Publications by authors named "Loreall Pooler"

39 Publications

Genome-wide association study of pancreatic fat: The Multiethnic Cohort Adiposity Phenotype Study.

PLoS One 2021 30;16(7):e0249615. Epub 2021 Jul 30.

University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, Hawaii, United States of America.

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10-8) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUTO, and rs79967607 is in intron 1 of EPM2A. PLUTO, a lncRNA, regulates transcription of an adjacent gene, PDX1, that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249615PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323875PMC
July 2021

Prognostic impact of pre-transplant chromosomal aberrations in peripheral blood of patients undergoing unrelated donor hematopoietic cell transplant for acute myeloid leukemia.

Sci Rep 2021 07 22;11(1):15004. Epub 2021 Jul 22.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD, 20850, USA.

To improve risk stratification and treatment decisions for patients with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT). We used SNP-array data from the DISCOVeRY-BMT study to detect chromosomal aberrations in pre-HCT peripheral blood (collected 2-4 weeks before the administration of conditioning regimen) from 1974 AML patients who received HCT between 2000 and 2011. All aberrations detected in ≥ 10 patients were tested for their association with overall survival (OS), separately by remission status, using the Kaplan-Meier estimator. Cox regression models were used for multivariable analyses. Follow-up was through January 2019. We identified 701 unique chromosomal aberrations in 285 patients (7% of 1438 in complete remission (CR) and 36% of 536 not in CR). Copy-neutral loss-of-heterozygosity (CNLOH) in chr17p in CR patients (3-year OS = 20% vs. 50%, with and without chr17p CNLOH, p = 0.0002), and chr13q in patients not in CR (3-year OS = 4% vs. 26%, with and without chr13q CNLOH, p < 0.0001) are risk factors for poor survival. Models adjusted for clinical factors showed approximately three-fold excess risk of post-HCT mortality with chr17p CNLOH in CR patients (hazard ratio, HR = 3.39, 95% confidence interval CI 1.74-6.60, p = 0.0003), or chr13q CNLOH in patients not in CR (HR = 2.68, 95% CI 1.75-4.09, p < 0.0001). The observed mortality was mostly driven by post-HCT relapse (HR = 2.47, 95% CI 1.01-6.02, p = 0.047 for chr17p CNLOH in CR patients, and HR = 2.58, 95% CI 1.63-4.08, p < 0.0001 for chr13q CNLOH in patients not in CR. Pre-transplant CNLOH in chr13q or chr17p predicts risk of poor outcomes after unrelated donor HCT in AML patients. A large prospective study is warranted to validate the results and evaluate novel strategies to improve survival in those patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-94539-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298542PMC
July 2021

Genome-Wide Association Analyses Identify Variants in Associated With Acute Myeloid Leukemia and Myelodysplastic Syndrome Susceptibility.

Front Genet 2021 17;12:554948. Epub 2021 Jun 17.

College of Pharmacy, The Ohio State University, Columbus, OH, United States.

The role of common genetic variation in susceptibility to acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS), a group of rare clonal hematologic disorders characterized by dysplastic hematopoiesis and high mortality, remains unclear. We performed AML and MDS genome-wide association studies (GWAS) in the DISCOVeRY-BMT cohorts (2,309 cases and 2,814 controls). Association analysis based on subsets (ASSET) was used to conduct a summary statistics SNP-based analysis of MDS and AML subtypes. For each AML and MDS case and control we used PrediXcan to estimate the component of gene expression determined by their genetic profile and correlate this imputed gene expression level with risk of developing disease in a transcriptome-wide association study (TWAS). ASSET identified an increased risk for AML and MDS (OR = 1.38, 95% CI, 1.26-1.51, Pmeta = 2.8 × 10) in patients carrying the T allele at s12203592 in (), a transcription factor which regulates myeloid and lymphoid hematopoietic differentiation. Our TWAS analyses showed increased gene expression is associated with increased risk of AML and MDS (OR = 3.90, 95% CI, 2.36-6.44, Pmeta = 1.0 × 10). The identification of by both GWAS and TWAS contributes valuable insight on the role of genetic variation in AML and MDS susceptibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2021.554948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248805PMC
June 2021

Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.

J Natl Cancer Inst 2021 May;113(5):616-625

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Background: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease.

Methods: Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided.

Results: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4).

Conclusions: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djaa132DOI Listing
May 2021

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Int J Cancer 2021 01 7;148(2):307-319. Epub 2020 Aug 7.

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA.

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 ) 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.33206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757859PMC
January 2021

Genome-Wide Association Study of Liver Fat: The Multiethnic Cohort Adiposity Phenotype Study.

Hepatol Commun 2020 Aug 25;4(8):1112-1123. Epub 2020 Jun 25.

Department of Epidemiology and Biostatistics University of California, San Francisco San Francisco CA USA.

The global rise in fatty liver is a major public health problem. Thus, it is critical to identify both global and population-specific genetic variants associated with liver fat. We conducted a genome-wide association study (GWAS) of percent liver fat and nonalcoholic fatty liver disease (NAFLD) assessed by magnetic resonance imaging in 1,709 participants from the population-based Multiethnic Cohort Adiposity Phenotype Study. Our participants comprised older adults of five U.S. racial/ethnic groups: African Americans (n = 277), Japanese Americans (n = 424), Latinos (n = 348), Native Hawaiians (n = 274), and European Americans (n = 386). The established missense risk variant rs738409 located in patatin-like phospholipase domain containing 3 () at 22q13 was confirmed to be associated with percent liver fat ( = 3.52 × 10) but more strongly in women than men ( heterogeneity = 0.002). Its frequency correlated with the prevalence of NAFLD across the five ethnic/racial groups. Rs738409 was also associated with homeostasis model assessment of insulin resistance (HOMA-IR) (beta = 0.028;  = 0.009) and circulating levels of insulin (beta = 0.022;  = 0.020) and alanine aminotransferase (beta = 0.016;  = 0.030). A novel association of percent liver fat with rs77249491 (located at 6q13 between limb region 1 domain containing 1 [] and collagen type XIX alpha 1 chain [] ( = 1.42 × 10) was also observed. Rs7724941 was associated with HOMA-IR (beta = 0.12;  = 0.0005), insulin (beta = 0.11;  = 0.0003), triglycerides (beta = 0.059;  = 0.01), high-density lipoprotein (beta = -0.046;  = 0.04), and sex hormone binding globulin (beta = -0.084;  = 0.0012). This variant was present in Japanese Americans (minor allele frequency [MAF], 8%) and Native Hawaiians (MAF, 2%). : We replicated the rs738409 association in a multiethnic population and identified a novel liver fat risk variant in Japanese Americans and Native Hawaiians. GWASes of percent liver fat in East Asian and Oceanic populations are needed to replicate the rs77249491 association.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep4.1533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395069PMC
August 2020

Population-specific reference panels are crucial for genetic analyses: an example of the CREBRF locus in Native Hawaiians.

Hum Mol Genet 2020 08;29(13):2275-2284

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

Statistical imputation applied to genome-wide array data is the most cost-effective approach to complete the catalog of genetic variation in a study population. However, imputed genotypes in underrepresented populations incur greater inaccuracies due to ascertainment bias and a lack of representation among reference individuals, further contributing to the obstacles to study these populations. Here we examined the consequences due to the lack of representation by genotyping in a large number of self-reported Native Hawaiians (N = 3693) a functionally important, Polynesian-specific variant in the CREBRF gene, rs373863828. We found the derived allele was significantly associated with several adiposity traits with large effects (e.g. ~ 1.28 kg/m2 per allele in body mass index as the most significant; P = 7.5 × 10-5), consistent with the original findings in Samoans. Due to the current absence of Polynesian representation in publicly accessible reference sequences, rs373863828 or its proxies could not be tested through imputation using these existing resources. Moreover, the association signals at the entire CREBRF locus could not be captured by alternative approaches, such as admixture mapping. In contrast, highly accurate imputation can be achieved even if a small number (<200) of internally constructed Polynesian reference individuals were available; this would increase sample size and improve the statistical evidence of associations. Taken together, our results suggest the alarming possibility that lack of representation in reference panels could inhibit discovery of functionally important loci such as CREBRF. Yet, they could be easily detected and prioritized with improved representation of diverse populations in sequencing studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddaa083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399533PMC
August 2020

A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry.

Eur Urol 2020 09 12;78(3):316-320. Epub 2020 May 12.

Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eururo.2020.04.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805560PMC
September 2020

The Four-Kallikrein Panel Is Effective in Identifying Aggressive Prostate Cancer in a Multiethnic Population.

Cancer Epidemiol Biomarkers Prev 2020 07 8;29(7):1381-1388. Epub 2020 May 8.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.

Background: The four-kallikrein (4K) panel has been demonstrated to improve prediction of aggressive prostate cancer compared with prostate-specific antigen (PSA) among men with moderately elevated PSA levels. However, the development and testing of the 4K panel has been conducted primarily in White men, with limited data in African Americans and no studies in other racial and ethnic groups.

Methods: We evaluated the 4K panel in a nested case-control study among African American, Latino, Japanese, Native Hawaiian, and White men in the Multiethnic Cohort. Prediagnostic blood levels of free, intact, and total PSA and human kallikrein-related peptidase 2 were measured among 1,667 incident prostate cancer cases and 691 controls with PSA ≥2 ng/mL. We evaluated the discriminative ability of the 4K panel within and across all racial/ethnic groups.

Results: The 4K panel enhanced discrimination of overall prostate cancer compared with free plus total PSA and total PSA alone (AUC 0.748 vs. 0.711 and 0.669, respectively). Discrimination was further enhanced for Gleason 8+ prostate cancer, aggressive prostate cancer, and death due to prostate cancer, and to a lesser degree for nonaggressive prostate cancer. Improvement of the 4K panel over PSA was observed in each population. Adding a prostate cancer polygenic risk score slightly improved upon the discriminative ability of the 4K panel.

Conclusions: The superior discriminative ability of the 4K panel over PSA for overall and aggressive prostate cancer across multiethnic populations indicates the broad clinical applicability of the 4K panel.

Impact: Our multiethnic investigation suggests potential for the 4K panel to improve current prostate cancer screening practices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-19-1560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334056PMC
July 2020

Multiple functional variants in the region are pretransplant markers for risk of GVHD and infection deaths.

Blood Adv 2019 08;3(16):2512-2524

Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH.

Graft-versus-host disease (GVHD) and infections are the 2 main causes of death without relapse after allogeneic hematopoietic cell transplantation (HCT). Elevated soluble serum simulation-2 (sST2), the product of in plasma/serum post-HCT, is a validated GVHD biomarker. Hundreds of SNPs at 2q12.1 have been shown to be strongly associated with sST2 concentrations in healthy populations. We therefore hypothesized that the donor genetic variants in correlate with sST2 protein levels associated with patient survival outcomes after HCT. We used DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to 1-Year Mortality after Blood and Marrow Transplantation), a genomic study of >3000 donor-recipient pairs, to inform our hypothesis. We first measured pre-HCT plasma/serum sST2 levels in a subset of DISCOVeRY-BMT donors (n = 757) and tested the association of donor sST2 levels with donor single nucleotide polymorphisms (SNPs) in the 2q12.1 region. Donor SNPs associated with sST2 levels were then tested for association with recipient death caused by acute GVHD (aGVHD)-, infection-, and transplant-related mortality in cohorts 1 and 2. Meta-analyses of cohorts 1 and 2 were performed using fixed-effects inverse variance weighting, and values were corrected for multiple comparisons. Donor risk alleles in rs22441131 ( = .00026) and rs2310241 ( = .00033) increased the cumulative incidence of aGVHD death up to fourfold and were associated with high sST2 levels. Donor risk alleles at rs4851601 ( = 9.7 × 10), rs13019803 ( = 8.9 × 10), and rs13015714 ( = 5.3 × 10) increased cumulative incidence of infection death to almost sevenfold and were associated with low sST2 levels. These functional variants are biomarkers of infection or aGVHD death and could facilitate donor selection, prophylaxis, and a conditioning regimen to reduce post-HCT mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019000075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712530PMC
August 2019

Genetic analyses of diverse populations improves discovery for complex traits.

Nature 2019 06 19;570(7762):514-518. Epub 2019 Jun 19.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-019-1310-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785182PMC
June 2019

Identification of nine new susceptibility loci for endometrial cancer.

Nat Commun 2018 08 9;9(1):3166. Epub 2018 Aug 9.

Department of Obstetrics and Gynecology, University Hospitals KU Leuven, University of Leuven, Division of Gynecologic Oncology, Leuven, 3000, Belgium.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-05427-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085317PMC
August 2018

Exome chip analyses identify genes affecting mortality after HLA-matched unrelated-donor blood and marrow transplantation.

Blood 2018 05 2;131(22):2490-2499. Epub 2018 Apr 2.

College of Pharmacy, The Ohio State University, Columbus, OH.

Although survival outcomes have significantly improved, up to 40% of patients die within 1 year of HLA-matched unrelated-donor blood and marrow transplantation (BMT). To identify non-HLA genetic contributors to mortality after BMT, we performed the first exome-wide association study in the DISCOVeRY-BMT cohorts using the Illumina HumanExome BeadChip. This study includes 2473 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome and 2221 10/10 HLA-matched donors treated from 2000 to 2011. Single-variant and gene-level analyses were performed on overall survival (OS), transplantation-related mortality (TRM), and disease-related mortality (DRM). Genotype mismatches between recipients and donors in a rare nonsynonymous variant of testis-expressed gene significantly increased risk of TRM, which was more dramatic when either the recipient or donor was female. Using the SKAT-O test to evaluate gene-level effects, variant genotypes of in recipients were significantly associated with OS and TRM. In donors, 4 (, , , ), 1 (), and 2 genes (, ) were significantly associated with OS, TRM, and DRM, respectively. Inspection of NT5E crystal structures showed 4 of the associated variants affected the enzyme structure and likely decreased the catalytic efficiency of the enzyme. Further confirmation of these findings and additional functional studies may provide individualized risk prediction and prognosis, as well as alternative donor selection strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2017-11-817973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5981168PMC
May 2018

Genetic association with B-cell acute lymphoblastic leukemia in allogeneic transplant patients differs by age and sex.

Blood Adv 2017 Sep 8;1(20):1717-1728. Epub 2017 Sep 8.

Center for International Blood and Marrow Transplant Research, Minneapolis, MN; and.

The incidence and mortality rates of B-cell acute lymphoblastic leukemia (B-ALL) differ by age and sex. To determine if inherited genetic susceptibility contributes to these differences we performed 2 genome-wide association studies (GWAS) by age, sex, and subtype and subsequent meta-analyses. The GWAS included 446 B-ALL cases, and 3027 healthy unrelated blood and marrow transplant (BMT) donors as controls from the Determining the Influence of Susceptibility Conveying Variants Related to One-Year Mortality after BMT (DISCOVeRY-BMT) study. We identified 1 novel variant, rs189434316, significantly associated with odds of normal cytogenetic B-ALL (odds ratio from meta-analysis [OR] = 3.7; 95% confidence interval [CI], 2.5, 6.2; value from meta-analysis [] = 6.0 × 10). The previously reported pediatric B-ALL GWAS variant, rs11980379 (), replicated in B-ALL pediatric patients (OR = 2.3; 95% CI, 1.5, 3.7; = 1.0 × 10), with evidence of heterogeneity ( = .02) between males and females. Sex differences in single-nucleotide polymorphism effect were seen in those >15 years (OR = 1.7; 95% CI, 1.4, 2.2, = 6.38 × 10/OR = 1.1; 95% CI, 0.8, 1.5; = .6) but not ≤15 years (OR = 2.3; 95% CI, 1.4, 3.8; = .0007/OR = 1.9; 95% CI, 1.2, 3.2; = .007). The latter association replicated in independent pediatric B-ALL cohorts. A previously identified adolescent and young-adult onset ALL-associated variant in is associated with B-ALL risk in those >40 years. Our findings provide more evidence of the influence of genetics on B-ALL age of onset and we have shown the first evidence that associations with B-ALL may be sex and age specific.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2017006023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728332PMC
September 2017

Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry.

J Natl Cancer Inst 2017 08;109(8)

Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL.

Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10 × 10-12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 × 10-10). At 13q34, the signal is located 5' of the gene IRS2 and 3' of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djx084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448553PMC
August 2017

Replication and validation of genetic polymorphisms associated with survival after allogeneic blood or marrow transplant.

Blood 2017 09 15;130(13):1585-1596. Epub 2017 Aug 15.

College of Pharmacy, The Ohio State University, Columbus, OH.

Multiple candidate gene-association studies of non-HLA single-nucleotide polymorphisms (SNPs) and outcomes after blood or marrow transplant (BMT) have been conducted. We identified 70 publications reporting 45 SNPs in 36 genes significantly associated with disease-related mortality, progression-free survival, transplant-related mortality, and/or overall survival after BMT. Replication and validation of these SNP associations were performed using DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT), a well-powered genome-wide association study consisting of 2 cohorts, totaling 2888 BMT recipients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, and their HLA-matched unrelated donors, reported to the Center for International Blood and Marrow Transplant Research. Gene-based tests were used to assess the aggregate effect of SNPs on outcome. None of the previously reported significant SNPs replicated at < .05 in DISCOVeRY-BMT. Validation analyses showed association with one previously reported donor SNP at < .05 and survival; more associations would be anticipated by chance alone. No gene-based tests were significant at < .05. Functional annotation with publicly available data shows these candidate SNPs most likely do not have biochemical function; only 13% of candidate SNPs correlate with gene expression or are predicted to impact transcription factor binding. Of these, half do not impact the candidate gene of interest; the other half correlate with expression of multiple genes. These findings emphasize the peril of pursing candidate approaches and the importance of adequately powered tests of unbiased genome-wide associations with BMT clinical outcomes given the ultimate goal of improving patient outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2017-05-784637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620418PMC
September 2017

Replication of associations between genetic polymorphisms and chronic graft-versus-host disease.

Blood 2016 11 6;128(20):2450-2456. Epub 2016 Oct 6.

Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA.

Previous studies have identified single-nucleotide polymorphisms (SNPs) associated with the risk of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. The current study determined whether these associations could be replicated in large cohorts of donors and recipients. Each SNP was tested with cohorts of patients having the same donor type (HLA-matched related, unrelated, or both) reported in the original publication, and testing was limited to the same genome (recipient or donor) and genetic model (dominant, recessive, or allelic) reported in the original study. The 21 SNPs reported in this study represent 19 genes, and the analysis encompassed 22 SNP association tests. The hazard ratio (HR) point estimates and risk ratio point estimates corresponding to odds ratios in previous studies consistently fall outside the 95% confidence intervals of HR estimates in the current study. Despite the large size of the cohorts available for the current study, the 95% confidence intervals for most HRs did not exclude 1.0. Three SNPs representing CTLA4, HPSE, and IL1R1 showed evidence of association with the risk of chronic GVHD in unrelated donor-recipient pairs from 1 cohort, but none of these associations was replicated when tested in unrelated donor-recipient pairs from an independent cohort. Two SNPs representing CCR6 and FGFR1OP showed possible associations with the risk of chronic GVHD in related donor-recipient pairs but not in unrelated donor-recipient pairs. These results remain to be tested for replication in other cohorts of related donor-recipient pairs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2016-07-728063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114491PMC
November 2016

Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome.

Nat Commun 2016 06 13;7:11843. Epub 2016 Jun 13.

National Institute of Cancer Research, National Health Research Institutes, Zhunan 35053, Taiwan.

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms11843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909985PMC
June 2016

GWAS meta-analysis of 16 852 women identifies new susceptibility locus for endometrial cancer.

Hum Mol Genet 2016 06 23;25(12):2612-2620. Epub 2016 Mar 23.

Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt - Ingram Cancer Center, Vanderbilt University Medical Center, Nashville TN 27232, USA.

Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic risk remains unexplained. We present the meta-analysis results of four genome-wide association studies (4907 cases and 11 945 controls total) in women of European ancestry. We describe one new locus reaching genome-wide significance (P < 5 × 10 ) at 6p22.3 (rs1740828; P = 2.29 × 10 , OR = 1.20), providing evidence of an additional region of interest for genetic susceptibility to endometrial cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddw092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868213PMC
June 2016

Prostate Cancer Susceptibility in Men of African Ancestry at 8q24.

J Natl Cancer Inst 2016 Jul 27;108(7). Epub 2016 Jan 27.

Affiliations of authors: Department of Preventive Medicine (YH, KAR, DJH, SAI, FRS, GC, LCP, XS, GAC, DOS, DVC, BEH, CAH) and Department of Urology (GAC), Keck School of Medicine, and Norris Comprehensive Cancer Center (SAI, FRS, GC, GAC, DOS, DVC, BEH, CAH), University of Southern California , Los Angeles, CA ; University of Arizona College of Medicine and University of Arizona Cancer Center , Tucson, AZ (RAK); Department of Epidemiology (SSS) and Department of Urology (CAP), University of Texas M. D. Anderson Cancer Center , Houston, TX ; Department of Public Health Sciences (BAR) and Department of Public Health Sciences (CND), Henry Ford Hospital , Detroit, MI ; Department of Preventive Medicine, Stony Brook University , Stony Brook, NY (BN, MCL, SYW, AJMH); James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution , Baltimore, MD (WBI); Division of Public Health Sciences (JLS, SK) and SWOG Statistical Center (PJG), Fred Hutchinson Cancer Research Center , Seattle, WA ; Department of Epidemiology, School of Public Health, University of Washington , Seattle, WA (JLS); Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine , Nashville, TN (WZ, WJB); Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Bethesda, MD (SIB, ZW, MBC, SJC); Cancer Genomics Research Laboratory, NCI-DCEG, SAIC-Frederick Inc. , Frederick, MD (ZW); Program for Personalized Cancer Care and Department of Surgery, NorthShore University HealthSystem , Evanston, IL (JX); Department of Genetics (NR, DR, AT, AA, DQ, SM) and Howard Hughes Medical Institute (DR, SM), Harvard Medical School, Harvard University , Boston, MA ; Broad Institute of MIT and Harvard , Cambridge, MA (NR, DR, AT, AA, DQ, SM); Department of Pathology and Laboratory Medicine and Department of Human Genetics, David Geffen School of Medicine, University of California , Los Angeles, Los Angeles, CA (BP); Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California , San Diego, San Diego, CA (DN, MGR, RSJ); Epidemiology Research Program, American Cancer Society , Atlanta, GA (SMG, VLS); Korle Bu Teaching Hospital , Accra , Ghana (EDY, YT, RBB, AAA, ET); University of Ghana Medical School , Accra , Ghana (EDY, YT, RBB, AAA, ET); Westat , Rockville, MD (AT, SN); School of Public Health, University of California , Berkeley, Berkeley, CA (APC); Cancer Prevention Institute of California , Fremont, CA (EMJ, AWH, LC); Stanford University School of Medicine and Stanford Cancer Institute , Palo Alto, CA (EMJ, AWH, LC); Department of Urology, Northwestern University , Chicago, IL (ABM); Department of Epidemiology, Harvard School of Public Health , Boston, MA (LBS, WJB); The Translational Genomics Research Institute , Phoenix, AZ (JC); Chronic Disease Research Centre and Faculty of Medical Sciences, University of the West Indies , Bridgetown, Barbados (AJMH); Glickman Urological & Kidney Institute, Cleveland Clinic , Cleveland, OH (EAK); Center for Cancer Genomics, Wake Forest School of Medicine , Winston-Salem, NC (SLZ); Department of Epidemiology and Biostatistics and Institute for Human Genetics, University of California , San Francisco, San Francisco, CA (JSW); School of Public Health, Makerere University College of Health Sciences , Kampala, Uganda (AL, SW); Uro Care , Kampala , Uganda (SW).

The 8q24 region harbors multiple risk variants for distinct cancers, including >8 for prostate cancer. In this study, we conducted fine mapping of the 8q24 risk region (127.8-128.8Mb) in search of novel associations with common and rare variation in 4853 prostate cancer case patients and 4678 control subjects of African ancestry. All statistical tests were two-sided. We identified three independent associations at P values of less than 5.00×10(-8), all of which were replicated in studies from Ghana and Uganda (combined sample = 5869 case patients, 5615 control subjects; rs114798100: risk allele frequency [RAF] = 0.04, per-allele odds ratio [OR] = 2.31, 95% confidence interval [CI] = 2.04 to 2.61, P = 2.38×10(-40); rs72725879: RAF = 0.33, OR = 1.37, 95% CI = 1.30 to 1.45, P = 3.04×10(-27); and rs111906932: RAF = 0.03, OR = 1.79, 95% CI = 1.53 to 2.08, P = 1.39×10(-13)). Risk variants rs114798100 and rs111906923 are only found in men of African ancestry, with rs111906923 representing a novel association signal. The three variants are located within or near a number of prostate cancer-associated long noncoding RNAs (lncRNAs), including PRNCR1, PCAT1, and PCAT2. These findings highlight ancestry-specific risk variation and implicate prostate-specific lncRNAs at the 8q24 prostate cancer susceptibility region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djv431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948565PMC
July 2016

Characterization of large structural genetic mosaicism in human autosomes.

Am J Hum Genet 2015 Mar;96(3):487-97

Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, College of Medicine, Seoul National University, Seoul 151-742, Republic of Korea.

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2015.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375431PMC
March 2015

A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.

Nat Genet 2014 Oct 14;46(10):1103-9. Epub 2014 Sep 14.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institute of Health, Bethesda, Maryland, USA.

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383163PMC
October 2014

Exome-wide association study of endometrial cancer in a multiethnic population.

PLoS One 2014 8;9(5):e97045. Epub 2014 May 8.

University of Southern California, Los Angeles, California, United States of America.

Endometrial cancer (EC) contributes substantially to total burden of cancer morbidity and mortality in the United States. Family history is a known risk factor for EC, thus genetic factors may play a role in EC pathogenesis. Three previous genome-wide association studies (GWAS) have found only one locus associated with EC, suggesting that common variants with large effects may not contribute greatly to EC risk. Alternatively, we hypothesize that rare variants may contribute to EC risk. We conducted an exome-wide association study (EXWAS) of EC using the Infinium HumanExome BeadChip in order to identify rare variants associated with EC risk. We successfully genotyped 177,139 variants in a multiethnic population of 1,055 cases and 1,778 controls from four studies that were part of the Epidemiology of Endometrial Cancer Consortium (E2C2). No variants reached global significance in the study, suggesting that more power is needed to detect modest associations between rare genetic variants and risk of EC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097045PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014590PMC
June 2015

Genome-wide association study of endometrial cancer in E2C2.

Hum Genet 2014 Feb 6;133(2):211-24. Epub 2013 Oct 6.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA,

Endometrial cancer (EC), a neoplasm of the uterine epithelial lining, is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Women with a family history of EC have an increased risk for the disease, suggesting that inherited genetic factors play a role. We conducted a two-stage genome-wide association study of Type I EC. Stage 1 included 5,472 women (2,695 cases and 2,777 controls) of European ancestry from seven studies. We selected independent single-nucleotide polymorphisms (SNPs) that displayed the most significant associations with EC in Stage 1 for replication among 17,948 women (4,382 cases and 13,566 controls) in a multiethnic population (African America, Asian, Latina, Hawaiian and European ancestry), from nine studies. Although no novel variants reached genome-wide significance, we replicated previously identified associations with genetic markers near the HNF1B locus. Our findings suggest that larger studies with specific tumor classification are necessary to identify novel genetic polymorphisms associated with EC susceptibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-013-1369-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898362PMC
February 2014

Fine Mapping and Identification of BMI Loci in African Americans.

Am J Hum Genet 2013 Oct;93(4):661-71

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address:

Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2013.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791273PMC
October 2013

Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population.

PLoS Genet 2013 Mar 28;9(3):e1003419. Epub 2013 Mar 28.

Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America.

Rare variation in protein coding sequence is poorly captured by GWAS arrays and has been hypothesized to contribute to disease heritability. Using the Illumina HumanExome SNP array, we successfully genotyped 191,032 common and rare non-synonymous, splice site, or nonsense variants in a multiethnic sample of 2,984 breast cancer cases, 4,376 prostate cancer cases, and 7,545 controls. In breast cancer, the strongest associations included either SNPs in or gene burden scores for genes LDLRAD1, SLC19A1, FGFBP3, CASP5, MMAB, SLC16A6, and INS-IGF2. In prostate cancer, one of the most associated SNPs was in the gene GPRC6A (rs2274911, Pro91Ser, OR = 0.88, P = 1.3 × 10(-5)) near to a known risk locus for prostate cancer; other suggestive associations were noted in genes such as F13A1, ANXA4, MANSC1, and GP6. For both breast and prostate cancer, several of the most significant associations involving SNPs or gene burden scores (sum of minor alleles) were noted in genes previously reported to be associated with a cancer-related phenotype. However, only one of the associations (rs145889899 in LDLRAD1, p = 2.5 × 10(-7) only seen in African Americans) for overall breast or prostate cancer risk was statistically significant after correcting for multiple comparisons. In addition to breast and prostate cancer, other cancer-related traits were examined (body mass index, PSA level, and alcohol drinking) with a number of known and potentially novel associations described. In general, these findings do not support there being many protein coding variants of moderate to high risk for breast and prostate cancer with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. Very large sample sizes will be required to better define the role of rare and less penetrant coding variation in prostate and breast cancer disease genetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1003419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610631PMC
March 2013

A genome-wide scan for breast cancer risk haplotypes among African American women.

PLoS One 2013 28;8(2):e57298. Epub 2013 Feb 28.

Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.

Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057298PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585353PMC
September 2013

A genome-wide association study of breast cancer in women of African ancestry.

Hum Genet 2013 Jan 25;132(1):39-48. Epub 2012 Aug 25.

Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.

Genome-wide association studies (GWAS) in diverse populations are needed to reveal variants that are more common and/or limited to defined populations. We conducted a GWAS of breast cancer in women of African ancestry, with genotyping of >1,000,000 SNPs in 3,153 African American cases and 2,831 controls, and replication testing of the top 66 associations in an additional 3,607 breast cancer cases and 11,330 controls of African ancestry. Two of the 66 SNPs replicated (p < 0.05) in stage 2, which reached statistical significance levels of 10(-6) and 10(-5) in the stage 1 and 2 combined analysis (rs4322600 at chromosome 14q31: OR = 1.18, p = 4.3 × 10(-6); rs10510333 at chromosome 3p26: OR = 1.15, p = 1.5 × 10(-5)). These suggestive risk loci have not been identified in previous GWAS in other populations and will need to be examined in additional samples. Identification of novel risk variants for breast cancer in women of African ancestry will demand testing of a substantially larger set of markers from stage 1 in a larger replication sample.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-012-1214-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749077PMC
January 2013
-->