scholarly journals Characterization of population-based variation and putative functional elements for the multiple-cancer susceptibility loci at 5p15.33

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 231
Author(s):  
Lisa Mirabello ◽  
Charles C. Chung ◽  
Meredith Yeager ◽  
Sharon A Savage
Keyword(s):  
Cancer Susceptibility ◽  
Association Studies ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Multiple Cancer ◽  
Functional Variants ◽  
Genotype Frequencies ◽  
Common Genetic Variants ◽  
Increased Risk ◽  
Synonymous Sites

Background:TERTencodes the telomerase reverse transcriptase, which is responsible for maintaining telomere ends by addition of (TTAGGG)nnucleotide repeats at the telomere.  Recent genome-wide association studies have found common genetic variants at theTERT-CLPTM1Llocus (5p15.33) associated with an increased risk of several cancers. Results:Data were acquired for 1627 variants in 1092 unrelated individuals from 14 populations within the 1000 Genomes Project.  We assessed the population genetics of the 5p15.33 region, including recombination hotspots, diversity, heterozygosity, differentiation among populations, and potential functional impacts. There were significantly lower polymorphism rates, divergence, and heterozygosity for the coding variants, particularly for non-synonymous sites, compared with non-coding and silent changes. Many of the cancer-associated SNPs had differing genotype frequencies among ancestral groups and were associated with potential regulatory changes. Conclusions:Surrogate SNPs in linkage disequilibrium with the majority of cancer-associated SNPs were functional variants with a likely role in regulation ofTERTand/orCLPTM1L. Our findings highlight several SNPs that future studies should prioritize for evaluation of functional consequences.

scholarly journals Chronic lymphocytic leukemia (CLL) risk is mediated by multiple enhancer variants within CLL risk loci

2020 ◽  
Vol 29 (16) ◽  
pp. 2761-2774
Author(s):  
Huihuang Yan ◽  
Shulan Tian ◽  
Geffen Kleinstern ◽  
Zhiquan Wang ◽  
Jeong-Heon Lee ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Immune Cell ◽  
Association Studies ◽  
Cell Types ◽  
Lymphocytic Leukemia ◽  
Type I ◽  
Genome Wide Association Studies ◽  
Gene Promoters ◽  
Functional Variants ◽  
Increased Risk

Abstract Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. It has a strong genetic basis, showing a ~ 8-fold increased risk of CLL in first-degree relatives. Genome-wide association studies (GWAS) have identified 41 risk variants across 41 loci. However, for a majority of the loci, the functional variants and the mechanisms underlying their causal roles remain undefined. Here, we examined the genetic and epigenetic features associated with 12 index variants, along with any correlated (r2 ≥ 0.5) variants, at the CLL risk loci located outside of gene promoters. Based on publicly available ChIP-seq and chromatin accessibility data as well as our own ChIP-seq data from CLL patients, we identified six candidate functional variants at six loci and at least two candidate functional variants at each of the remaining six loci. The functional variants are predominantly located within enhancers or super-enhancers, including bi-directionally transcribed enhancers, which are often restricted to immune cell types. Furthermore, we found that, at 78% of the functional variants, the alternative alleles altered the transcription factor binding motifs or histone modifications, indicating the involvement of these variants in the change of local chromatin state. Finally, the enhancers carrying functional variants physically interacted with genes enriched in the type I interferon signaling pathway, apoptosis, or TP53 network that are known to play key roles in CLL. These results support the regulatory roles for inherited noncoding variants in the pathogenesis of CLL.

Known colorectal cancer susceptibility loci and survival after colorectal cancer diagnosis.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 394-394 ◽  
Author(s):  
Amanda Phipps ◽  
Xabier Garcia-Albeniz ◽  
Carolyn Hutter ◽  
Emily White ◽  
Charles S. Fuchs ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Fixed Effects ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Cox Proportional Hazards ◽  
Health Study ◽  
Genome Wide Association Studies ◽  
Increased Risk

394 Background: Beyond clinicopathologic stage, there are few established markers of prognosis in colorectal cancer (CRC). Recent genome-wide association studies have identified 17 germline single nucleotide polymorphisms (SNPs) significantly associated with incident CRC. However, it is unclear if these CRC susceptibility SNPs influence survival after CRC diagnosis. Although the functionality of many of these SNPs remains unknown, a few, including rs4939827 in SMAD7, map to genes with plausible biological mechanisms associated with both cancer risk and prognosis. We examined 17 CRC susceptibility SNPs in relation to survival after CRC diagnosis. Methods: We genotyped 2,611 men and women enrolled in five prospective cohort studies who were diagnosed with invasive CRC during study follow-up: the Physicians’ Health Study (N=281), Health Professionals Follow-up Study (N=268), Nurses’ Health Study (N=367), Vitamins and Lifestyle Study (N=281), and the Women’s Health Initiative (N=1414). Analyses were limited to Caucasians with known vital status, cause of death, and survival time. We used Cox proportional hazards regression to assess associations between each SNP and CRC-specific and overall survival in study-specific models adjusted for age, sex, and stage; SNPs were modeled additively to reflect associations per copy of the minor allele. Study-specific results were combined via fixed-effects meta-analysis. Results: The G allele in rs4939827 was associated with poorer CRC-specific survival [hazard ratio (HR)=1.16, p=0.02] and overall survival (HR=1.13, p=0.03) in CRC patients. The A alleles in rs10795668 and in rs4925386 were associated with a 1.14-fold increased risk of overall mortality (both p-values=0.03) but not CRC-specific mortality. Other evaluated SNPs were not associated with survival. Conclusions: Genetic variation in rs4939827 (SMAD7) is associated with CRC-specific and overall survival. These results suggest that SMAD7 may have a role in CRC progression, and provide proof-of-principle that common germline variation may provide prognostic information beyond traditional considerations such as stage.

scholarly journals Single nucleotide polymorphism within gene in NFKBIA is associated with the risks of nasopharyngeal carcinoma in Chinese Han population.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 67-67
Author(s):  
Hanyi Zhang ◽  
Shun Lu ◽  
Chang Sun ◽  
Siyao Deng ◽  
Jin Yi Lang
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Association Studies ◽  
Sample Size Calculation ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Chinese Han ◽  
Single Nucleotide ◽  
Significance Level ◽  
Genotype Frequencies ◽  
Increased Risk

67 Background: Nasopharyngeal Carcinoma(NPC) is an Epstein-Barr virus(EBV) associated malignancy with remarkable ethnic and geographical distribution. The EBV oncoprotein latent membrane protein 1 (LMP1) is the primary oncogene of EBV infection through the its signaling cascade and its connections to other pathways including NF-κB, TGF-β and JNK signaling, which plays an important role in the pathogenesis of NPC. In GWASs (Genome-wide association studies) associations these pathways were also identified. Single nucleotide polymorphisms (SNPs) in the regulatory regions may regulate the expression of genes in these pathways, or affect the function of the coded protein. Methods: Altogether 149 SNPs were covered by the 15 SNPs in the TRAF2, TRAF3, NFKBIA, MAP2K4, and CHUK genes were genotyped in a hospital-based case-control study of 350 NPC cases and 587 healthy controls from the Chinese Han. The observed genotype frequencies in the controls were tested for Hardy–Weinberg equilibrium (HWE) using the chi-square test. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations between genotypes and NPC risk and tumor characteristics were calculated by logistic regression, and they were adjusted for multiple testing using the SNP spectral deposition (SNPSpD) approach for multilocus analyses. Results: We found one NFKBIA SNP was associated with NPC risk after adjustment for multiple comparisons. Minor allele carriers of the NFKBIA had an increased risk of NPC (P 0.05). The analyses were adjusted for age and gender. For a polymorphism with a variant allele frequency between 10 %and 50%, the study had greater than 90% power to detect an OR of 1.50 at a significance level of 0.05 (PS—software for power and sample size calculation, http://biostat.mc.vanderbilt.edu/twiki/bin/view/Main/PowerSampleSize). The other genotyped SNPs that we found were not associated with NPC risk. Conclusions: Our data suggests that genetic variation especially in the NFKBIA maybe a useful biomarker for NPC screening and further studies are warranted.

scholarly journals Breed-Predispositions to Cancer in Pedigree Dogs

2013 ◽  
Vol 2013 ◽  
pp. 1-23 ◽  
Author(s):  
Jane M. Dobson
Keyword(s):  
Cancer Susceptibility ◽  
Association Studies ◽  
Molecular Genetic ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Complex Disorders ◽  
Genome Wide ◽  
Increased Risk ◽  
Purebred Dogs ◽  
Limited Genetic Diversity

Cancer is a common problem in dogs and although all breeds of dog and crossbred dogs may be affected, it is notable that some breeds of pedigree dogs appear to be at increased risk of certain types of cancer suggesting underlying genetic predisposition to cancer susceptibility. Although the aetiology of most cancers is likely to be multifactorial, the limited genetic diversity seen in purebred dogs facilitates genetic linkage or association studies on relatively small populations as compared to humans, and by using newly developed resources, genome-wide association studies in dog breeds are proving to be a powerful tool for unravelling complex disorders. This paper will review the literature on canine breed susceptibility to histiocytic sarcoma, osteosarcoma, haemangiosarcoma, mast cell tumours, lymphoma, melanoma, and mammary tumours including the recent advances in knowledge through molecular genetic, cytogenetic, and genome wide association studies.

scholarly journals Functional Deletion/Insertion Promoter Variants in SCARB1 Associated With Increased Susceptibility to Lipid Profile Abnormalities and Coronary Heart Disease

2022 ◽  
Vol 8 ◽  
Author(s):  
Senlin Hu ◽  
Dong Hu ◽  
Haoran Wei ◽  
Shi-yang Li ◽  
Dong Wang ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Genetic Variants ◽  
Promoter Region ◽  
Association Studies ◽  
Density Lipoprotein ◽  
Genome Wide Association Studies ◽  
Control Subjects ◽  
Functional Variants ◽  
Increased Risk

Background: Genetic variants in Scavenger receptor Class B Type 1 (SCARB1) influencing high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD) risk were identified by recent genome-wide association studies. Further study of potential functional variants in SCARB1 may provide new ideas of the complicated relationship between HDL-C and CHD.Methods: 2000 bp in SCARB1 promoter region was re-sequenced in 168 participants with extremely high plasma HDL-C and 400 control subjects. Putative risk alleles were identified using bioinformatics analysis and reporter-gene assays. Two indel variants, rs144334493 and rs557348251, respectively, were genotyped in 5,002 CHD patients and 5,175 control subjects. The underlying mechanisms were investigated.Results: Through resequencing, 27 genetic variants were identified. Results of genotyping in 5,002 CHD patients and 5,175 control subjects revealed that rs144334493 and rs557348251 were significantly associated with increased risk of CHD [odds ratio (OR): 1.28, 95% confidence interval (CI): 1.09 to 1.52, p = 0.003; OR: 2.65, 95% CI: 1.66–4.24, p = 4.4 × 10−5). Subsequent mechanism experiments demonstrated that rs144334493 deletion allele attenuated forkhead box A1 (FOXA1) binding to the promoter region of SCARB1, while FOXA1 overexpression reversely increased SR-BI expression.Conclusion: Genetic variants in SCARB1 promoter region significantly associated with the plasma lipid levels by affecting SR-BI expression and contribute to the susceptibility of CHD.

scholarly journals Colorectal cancer susceptibility variants and risk of conventional adenomas and serrated polyps: results from three cohort studies

2019 ◽  
Vol 49 (1) ◽  
pp. 259-269 ◽  
Author(s):  
Dong Hang ◽  
Amit D Joshi ◽  
Xiaosheng He ◽  
Andrew T Chan ◽  
Manol Jovani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cohort Studies ◽  
Genetic Variants ◽  
Association Studies ◽  
Genetic Risk Score ◽  
Genome Wide Association Studies ◽  
Serrated Polyps ◽  
Common Genetic Variants ◽  
Increased Risk ◽  
Weighted Genetic Risk Score

Abstract Background Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown. Methods Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis. Results During 18–20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584). Conclusions Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC.

scholarly journals Functional regulatory variants implicate distinct transcriptional networks in dementia

2021 ◽  
Author(s):  
Yonatan A. Cooper ◽  
Jessica E. Davis ◽  
Sriram Kosuri ◽  
Giovanni Coppola ◽  
Daniel H. Geschwind
Keyword(s):  
Genetic Risk ◽  
Disease Risk ◽  
Specific Activity ◽  
Association Studies ◽  
Transcriptional Networks ◽  
Genome Wide Association Studies ◽  
Regulatory Variants ◽  
Functional Variants ◽  
Common Genetic Variants ◽  
Complement 4

Predicting functionality of noncoding variation is one of the major challenges in modern genetics. We employed massively parallel reporter assays to screen 5,706 variants from genome-wide association studies for both Alzheimers disease (AD) and Progressive Supranuclear Palsy (PSP). We identified 320 functional regulatory polymorphisms (SigVars) comprising 27 of 34 unique tested loci, including multiple independent signals across the complex 17q21.31 region. We identify novel risk genes including PLEKHM1 in PSP and APOC1 in AD, and perform gene-editing to validate four distinct causal loci, confirming complement 4 (C4A) as a novel genetic risk factor for AD. Moreover, functional variants preferentially disrupt transcription factor binding sites that converge on enhancers with differential cell-type specific activity in PSP and AD, implicating a neuronal SP1-driven regulatory network in PSP pathogenesis. These analyses support a novel mechanism underlying noncoding genetic risk, whereby common genetic variants drive disease risk via their aggregate activity on specific transcriptional programs.

scholarly journals Functional Annotation of Putative Regulatory Elements at Cancer Susceptibility Loci

2014 ◽  
Vol 13s2 ◽  
pp. CIN.S13789
Author(s):  
Stephanie A. Rosse ◽  
Paul L. Auer ◽  
Christopher S. Carlson
Keyword(s):  
Cancer Susceptibility ◽  
Association Studies ◽  
Regulatory Elements ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Functional Polymorphisms ◽  
Functional Variants ◽  
Genome Wide ◽  
Regulatory Variant ◽  
Causal Variants

Most cancer-associated genetic variants identified from genome-wide association studies (GWAS) do not obviously change protein structure, leading to the hypothesis that the associations are attributable to regulatory polymorphisms. Translating genetic associations into mechanistic insights can be facilitated by knowledge of the causal regulatory variant (or variants) responsible for the statistical signal. Experimental validation of candidate functional variants is onerous, making bioinformatic approaches necessary to prioritize candidates for laboratory analysis. Thus, a systematic approach for recognizing functional (and, therefore, likely causal) variants in noncoding regions is an important step toward interpreting cancer risk loci. This review provides a detailed introduction to current regulatory variant annotations, followed by an overview of how to leverage these resources to prioritize candidate functional polymorphisms in regulatory regions.

scholarly journals The Role of Colorectal Cancer Risk Chromosomal Regions in Colombian Admixed Populations

2018 ◽  
Vol 4 (Supplement 2) ◽  
pp. 207s-207s
Author(s):  
A. Criollo-Rayo ◽  
M. Bohórquez ◽  
P. Lott ◽  
A. Carracedo ◽  
I. Tomlinson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Demographic History ◽  
Recessive Model ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Risk Snps ◽  
Population Demographic

Background: Several colorectal cancer susceptibility disease loci have been discovered through genome-wide association studies. However most of the variants were originally identified in Caucasian populations. Aim: To analyze the role of 20 known risk SNPs for colorectal cancer. Methods: Given that linkage disequilibrium is highly dependent on population demographic history and admixture background, we studied 20 risk SNPs in a pooled sample of 955 cases and 968 controls from admixed populations in Colombia. Results: The replication was reached for 11 out of 20 nominally associated SNPs; with allelic odds ratios (OR) ranging from 1.14 to 1.41, indicating a minimal increase in risk individually, however coinheritance of those SNPs resulted in an overall OR = 5.4 (95% CI: 3.052-9.731, P = 1.16E−08). Most of the variants followed a recessive model consistent with significant homozygous ORs distributed between 1.3 and 1.65. Among the most associated markers we found: rs4939827 (18q21.1, P = 7.35E−6), rs10411210 (19q13.11, P = 0.001), rs10795668 (10p14, P = 0.0024), rs4444235 (14q.2.2, P = 0.005), rs961253 (20p12.3, P = 0.006), rs16892766 (8q23.3, P = 0.011) and rs1050547 (8q24.21, P = 0.017). Conclusion: Our findings in Colombia have addressed the admixture and how this has influenced the risk associated with the known/unknown colorectal cancer regions, providing a comprehensive vision about several CRC-susceptibility SNPs identified in European populations, which also resulted, associated with an increased risk to CRC in the Colombian population, even though frequency and genetic structure differences accounted for those nonreplicated SNPs.

TLR1 and PRKAA1 Gene Polymorphisms in the Development of Atrophic Gastritis and Gastric Cancer

2018 ◽  
Vol 27 (4) ◽  
pp. 363-369 ◽  
Author(s):  
Gintare Dargiene ◽  
Greta Streleckiene ◽  
Jurgita Skieceviciene ◽  
Marcis Leja ◽  
Alexander Link ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Atrophic Gastritis ◽  
Genetic Polymorphisms ◽  
Association Studies ◽  
Control Group ◽  
Similar Distribution ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Infection Susceptibility ◽  
H Pylori

Background & Aims: Previous genome-wide association studies showed that genetic polymorphisms in toll-like receptor 1 (TLR1) and protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) genes were associated with gastric cancer (GC) or increased Helicobacter pylori (H. pylori) infection susceptibility. The aim of this study was to evaluate the association between TLR1 and PRKAA1 genes polymorphisms and H.pylori infection, atrophic gastritis (AG) or GC in the European population.Methods: Single-nucleotide polymorphisms (SNPs) were analysed in 511 controls, 340 AG patients and 327 GC patients. TLR1 C>T (rs4833095) and PRKAA1 C>T (rs13361707) were genotyped by the real-time polymerase chain reaction. H. pylori status was determined by testing for anti-H. pylori IgG antibodies in the serum.Results: The study included 697 (59.2%) H. pylori positive and 481 (40.8%) H. pylori negative cases. We observed similar distribution of TLR1 and PRKAA1 alleles and genotypes in H. pylori positive and negative cases. TLR1 and PRKAA1 SNPs were not linked with the risk of AG. TC genotype of TLR1 gene was more prevalent in GC patients compared to the control group (29.7% and 22.3% respectively, p=0.002). Carriers of TC genotype had a higher risk of GC (aOR=1.89, 95% CI: 1.26–2.83, p=0.002). A similar association was observed in a dominant inheritance model for TLR1 gene SNP, where comparison of CC+TC vs. TT genotypes showed an increased risk of GC (aOR=1.86, 95% CI: 1.26–2.75, p=0.002). No association between genetic polymorphism in PRKAA1 gene and GC was observed.Conclusions: TLR1 rs4833095 SNP was associated with an increased risk of GC in a European population, while PRKAA1 rs13361707 genetic variant was not linked with GC. Both genetic polymorphisms were not associated with H. pylori infection susceptibility or the risk of AG.

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