Identification of genetic risk associated with prostate cancer using ancestry informative markers

L. J. Ricks-Santi, V. Apprey, T. Mason, B. Wilson, M. Abbas, W. Hernandez, S. Hooker, M. Doura, G. Bonney, G. Dunston, Rick A Kittles, C. Ahaghotu

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

BACKGROUND: Prostate cancer (PCa) is a common malignancy and a leading cause of cancer death among men in the United States with African-American (AA) men having the highest incidence and mortality rates. Given recent results from admixture mapping and genome-wide association studies for PCa in AA men, it is clear that many risk alleles are enriched in men with West African genetic ancestry.METHODS: A total of 77 ancestry informative markers (AIMs) within surrounding candidate gene regions were genotyped and haplotyped using Pyrosequencing in 358 unrelated men enrolled in a PCa genetic association study at the Howard University Hospital between 2000 and 2004. Sequence analysis of promoter region single-nucleotide polymorphisms (SNPs) to evaluate disruption of transcription factor-binding sites was conducted using in silico methods.RESULTS: Eight AIMs were significantly associated with PCa risk after adjusting for age and West African ancestry. SNP rs1993973 (intervening sequences) had the strongest association with PCa using the log-additive genetic model (P0.002). SNPs rs1561131 (genotypic, P0.007), rs1963562 (dominant, P0.01) and rs615382 (recessive, P0.009) remained highly significant after adjusting for both age and ancestry. We also tested the independent effect of each significantly associated SNP and rs1561131 (P0.04) and rs1963562 (P0.04) remained significantly associated with PCa development. After multiple comparisons testing using the false discovery rate, rs1993973 remained significant. Analysis of the rs156113-, rs1963562-rs615382l and rs1993973-rs585224 haplotypes revealed that the least frequently found haplotypes in this population were significantly associated with a decreased risk of PCa (P0.032 and 0.0017, respectively).CONCLUSIONS: The approach for SNP selection utilized herein showed that AIMs may not only leverage increased linkage disequilibrium in populations to identify risk and protective alleles, but may also be informative in dissecting the biology of PCa and other health disparities.

Original languageEnglish (US)
Pages (from-to)359-364
Number of pages6
JournalProstate Cancer and Prostatic Diseases
Volume15
Issue number4
DOIs
StatePublished - Dec 2012
Externally publishedYes

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Prostatic Neoplasms
Single Nucleotide Polymorphism
African Americans
Haplotypes
Alleles
Genome-Wide Association Study
Genetic Models
Linkage Disequilibrium
Genetic Association Studies
Genetic Promoter Regions
Computer Simulation
Introns
Population
Sequence Analysis
Cause of Death
Neoplasms
Transcription Factors
Binding Sites
Mortality
Incidence

Keywords

  • African-American
  • ancestry informative markers
  • health disparities

ASJC Scopus subject areas

  • Oncology
  • Urology
  • Cancer Research

Cite this

Ricks-Santi, L. J., Apprey, V., Mason, T., Wilson, B., Abbas, M., Hernandez, W., ... Ahaghotu, C. (2012). Identification of genetic risk associated with prostate cancer using ancestry informative markers. Prostate Cancer and Prostatic Diseases, 15(4), 359-364. https://doi.org/10.1038/pcan.2012.19

Identification of genetic risk associated with prostate cancer using ancestry informative markers. / Ricks-Santi, L. J.; Apprey, V.; Mason, T.; Wilson, B.; Abbas, M.; Hernandez, W.; Hooker, S.; Doura, M.; Bonney, G.; Dunston, G.; Kittles, Rick A; Ahaghotu, C.

In: Prostate Cancer and Prostatic Diseases, Vol. 15, No. 4, 12.2012, p. 359-364.

Research output: Contribution to journalArticle

Ricks-Santi, LJ, Apprey, V, Mason, T, Wilson, B, Abbas, M, Hernandez, W, Hooker, S, Doura, M, Bonney, G, Dunston, G, Kittles, RA & Ahaghotu, C 2012, 'Identification of genetic risk associated with prostate cancer using ancestry informative markers', Prostate Cancer and Prostatic Diseases, vol. 15, no. 4, pp. 359-364. https://doi.org/10.1038/pcan.2012.19
Ricks-Santi, L. J. ; Apprey, V. ; Mason, T. ; Wilson, B. ; Abbas, M. ; Hernandez, W. ; Hooker, S. ; Doura, M. ; Bonney, G. ; Dunston, G. ; Kittles, Rick A ; Ahaghotu, C. / Identification of genetic risk associated with prostate cancer using ancestry informative markers. In: Prostate Cancer and Prostatic Diseases. 2012 ; Vol. 15, No. 4. pp. 359-364.
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abstract = "BACKGROUND: Prostate cancer (PCa) is a common malignancy and a leading cause of cancer death among men in the United States with African-American (AA) men having the highest incidence and mortality rates. Given recent results from admixture mapping and genome-wide association studies for PCa in AA men, it is clear that many risk alleles are enriched in men with West African genetic ancestry.METHODS: A total of 77 ancestry informative markers (AIMs) within surrounding candidate gene regions were genotyped and haplotyped using Pyrosequencing in 358 unrelated men enrolled in a PCa genetic association study at the Howard University Hospital between 2000 and 2004. Sequence analysis of promoter region single-nucleotide polymorphisms (SNPs) to evaluate disruption of transcription factor-binding sites was conducted using in silico methods.RESULTS: Eight AIMs were significantly associated with PCa risk after adjusting for age and West African ancestry. SNP rs1993973 (intervening sequences) had the strongest association with PCa using the log-additive genetic model (P0.002). SNPs rs1561131 (genotypic, P0.007), rs1963562 (dominant, P0.01) and rs615382 (recessive, P0.009) remained highly significant after adjusting for both age and ancestry. We also tested the independent effect of each significantly associated SNP and rs1561131 (P0.04) and rs1963562 (P0.04) remained significantly associated with PCa development. After multiple comparisons testing using the false discovery rate, rs1993973 remained significant. Analysis of the rs156113-, rs1963562-rs615382l and rs1993973-rs585224 haplotypes revealed that the least frequently found haplotypes in this population were significantly associated with a decreased risk of PCa (P0.032 and 0.0017, respectively).CONCLUSIONS: The approach for SNP selection utilized herein showed that AIMs may not only leverage increased linkage disequilibrium in populations to identify risk and protective alleles, but may also be informative in dissecting the biology of PCa and other health disparities.",
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T1 - Identification of genetic risk associated with prostate cancer using ancestry informative markers

AU - Ricks-Santi, L. J.

AU - Apprey, V.

AU - Mason, T.

AU - Wilson, B.

AU - Abbas, M.

AU - Hernandez, W.

AU - Hooker, S.

AU - Doura, M.

AU - Bonney, G.

AU - Dunston, G.

AU - Kittles, Rick A

AU - Ahaghotu, C.

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N2 - BACKGROUND: Prostate cancer (PCa) is a common malignancy and a leading cause of cancer death among men in the United States with African-American (AA) men having the highest incidence and mortality rates. Given recent results from admixture mapping and genome-wide association studies for PCa in AA men, it is clear that many risk alleles are enriched in men with West African genetic ancestry.METHODS: A total of 77 ancestry informative markers (AIMs) within surrounding candidate gene regions were genotyped and haplotyped using Pyrosequencing in 358 unrelated men enrolled in a PCa genetic association study at the Howard University Hospital between 2000 and 2004. Sequence analysis of promoter region single-nucleotide polymorphisms (SNPs) to evaluate disruption of transcription factor-binding sites was conducted using in silico methods.RESULTS: Eight AIMs were significantly associated with PCa risk after adjusting for age and West African ancestry. SNP rs1993973 (intervening sequences) had the strongest association with PCa using the log-additive genetic model (P0.002). SNPs rs1561131 (genotypic, P0.007), rs1963562 (dominant, P0.01) and rs615382 (recessive, P0.009) remained highly significant after adjusting for both age and ancestry. We also tested the independent effect of each significantly associated SNP and rs1561131 (P0.04) and rs1963562 (P0.04) remained significantly associated with PCa development. After multiple comparisons testing using the false discovery rate, rs1993973 remained significant. Analysis of the rs156113-, rs1963562-rs615382l and rs1993973-rs585224 haplotypes revealed that the least frequently found haplotypes in this population were significantly associated with a decreased risk of PCa (P0.032 and 0.0017, respectively).CONCLUSIONS: The approach for SNP selection utilized herein showed that AIMs may not only leverage increased linkage disequilibrium in populations to identify risk and protective alleles, but may also be informative in dissecting the biology of PCa and other health disparities.

AB - BACKGROUND: Prostate cancer (PCa) is a common malignancy and a leading cause of cancer death among men in the United States with African-American (AA) men having the highest incidence and mortality rates. Given recent results from admixture mapping and genome-wide association studies for PCa in AA men, it is clear that many risk alleles are enriched in men with West African genetic ancestry.METHODS: A total of 77 ancestry informative markers (AIMs) within surrounding candidate gene regions were genotyped and haplotyped using Pyrosequencing in 358 unrelated men enrolled in a PCa genetic association study at the Howard University Hospital between 2000 and 2004. Sequence analysis of promoter region single-nucleotide polymorphisms (SNPs) to evaluate disruption of transcription factor-binding sites was conducted using in silico methods.RESULTS: Eight AIMs were significantly associated with PCa risk after adjusting for age and West African ancestry. SNP rs1993973 (intervening sequences) had the strongest association with PCa using the log-additive genetic model (P0.002). SNPs rs1561131 (genotypic, P0.007), rs1963562 (dominant, P0.01) and rs615382 (recessive, P0.009) remained highly significant after adjusting for both age and ancestry. We also tested the independent effect of each significantly associated SNP and rs1561131 (P0.04) and rs1963562 (P0.04) remained significantly associated with PCa development. After multiple comparisons testing using the false discovery rate, rs1993973 remained significant. Analysis of the rs156113-, rs1963562-rs615382l and rs1993973-rs585224 haplotypes revealed that the least frequently found haplotypes in this population were significantly associated with a decreased risk of PCa (P0.032 and 0.0017, respectively).CONCLUSIONS: The approach for SNP selection utilized herein showed that AIMs may not only leverage increased linkage disequilibrium in populations to identify risk and protective alleles, but may also be informative in dissecting the biology of PCa and other health disparities.

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