Freedman, M. L. et al. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc. Natl Acad. Sci. USA 103, 14068-14073

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2006; 103(38):14068-73. DOI: 10.1073/pnas.0605832103
Source: PubMed


A whole-genome admixture scan in 1,597 African Americans identified a 3.8 Mb interval on chromosome 8q24 as significantly associated with susceptibility to prostate cancer [logarithm of odds (LOD) = 7.1]. The increased risk because of inheriting African ancestry is greater in men diagnosed before 72 years of age (P < 0.00032) and may contribute to the epidemiological observation that the higher risk for prostate cancer in African Americans is greatest in younger men (and attenuates with older age). The same region was recently identified through linkage analysis of prostate cancer, followed by fine-mapping. We strongly replicated this association (P < 4.2 x 10(-9)) but find that the previously described alleles do not explain more than a fraction of the admixture signal. Thus, admixture mapping indicates a major, still-unidentified risk gene for prostate cancer at 8q24, motivating intense work to find it.

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    • "One of the most significant risk factors associated with prostate cancer is an African ancestry. An admixture study of prostate cancer within African Americans led to the identification of the 8q24 prostate cancer susceptibility locus [29], arguably one of the most significant prostate cancer risk loci identified to date [30]. Prostate cancer association studies within African Americans are becoming more prevalent yet the impact of risk alleles within non-admixed African populations has been largely overlooked, mainly due to logistic issues associated with establishing African-based prostate cancer studies. "
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    ABSTRACT: Although African ancestry represents a significant risk factor for prostate cancer, few studies have investigated the significance of prostate cancer and relevance of previously defined genetic and epidemiological prostate cancer risk factors within Africa. We recently established the Southern African Prostate Cancer Study (SAPCS), a resource for epidemiological and genetic analysis of prostate cancer risk and outcomes in Black men from South Africa. Biased towards highly aggressive prostate cancer disease, this is the first reported data analysis. The SAPCS is an ongoing population-based study of Black men with or without prostate cancer. Pilot analysis was performed for the first 837 participants, 522 cases and 315 controls. We investigate 46 pre-defined prostate cancer risk alleles and up to 24 epidemiological measures including demographic, lifestyle and environmental factors, for power to predict disease status and to drive on-going SAPCS recruitment, sampling procedures and research direction. Preliminary results suggest that no previously defined risk alleles significantly predict prostate cancer occurrence within the SAPCS. Furthermore, genetic risk profiles did not enhance the predictive power of prostate specific antigen (PSA) testing. Our study supports several lifestyle/environmental factors contributing to prostate cancer risk including a family history of cancer, diabetes, current sexual activity and erectile dysfunction, balding pattern, frequent aspirin usage and high PSA levels. Despite a clear increased prostate cancer risk associated with an African ancestry, experimental data is lacking within Africa. This pilot study is therefore a significant contribution to the field. While genetic risk factors (largely European-defined) show no evidence for disease prediction in the SAPCS, several epidemiological factors were associated with prostate cancer status. We call for improved study power by building on the SAPCS resource, further validation of associated factors in independent African-based resources, and genome-wide approaches to define African-specific risk alleles.
    BMC Urology 12/2013; 13(1):74. DOI:10.1186/1471-2490-13-74 · 1.41 Impact Factor
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    • "Table 1 Successful admixture mapping studies in African Americans Disease phenotype Disease locus References BMI Xq25 Cheng et al. (2009) Hypertension 6p21.1 Cheng et al. (2010) Interleukin 6 soluble receptor levels 1 Reich et al. (2007) Lung cancer (non-smallcell lung cancer) 1q42.13 Schwartz et al. (2011) Multiple sclerosis 1 Reich et al. (2005) Nondiabetic end-stage renal disease (ESRD) 22 Kao et al. (2008) Prostate cancer (\age 72) 8q24 Freedman et al. (2006) "
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    ABSTRACT: Knowledge from human genetic research continuously challenges the notion that race and biology are inextricably linked, with implications across biomedical and public health disciplines. However, biomedical research continues to explore health and disease under a racial framework ignoring and at times confounding the identification of true biological and/or environmental risk factors. Within this article, we present a brief overview of the use of race in biomedical research and studies of human genome variation and how genetic ancestry may help us understand health disparities. We believe that the casual use of “race” to define groups in biomedical research has contributed to our limited understanding of complex disease etiology and risk factors driving health disparities.
    Race and Social Problems 06/2013; 5(2). DOI:10.1007/s12552-013-9094-x
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    • "With the development of SNP array technology, a genome wide association study (GWAS) emerged for identifying small and moderate risk SNPs. The first two GWAS studies identified a 3.8 Mb interval on chromosome 8q24 as significantly associated with susceptibility to PCa in 2006 [237] [238]. Today GWAS have been remarkably successful in identifying dozens of common genetic variants or loci associated with PCa [239] [240] [241]. "
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    ABSTRACT: Prostate cancer (PCa) is the most commonly diagnosed male malignancy and the second biggest cause of cancer death in men of the Western world. Higher incidences of PCa occur in men from North America, Oceania and Western countries, whereas men from Asia and North Africa have a much lower PCa incidence rate. Investigations into this population disparity of PCa incidence, in order to identify potential preventive factors or targets for the therapeutic intervention of PCa, have found differences in both environmental and genetic variations between these populations. Environmental variations include both diet and lifestyle, which vary widely between populations. Evidence that diet comes into play has been shown by men who immigrate from Eastern to Western countries. PCa incidence in these men is higher than men in their native countries. However the number of immigrants developing PCa still doesn't match native black/white men, therefore genetic factors also contribute to PCa risk, which are supported by familial studies. There are a number of genetic polymorphisms that are differentially presented between Western and Eastern men, which are potentially associated with PCa incidence. Androgen and its receptor (AR) play a major role in PCa development and progression. In this study, we focus on genes involved in androgen biosynthesis and metabolism, as well as those associated with AR pathway, whose polymorphisms affect androgen level and biological or physiological functions of androgen. While many of the genetic polymorphisms in this androgen/AR system showed different frequencies between populations, contradictory evidences exist for most of these genes investigated individually as to the true contribution to PCa risk. More accurate measurements of androgen activity within the prostate are required and further studies need to include more African and Asian subjects. As many of these genetic polymorphisms may contribute to different steps in the same biological/physiological function of androgen and AR pathway, an integrated analysis considering the combined effect of all the genetic polymorphisms may be necessary to assess their contribution to PCa initiation and progression.
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