Dataset Information

Association between GSTM1 copy number, promoter variants and susceptibility to urinary bladder cancer.

ABSTRACT: This study sought to determine the role of copy number variants (CNV) combined with other genetic variants in the Glutathione S-transferases Mu class1 (GSTM1) promoter in the development of urinary bladder cancer. TaqMan real-time PCR and direct sequencing were used to determine genetic variants. Haploblocks and haplotype were constructed and estimated by Haploview and Phase, respectively. Logistic regression revealed a significantly decreased bladder cancer risk in subjects with at least 2 copies of GSTM1 (OR=0.56; 95%CI=0.39-0.81) but not in those with 1 copy of the gene. GSTM1 promoter screening revealed an insertion variant (-1543TTCT) and 14 single nucleotide polymorphisms (SNPs) (-1529C>G, -1490A>G, -1143A>G, -888A>T, -498G>C, -486C>G, -471C>T, -426G>A, -344C>T, -343A>T, -341C>T, -339C>T, -304G>A, and -164C>T). Four haploblocks were evident by Haploview. There was no significant association between any single SNP/haplotype and bladder cancer risk. However, when stratified by copy number, the two copy carriers with the -1543 insertion had decreased bladder cancer risk (OR, 0.58; 95%CI, 0.32-0.10) and similar results were found in two copy carriers with -888 A, -486G, - 344 C, -343 A, -341 C allele and haplotype INS(-1543)-C(-1529)-A(-1429) in LD block 1, A(-1143)-A(-888) in LD block 2, C(-498)-G(-486)-T(-471) in LD block 3, C(-344)-A(-343)-C(-341)-C(-339) and C(-344)-A(-343)-C(-341)-T(-339) in LD block 4. These results suggest that GSTM1 CNV is a better predictor of bladder cancer susceptibility than measuring presence/absence of GSTM1 and other genetic variants also can modify bladder cancer risk.

SUBMITTER: Zhang X

PROVIDER: S-EPMC3459215 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Association between GSTM1 copy number, promoter variants and susceptibility to urinary bladder cancer.

Zhang Xuemei X Lin Jie J Wu Xifeng X Lin Zhongning Z Ning Baitang B Kadlubar Susan S Kadlubar Fred F FF

International journal of molecular epidemiology and genetics 20120831 3

This study sought to determine the role of copy number variants (CNV) combined with other genetic variants in the Glutathione S-transferases Mu class1 (GSTM1) promoter in the development of urinary bladder cancer. TaqMan real-time PCR and direct sequencing were used to determine genetic variants. Haploblocks and haplotype were constructed and estimated by Haploview and Phase, respectively. Logistic regression revealed a significantly decreased bladder cancer risk in subjects with at least 2 copi ...[more]

PMID: 23050053

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Project description:BackgroundCopy-number variations (CNVs) have been associated with rare and debilitating genomic disorders (GDs) but their impact on health later in life in the general population remains poorly described.MethodsAssessing four modes of CNV action, we performed genome-wide association scans (GWASs) between the copy-number of CNV-proxy probes and 60 curated ICD-10 based clinical diagnoses in 331,522 unrelated white British UK Biobank (UKBB) participants with replication in the Estonian Biobank.ResultsWe identified 73 signals involving 40 diseases, all of which indicating that CNVs increased disease risk and caused earlier onset. We estimated that 16% of these associations are indirect, acting by increasing body mass index (BMI). Signals mapped to 45 unique, non-overlapping regions, nine of which being linked to known GDs. Number and identity of genes affected by CNVs modulated their pathogenicity, with many associations being supported by colocalization with both common and rare single-nucleotide variant association signals. Dissection of association signals provided insights into the epidemiology of known gene-disease pairs (e.g., deletions in BRCA1 and LDLR increased risk for ovarian cancer and ischemic heart disease, respectively), clarified dosage mechanisms of action (e.g., both increased and decreased dosage of 17q12 impacted renal health), and identified putative causal genes (e.g., ABCC6 for kidney stones). Characterization of the pleiotropic pathological consequences of recurrent CNVs at 15q13, 16p13.11, 16p12.2, and 22q11.2 in adulthood indicated variable expressivity of these regions and the involvement of multiple genes. Finally, we show that while the total burden of rare CNVs-and especially deletions-strongly associated with disease risk, it only accounted for ~ 0.02% of the UKBB disease burden. These associations are mainly driven by CNVs at known GD CNV regions, whose pleiotropic effect on common diseases was broader than anticipated by our CNV-GWAS.ConclusionsOur results shed light on the prominent role of rare CNVs in determining common disease susceptibility within the general population and provide actionable insights for anticipating later-onset comorbidities in carriers of recurrent CNVs.

Project description:ImportanceThe role of large, rare copy number variants (CNVs) in neuropsychiatric disorders is well established, but their association with common psychiatric disorders, such as depression, remains unclear.ObjectiveTo examine the association of a group of 53 CNVs associated with neurodevelopmental disorders and burden of rare CNVs with risk of depression.Design, setting, and participantsThis case-control study used data from the UK Biobank study sample, which comprised 502 534 individuals living in the United Kingdom. Individuals with autism spectrum disorder, intellectual disability, attention-deficit/hyperactivity disorder, schizophrenia, or bipolar affective disorder diagnoses were excluded. Analyses were further restricted to individuals of European genetic ancestry (n = 407 074). The study was conducted from January 2017 to September 2018.ExposuresCNV carrier status.Main outcomes and measuresFor the primary outcome, individuals who reported that a physician had told them they had a depression diagnosis were defined as cases. Analyses were repeated using 2 alternative depression definitions: self-reported lifetime depression with current antidepressant prescription at the time of visit 1, and hospital discharge diagnosis of depression.ResultsCopy number variants were identified in 488 366 individuals aged 37 to 73 years. In total, 407 074 individuals with European genetic ancestry (220 201 female [54.1%]; mean [SD] age of 56.9 [8.0] years) were included in the study. Of these individuals, 23 979 (5.9%) had self-reported lifetime depression and 383 095 (94.1%) reported no lifetime depression. The group of 53 neurodevelopmental CNVs was associated with self-reported depression (odds ratio [OR], 1.34; 95% CI, 1.19-1.49, uncorrected P = 1.38 × 10-7), and these results were consistent when using 2 alternative definitions of depression. This association was partially explained by physical health, educational attainment, social deprivation, smoking status, and alcohol consumption. A strong independent association remained between the neurodevelopmental CNVs and depression in analyses that incorporated these other measures (OR, 1.26; 95% CI, 1.11-1.43; P = 2.87 × 10-4). Eight individual CNVs were nominally associated with risk of depression, and 3 of these 8 CNVs (1q21.1 duplication, Prader-Willi syndrome duplication, and 16p11.2 duplication) survived Bonferroni correction for the 53 CNVs tested. After the exclusion of carriers of neurodevelopmental CNVs, no association was found between measures of CNV burden and depression.Conclusions and relevanceNeurodevelopmental CNVs appear to be associated with depression, extending the spectrum of clinical phenotypes that are associated with CNV carrier status.

Project description:Copy number variants (CNVs) are a major source of genetic variation and can disrupt genes or affect gene dosage. They are known to be causal or underlie predisposition to various diseases. However, the role of CNVs in inherited breast cancer susceptibility has not been thoroughly investigated. To address this, we performed whole-exome sequencing based analysis of rare CNVs in 98 high-risk Northern Finnish breast cancer cases. After filtering, selected candidate alleles were validated and characterized with a combination of orthogonal methods, including PCR-based approaches, optical genome mapping and long-read sequencing. This revealed three recurrent alterations: a 31 kb deletion co-occurring with a retrotransposon insertion (delins) in RAD52, a 13.4 kb deletion in HSD17B14 and a 64 kb partial duplication of RAD51C. Notably, all these genes encode proteins involved in pathways previously identified as essential for breast cancer development. Variants were genotyped in geographically matched cases and controls (altogether 278 hereditary and 1983 unselected breast cancer cases, and 1229 controls). The RAD52 delins and HSD17B14 deletion both showed significant enrichment among cases with indications of hereditary disease susceptibility. RAD52 delins was identified in 7/278 cases (2.5%, P = 0.034, OR = 2.86, 95% CI = 1.10-7.45) and HSD17B14 deletion in 8/278 cases (2.9%, P = 0.014, OR = 3.28, 95% CI = 1.31-8.23), the frequency of both variants in the controls being 11/1229 (0.9%). This suggests a role for RAD52 and HSD17B14 in hereditary breast cancer susceptibility. The RAD51C duplication was very rare, identified only in 2/278 of hereditary cases and 2/1229 controls (P = 0.157, OR = 4.45, 95% CI = 0.62-31.70). The identification of recurrent CNVs in these genes, and especially the relatively high frequency of RAD52 and HSD17B14 alterations in the Finnish population, highlights the importance of studying CNVs alongside single nucleotide variants when searching for genetic factors underlying hereditary disease predisposition.

Project description:ImportanceAt least 11 rare copy number variants (CNVs) have been shown to be major risk factors for schizophrenia (SZ). These CNVs also increase the risk for other neurodevelopmental disorders, such as intellectual disability. It is possible that additional intellectual disability-associated CNVs increase the risk for SZ but have not yet been implicated in SZ because of previous studies being underpowered.ObjectiveTo examine whether additional CNVs implicated in intellectual disability represent novel SZ risk loci.Design, setting, and participantsWe used single-nucleotide polymorphism (SNP) array data to evaluate a set of 51 CNVs implicated in intellectual disability (excluding the known SZ loci) in a large data set of patients with SZ and healthy persons serving as controls recruited in a variety of settings. We analyzed a new sample of 6934 individuals with SZ and 8751 controls and combined those data with previously published large data sets for a total of 20 403 cases of SZ and 26 628 controls.Main outcomes and measuresBurden analysis of CNVs implicated in intellectual disability (excluding known SZ CNVs) for association with SZ. Association of individual intellectual disability CNV loci with SZ.ResultsOf data on the 20 403 cases (6151 [30.15%] female) and 26 628 controls (14 252 [53.52%] female), 51 intellectual disability CNVs were analyzed. Collectively, intellectual disability CNVs were significantly enriched for SZ (P = 1.0 × 10-6; odds ratio [OR], 1.9 [95% CI, 1.46-2.49]). Of the 51 CNVs tested, 19 (37%) were more common in SZ cases; only 4 (8%) were more common in controls (no observations were made for the remaining 28 [55%] loci). One novel locus, deletion at 16p12.1, was significantly associated with SZ after correction for multiple testing (rate in SZ, 33 [0.16%]; rate in controls, 12 [0.05%]; corrected P = .017; OR, 3.3; 95% CI, 1.61-7.05), and 2 loci reached nominal levels of significance (deletions at 2q11.2: 6 [0.03%] vs 1 [0.004%]; OR, 9.3; 95% CI, 1.03-447.76; corrected P > .99; and duplications at 10q11.21q11.23: 5 [0.2%] vs 0 [0.03%]; OR, infinity; 95% CI, 1.26-infinity; corrected P = .71). Our new data set also provided independent support for the 11 SZ risk loci previously reported to be associated with the disorder and for the protective effect of 22q11.2 duplication.Conclusions and relevanceA large proportion of CNV loci implicated in intellectual disability are risk factors for SZ, but the available sample size precludes statistical confirmation for additional individual loci.

Dataset Information

Association between GSTM1 copy number, promoter variants and susceptibility to urinary bladder cancer.

Publications

Association between GSTM1 copy number, promoter variants and susceptibility to urinary bladder cancer.

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