|Grant Number:||3U01CA136792-03S1 Interpret this number|
|Primary Investigator:||Henderson, Brian|
|Organization:||University Of Southern California|
|Project Title:||A Genome-Wide Association Study of Prostate Cancer in African Americans|
DESCRIPTION (provided by applicant): Prostate cancer is one of the leading causes of morbidity and mortality among men. We do not have an understanding of the underlying etiology of prostate cancer, or why different groups such as African Americans have higher rates of this disease. Risk factors for prostate cancer have remained elusive, other than age, having a family history of the disease and African ancestry, until recently with the discovery of multiple disease risk loci utilizing Genome Wide Association Studies( GWAS ). The first such loci were discovered in a gene " desert " in 8q24, and now the total number of loci number at least 30. Many of the allelic loci identified since those in 8q24, lie within introns or nearby known gene regions. Given the SNP density of the current tools used for GWAS, virtually all the risk loci identified have been found to be common allelic variants and the relative risk of prostate cancer from each such risk locus tends to be modest, e.g. 1.1-1.3. While differences in the frequency of such individual risk alleles, particularly in the 8q24 region, can partially account for the higher risk in populations of African ancestry, all the risk loci detected to date account for no more than 20-25% of the familial risk of prostate cancer. It has been hypothesized that less common or rare functional risk alleles might be identifiable in those loci located within or near to known functional candidate gene regions, and that such less common or rare alleles might explain both the " signal " identified by a more common allele in LD and a somewhat greater familial and/ or population attributable risk. In this application we have assembled a multi- institutional team of investigators with experience in prostate cancer research in minority populations who are willing to pool resources for a large scale attempt to identify such less common or rare alleles. We propose to collaborate with David Reich at Harvard who has the capability to bar code and pool large numbers of DNA samples for deep sequencing across the risk regions where the common allelic variants have been discovered. To optimize our ability to identify these less common and rare variants we propose to include 4500 prostate cases and controls from the Multiethnic Cohort ( Japanese, African American, European American, Latino and Native Hawaiian ) as well as 500 African American prostate cancer cases with a family history of prostate cancer from among those populations currently participating in the collaborative GWAS of African Americans being conducted at USC. We expect this effort to significantly advance knowledge of the genetic risk factors for sporadic and familial prostate cancer among a variety of different racial/ethnic groups, including the highest risk population of African ancestry. The specific identification of the functional genetic variants in the risk loci that have been discovered by GWAS should guide the development of future preventive, early detection, prognostic and even therapeutic measures. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify less common and rare risk alleles for prostate cancer in the approximately 30 allelic loci that have been discovered by genome wide association studies. For this effort, we will utilize the resources of the Multiethnic Cohort Study populations (African American, Japanese, Latino, European American, and Native Hawaiian) as well as several of the key populations of African Americans who are part of the funded African American prostate cancer genome wide association study. More specifically we propose to sequence 4500 individuals with prostate cancer and 4500 controls from the Multiethnic Cohort Study and an additional 500 African American prostate cancer cases with a family history of prostate cancer.
Pleiotropy of cancer susceptibility variants on the risk of non-Hodgkin lymphoma: the PAGE consortium.
Authors: Lim U, Kocarnik JM, Bush WS, Matise TC, Caberto C, Park SL, Carlson CS, Deelman E, Duggan D, Fesinmeyer M, Haiman CA, Henderson BE, Hindorff LA, Kolonel LN, Peters U, Stram DO, Tiirikainen M, Wilkens LR, Wu C, Kooperberg C, Le Marchand L
Source: PLoS One, 2014;9(3), p. e89791.
EPub date: 2014 Mar 5.
Replication of Associations between GWAS SNPs and Melanoma Risk in the Population Architecture Using Genomics and Epidemiology (PAGE) Study.
Authors: Kocarnik JM, Park SL, Han J, Dumitrescu L, Cheng I, Wilkens LR, Schumacher FR, Kolonel L, Carlson CS, Crawford DC, Goodloe RJ, Dilks H, Baker P, Richardson D, Ambite JL, Song F, Quresh AA, Zhang M, Duggan D, Hutter C, Hindorff LA, Bush WS, Kooperberg C, Le Marchand L, Peters U
Source: J Invest Dermatol, 2014 Jan 30;null, p. null.
EPub date: 2014 Jan 30.
No evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population.
Authors: Dumitrescu L, Carty CL, Franceschini N, Hindorff LA, Cole SA, B??kovŠ P, Schumacher FR, Eaton CB, Goodloe RJ, Duggan DJ, Haessler J, Cochran B, Henderson BE, Cheng I, Johnson KC, Carlson CS, Love SA, Brown-Gentry K, Nato AQ, Quibrera M, Shohet RV, Ambite JL, Wilkens LR, Le Marchand L, Haiman CA, Buyske S, Kooperberg C, North KE, Fornage M, Crawford DC
Source: Hum Genet, 2013 Dec;132(12), p. 1427-31.
EPub date: 2013 Oct 8.
Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study.
Authors: Carlson CS, Matise TC, North KE, Haiman CA, Fesinmeyer MD, Buyske S, Schumacher FR, Peters U, Franceschini N, Ritchie MD, Duggan DJ, Spencer KL, Dumitrescu L, Eaton CB, Thomas F, Young A, Carty C, Heiss G, Le Marchand L, Crawford DC, Hindorff LA, Kooperberg CL, PAGE Consortium
Source: PLoS Biol, 2013 Sep;11(9), p. e1001661.
EPub date: 2013 Sep 17.
Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.
Authors: Fesinmeyer MD, Meigs JB, North KE, Schumacher FR, B??kovŠ P, Franceschini N, Haessler J, Goodloe R, Spencer KL, Voruganti VS, Howard BV, Jackson R, Kolonel LN, Liu S, Manson JE, Monroe KR, Mukamal K, Dilks HH, Pendergrass SA, Nato A, Wan P, Wilkens LR, Le Marchand L, Ambite JL, Buyske S, Florez JC, Crawford DC, Hindorff LA, Haiman CA, Peters U, Pankow JS
Source: BMC Med Genet, 2013 Sep 25;14, p. 98.
EPub date: 2013 Sep 25.
Genetic variation in the inflammation and innate immunity pathways and colorectal cancer risk.
Authors: Wang H, Taverna D, Stram DO, Fortini BK, Cheng I, Wilkens LR, Burnett T, Makar KW, Lindor NM, Hopper JL, Gallinger S, Baron JA, Haile R, Kolonel LN, Henderson BE, Newcomb PA, Casey G, Duggan D, Ulrich CM, Le Marchand L
Source: Cancer Epidemiol Biomarkers Prev, 2013 Nov;22(11), p. 2094-101.
EPub date: 2013 Sep 17.
Association of the FTO obesity risk variant rs8050136 with percentage of energy intake from fat in multiple racial/ethnic populations: the PAGE study.
Authors: Park SL, Cheng I, Pendergrass SA, Kucharska-Newton AM, Lim U, Ambite JL, Caberto CP, Monroe KR, Schumacher F, Hindorff LA, Oetjens MT, Wilson S, Goodloe RJ, Love SA, Henderson BE, Kolonel LN, Haiman CA, Crawford DC, North KE, Heiss G, Ritchie MD, Wilkens LR, Le Marchand L
Source: Am J Epidemiol, 2013 Sep 1;178(5), p. 780-90.
EPub date: 2013 Jul 2.
Post-genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study.
Authors: Dumitrescu L, Carty CL, Franceschini N, Hindorff LA, Cole SA, B??kovŠ P, Schumacher FR, Eaton CB, Goodloe RJ, Duggan DJ, Haessler J, Cochran B, Henderson BE, Cheng I, Johnson KC, Carlson CS, Love SA, Brown-Gentry K, Nato AQ Jr, Quibrera M, Anderson G, Shohet RV, Ambite JL, Wilkens LR, Marchand LL, Haiman CA, Buyske S, Kooperberg C, North KE, Fornage M, Crawford DC
Source: Ann Hum Genet, 2013 Sep;77(5), p. 416-25.
EPub date: 2013 Jun 28.
Lack of associations of ten candidate coronary heart disease risk genetic variants and subclinical atherosclerosis in four US populations: the Population Architecture using Genomics and Epidemiology (PAGE) study.
Authors: Zhang L, Buzkova P, Wassel CL, Roman MJ, North KE, Crawford DC, Boston J, Brown-Gentry KD, Cole SA, Deelman E, Goodloe R, Wilson S, Heiss G, Jenny NS, Jorgensen NW, Matise TC, McClellan BE Jr, Nato AQ Jr, Ritchie MD, Franceschini N, Kao WH
Source: Atherosclerosis, 2013 Jun;228(2), p. 390-9.
EPub date: 2013 Mar 13.
Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.
Authors: Wu Y, Waite LL, Jackson AU, Sheu WH, Buyske S, Absher D, Arnett DK, Boerwinkle E, Bonnycastle LL, Carty CL, Cheng I, Cochran B, Croteau-Chonka DC, Dumitrescu L, Eaton CB, Franceschini N, Guo X, Henderson BE, Hindorff LA, Kim E, Kinnunen L, Komulainen P, Lee WJ, Le Marchand L, Lin Y, LindstrŲm J, Lingaas-Holmen O, Mitchell SL, Narisu N, Robinson JG, Schumacher F, Stan?ŠkovŠ A, Sundvall J, Sung YJ, Swift AJ, Wang WC, Wilkens L, Wilsgaard T, Young AM, Adair LS, Ballantyne CM, B??kovŠ P, Chakravarti A, Collins FS, Duggan D, Feranil AB, Ho LT, Hung YJ, Hunt SC, Hveem K, Juang JM, Kesšniemi AY, Kuusisto J, Laakso M, Lakka TA, Lee IT, Leppert MF, Matise TC, Moilanen L, NjÝlstad I, Peters U, Quertermous T, Rauramaa R, Rotter JI, Saramies J, Tuomilehto J, Uusitupa M, Wang TD, Boehnke M, Haiman CA, Chen YD, Kooperberg C, Assimes TL, Crawford DC, Hsiung CA, North KE, Mohlke KL
Source: PLoS Genet, 2013 Mar;9(3), p. e1003379.
EPub date: 2013 Mar 21.
Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study.
Authors: Carty CL, Spencer KL, Setiawan VW, Fernandez-Rhodes L, Malinowski J, Buyske S, Young A, Jorgensen NW, Cheng I, Carlson CS, Brown-Gentry K, Goodloe R, Park A, Parikh NI, Henderson B, Le Marchand L, Wactawski-Wende J, Fornage M, Matise TC, Hindorff LA, Arnold AM, Haiman CA, Franceschini N, Peters U, Crawford DC
Source: Hum Reprod, 2013 Jun;28(6), p. 1695-706.
EPub date: 2013 Mar 18.
Genetic variation and reproductive timing: African American women from the Population Architecture using Genomics and Epidemiology (PAGE) Study.
Authors: Spencer KL, Malinowski J, Carty CL, Franceschini N, FernŠndez-Rhodes L, Young A, Cheng I, Ritchie MD, Haiman CA, Wilkens L, Chunyuanwu, Matise TC, Carlson CS, Brennan K, Park A, Rajkovic A, Hindorff LA, Buyske S, Crawford DC
Source: PLoS One, 2013;8(2), p. e55258.
EPub date: 2013 Feb 12.
Genetic predisposition to higher body mass index or type 2 diabetes and leukocyte telomere length in the Nurses' Health Study.
Authors: Du M, Prescott J, Cornelis MC, Hankinson SE, Giovannucci E, Kraft P, De Vivo I
Source: PLoS One, 2013;8(2), p. e52240.
EPub date: 2013 Feb 12.
A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.
Authors: Peters U, North KE, Sethupathy P, Buyske S, Haessler J, Jiao S, Fesinmeyer MD, Jackson RD, Kuller LH, Rajkovic A, Lim U, Cheng I, Schumacher F, Wilkens L, Li R, Monda K, Ehret G, Nguyen KD, Cooper R, Lewis CE, Leppert M, Irvin MR, Gu CC, Houston D, Buzkova P, Ritchie M, Matise TC, Le Marchand L, Hindorff LA, Crawford DC, Haiman CA, Kooperberg C
Source: PLoS Genet, 2013;9(1), p. e1003171.
EPub date: 2013 Jan 17.
Effects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study.
Authors: Fesinmeyer MD, North KE, Lim U, B??kovŠ P, Crawford DC, Haessler J, Gross MD, Fowke JH, Goodloe R, Love SA, Graff M, Carlson CS, Kuller LH, Matise TC, Hong CP, Henderson BE, Allen M, Rohde RR, Mayo P, Schnetz-Boutaud N, Monroe KR, Ritchie MD, Prentice RL, Kolonel LN, Manson JE, Pankow J, Hindorff LA, Franceschini N, Wilkens LR, Haiman CA, Le Marchand L, Peters U
Source: BMC Med Genet, 2013 Jan 11;14, p. 6.
EPub date: 2013 Jan 11.
Fine-mapping of IL16 gene and prostate cancer risk in African Americans.
Authors: Batai K, Shah E, Murphy AB, Newsome J, Ruden M, Ahaghotu C, Kittles RA
Source: Cancer Epidemiol Biomarkers Prev, 2012 Nov;21(11), p. 2059-68.
EPub date: 2012 Aug 24.
Fine-mapping and initial characterization of QT interval loci in African Americans.
Authors: Avery CL, Sethupathy P, Buyske S, He Q, Lin DY, Arking DE, Carty CL, Duggan D, Fesinmeyer MD, Hindorff LA, Jeff JM, Klein L, Patton KK, Peters U, Shohet RV, Sotoodehnia N, Young AM, Kooperberg C, Haiman CA, Mohlke KL, Whitsel EA, North KE
Source: PLoS Genet, 2012;8(8), p. e1002870.
EPub date: 2012 Aug 9.
Integrating genetic association, genetics of gene expression, and single nucleotide polymorphism set analysis to identify susceptibility Loci for type 2 diabetes mellitus.
Authors: Greenawalt DM, Sieberts SK, Cornelis MC, Girman CJ, Zhong H, Yang X, Guinney J, Qi L, Hu FB
Source: Am J Epidemiol, 2012 Sep 1;176(5), p. 423-30.
EPub date: 2012 Aug 2.