). High expression of a nearby gene,
, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of
in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the
promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin
.
The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer.
is a plausible candidate for the target of this association.
This finding provides insight into genetic markers associated with EOC outcome and potential treatment options.
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