Common variants at theCHEK2gene locus and risk of epithelial ovarian cancer

Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.Other Research Uni

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy.

Peer reviewe

Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P<1.4 × 10−3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10−10 for risk variants (P<10−4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec

Abstract 890: GWAS-based genetic variants and lung cancer in white postmenopausal women: The PAGE Consortium

Abstract Introduction: Lung cancer is the leading cause of cancer death in the United States, with an estimated 222,520 men and women diagnosed in 2010. While cigarette smoking is the primary causal agent in most lung cancer cases, genetic variation is known to contribute to lung cancer risk. In the present study, we aim to investigate the association between 25 single nucleotide polymorphisms (SNPs) identified in prior genome-wide association (GWA) studies of lung cancer and nicotine dependence and lung cancer in a sample of white postmenopausal women. Methods: We selected 5,857 white subjects (1,407 cases, 4,450 controls) from the 161,808 postmenopausal women who participated in the Women's Health Initiative component of the NHGRI-funded Population Architecture using Genomics and Epidemiology (PAGE) Consortium. Lung cancer cases were identified prospectively, and confirmed via medical records review. Smoking behavior was ascertained via questionnaire at baseline. We selected 25 SNPs based on statistically significant association with either lung cancer and/or nicotine dependence in prior GWAS. We used logistic regression to estimate the association between each SNP and lung cancer assuming an additive genetic model, after adjusting for age and smoking status (current/former/never), and calculated odds ratios (OR) and 95% confidence intervals. In the subset of controls who reported any history of smoking, we used linear regression to estimate the association between each SNP and continuous pack-years of smoking. Results: We identified nine SNPs (rs8042374, rs16969968, rs1051730, rs931794, rs8034191, rs2136100, rs578776, rs2036534, rs2836823) significantly associated with both pack-years of smoking and lung cancer adjusted for smoking status. We also identified four SNPs associated with reduced risk of lung cancer that were not significantly associated with pack-years of smoking. All four SNPs are located in CLPTM1L on Chr 5p15, a locus that has been previously associated with lung cancer in never-smokers. The A allele of rs31489 was associated with an OR of 0.79 (p = 9.03 × 10-7), the A allele of rs401681 was associated with an OR of 0.83 (p = 3.41 × 10-5), the A allele of rs402710 was associated with an OR of 0.82 (p = 5.5 × 10-5), and the G allele of rs4975616 was associated with an OR of 0.84 (p = 1.7 × 10-4). Conclusions: These analyses confirmed prior GWAS findings of statistically significant associations between CLPTM1L and lung cancer in whites after adjustment for age and smoking status. Additional studies with larger numbers of minority lung cancer cases are needed to investigate genetic risk factors for lung cancer in non-white populations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 890. doi:10.1158/1538-7445.AM2011-890</jats:p

Abstract 868: Replication of melanoma GWAS hits and exploration of pleiotropic effects of cancer GWAS hits with melanoma risk in the PAGE study

Abstract Introduction: As the most serious form of skin cancer, melanoma is a considerable public health burden. Genome wide association studies (GWAS) have successfully identified several loci important to melanoma susceptibility. Some of these loci have been associated with other cancers as well, similar to the pleiotropy previously demonstrated in the 8q24 and TERT regions. Such pleiotropy can highlight important regions and may help inform variant functionality. However, the potential pleiotropic effects of gene variants identified for other cancers have not been fully explored for melanoma. This study evaluates whether GWAS hits for melanoma, as well as hits for non-melanoma cancers, are associated with melanoma risk. Methods: We included 918 white melanoma cases and 4495 white controls in the Women's Health Initiative, which were genotyped as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. We evaluated 8 single nucleotide polymorphisms (SNPs) previously shown to be associated with melanoma in GWAS as well as 175 SNPs previously shown to be associated with other cancers. These findings were mostly based on GWAS in Caucasian populations. We used logistic regression to evaluate the association between each SNP and melanoma risk, using an age-adjusted additive genetic model. Results: Of the 8 melanoma SNPs evaluated, 7 were statistically significantly associated with melanoma risk (p&amp;lt;0.05). These SNPs were rs1393350 (p=0.001), rs16891982 (p=3.34e-05), rs258322 (p=1.53e-9), rs4785763 (p=3.29e-4), rs7023329 (p=2.20e-5), rs910873 (p=2.38e-4), and rs4636294 (p=5.82e-5). For each of these significant SNPs, the association was in the same direction of risk as previously reported. The SNP that did not replicate was rs2284063 (p=0.38). Our analysis for pleotropic effects of other cancer GWAS hits did not yield any significant associations after adjustment for multiple comparisons (p=2.87e-4). The most significant SNP was rs710521 (p=0.006), previously associated with urinary bladder cancer. Conclusions: This preliminary analysis demonstrates that nearly all previously discovered melanoma SNPs replicated. Our analysis did not discover any non-melanoma cancer SNPs that are also associated with melanoma. The next step in this analysis will be to incorporate data from the other three PAGE studies: the Multiethnic Cohort (MEC), Epidemiologic Architecture of Genes Linked to Environment (EAGLE), and the CALiCo Consortium (see pagestudy.org). This will substantially improve the power of our pleiotropy analyses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 868. doi:10.1158/1538-7445.AM2011-868</jats:p

Abstract 948: Investigation of breast cancer susceptibility loci in the PAGE study

Abstract Introduction: Recent genome-wide association studies (GWAS) of breast cancer have identified single nucleotide polymorphisms (SNPs) in more than 20 loci associated with increased risk of breast cancer, primarily in European-descent populations. Yet, the biological mechanisms underlying most of these genetic variants as well as their effect sizes in other populations differing by race/ethnicity remains unknown. We investigated breast cancer associations with previously reported SNPs in white and African American (AA) women from the Population Architecture using Genomics and Epidemiology (PAGE) study. Methods: We selected 28 common SNPs reported in breast cancer GWAS or candidate-gene association studies representing 21 different breast cancer susceptibility loci for our analysis. These SNPs were genotyped in 5878 white and 904 AA postmenopausal women sampled from the Women's Health Initiative Study, which is part of the PAGE consortium. Invasive breast cancer cases (n = 1366 in whites and n=226 in AA) were identified prospectively and confirmed via medical records review. We coded SNPs using additive genetic models and used logistic regression to estimate per allele odds ratios (OR) and 95% confidence intervals (CI). Race/ethnicity-specific models were adjusted for age; adjustment for risk factors such as body mass index, current smoking and postmenopausal hormone therapy (HT) were also investigated. Results: In whites, we observed statistically significant (p&amp;lt;0.05) associations for 14 of 28 SNPs; strongest associations were seen for SNPs in 10q26.13/FGFR2 and 16q12.1/TOX3, with p&amp;lt;0.0001. In AA, 5 of the 28 SNPs located in 1p11.2/NOTCH, 5q11.2/MAP3K1, 10q26.13/FGFR2, and 11p15.5/LSP1 were associated with breast cancer at p&amp;lt;0.05, while an additional 4 were marginally significant at p&amp;lt;0.07. FGFR2 has been strongly implicated as a breast cancer susceptibility locus, though a causal variant has not yet been identified (Udler et al., 2009). Our ORs of ∼1.2 in whites are consistent with prior reports. Additionally, we observed elevated odds of breast cancer, OR (95%CI) = 1.3(1.0-1.7), in AA for a SNP in this locus, rs2981578 (G allele). Conclusions: We confirm prior breast cancer associations in postmenopausal white women and report associations in 4 loci that extend to AA women. Our next steps will be to evaluate associations by cancer subtype and expand investigations in AA to include additional genotype data and women from the other PAGE studies. These results in women differing by race/ethnicity contribute to future research on breast cancer etiology by providing data that can be used to inform the identification and fine mapping of causal breast cancer variants. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 948. doi:10.1158/1538-7445.AM2011-948</jats:p

Abstract MP60: Investigation of Blood Pressure Genetic Loci in African Americans using the Metabochip

Introduction. African Americans (AA) have a higher burden of hypertension than European descent individuals, thus motivating research on blood pressure (BP) risk factors in AA, including genetic variants. Yet to date, few genome-wide association studies (GWAS) of BP have been conducted in AA and it is unclear whether genetic variants identified in mainly European descent populations are also associated with BP in AA. Furthermore, investigation of established BP loci in diverse race/ethnicity groups such as AA, who tend to have higher levels of genetic diversity, provides opportunities to narrow loci for identifying potential causal variants. Methods. We examined whether systolic BP (SBP) and diastolic BP (DBP) loci on the Illumina Metabochip array were associated with BP traits in 18,832 AA from the PAGE, HyperGen and GenNet studies. Only SNPs with minor allele frequency≥0.001 and passing stringent QC were tested. Using p-value&lt;0.05 as a significance threshold for replication of GWAS SNPs in our AA population, we investigated the original GWAS SNP and all SNPs ±500 kilobases in modest linkage disequilibrium with it (r 2 ≥0.3). To test SNPs in the 16 SBP and 14 DBP loci, we used a Bonferroni corrected p-value of 0.05/total SNPs per locus (the number SNPs at each BP locus ranges from 104 to 2,337). Results. In models adjusted for sex, age, body mass index and global ancestry, 5 prior GWAS SNPs were associated (p&lt;0.05) with DBP: rs13107325/ SLC39A8 (non-synonymous), rs1165196/ SLC17A1 (non-synonymous), rs6495122/ CPLX3 , rs1327235/intergenic and rs6015450/intergenic. At several loci, we identified finely-mapped SNPs more strongly associated with DBP in AA than the original GWAS SNPs. Notably, we identified rs56153133 in the gene-rich 1p26 region harboring the chloride channel-voltage-sensitive-6 ( CLCN6 ) gene, p=6.9E-5. This SNP is highly correlated with the GWAS SNP rs17367504/ MTHFR in European-descent individuals (r 2 =0.98) and less so in AA (r 2 =0.64). For SBP, we replicated two GWAS SNPs: rs16998073/intergenic and rs2681472/ ATP2B1 and at many loci (10q24, 1p26, 15q26 et al .), we identified SNPs more strongly associated with SBP in AA than the original GWAS SNPs. Conclusions. Overall, several BP loci originally reported in individuals of European and East Asian ancestry also generalize to AA, which confirms the relevance of specific BP susceptibility loci across diverse populations. In addition, we identified SNPs more strongly associated with BP traits in AA than the original GWAS SNPs, underlying the importance of leveraging differences in nucleotide diversity and LD patterns among populations to narrow GWAS signal boundaries. Future work will include conditional analysis to further refine GWAS loci, and to identify additional signals and population-specific variation. </jats:p