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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. [ABSTRACT FROM AUTHOR]

Prostate specific antigen (PSA) is widely used as a diagnostic biomarker for prostate cancer (PC). However, due to its low predictive performance, many patients without PC suffer from the harms of unnecessary prostate needle biopsies. The present study aims to evaluate the reproducibility and performance of a genetic risk prediction model in Japanese and estimate its utility as a diagnostic biomarker in a clinical scenario. We created a logistic regression model incorporating 16 SNPs that were significantly associated with PC in a genome-wide association study of Japanese population using 689 cases and 749 male controls. The model was validated by two independent sets of Japanese samples comprising 3,294 cases and 6,281 male controls. The areas under curve (AUC) of the model were 0.679, 0.655, and 0.661 for the samples used to create the model and those used for validation. The AUCs were not significantly altered in samples with PSA 1-10 ng/ml. 24.2% and 9.7% of the patients had odds ratio <0.5 (low risk) or >2 (high risk) in the model. Assuming the overall positive rate of prostate needle biopsies to be 20%, the positive biopsy rates were 10.7% and 42.4% for the low and high genetic risk groups respectively. Our genetic risk prediction model for PC was highly reproducible, and its predictive performance was not influenced by PSA. The model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA, which should be confirmed in future clinical studies. [ABSTRACT FROM AUTHOR]

GWAS of prostate cancer have been remarkably successful in revealing common genetic variants and novel biological pathways that are linked with its etiology. A more complete understanding of inherited susceptibility to prostate cancer in the general population will come from continuing such discovery efforts and from testing known risk alleles in diverse racial and ethnic groups. In this large study of prostate cancer in African American men (3,425 prostate cancer cases and 3,290 controls), we tested 49 risk variants located in 28 genomic regions identified through GWAS in men of European and Asian descent, and we replicated associations (at p≤0.05) with roughly half of these markers. Through fine-mapping, we identified nearby markers in many regions that better define associations in African Americans. At 8q24, we found 9 variants (p≤6×10(-4)) that best capture risk of prostate cancer in African Americans, many of which are more common in men of African than European descent. The markers found to be associated with risk at each locus improved risk modeling in African Americans (per allele OR = 1.17) over the alleles reported in the original GWAS (OR = 1.08). In summary, in this detailed analysis of the prostate cancer risk loci reported from GWAS, we have validated and improved upon markers of risk in some regions that better define the association with prostate cancer in African Americans. Our findings with variants at 8q24 also reinforce the importance of this region as a major risk locus for prostate cancer in men of African ancestry., Competing Interests: The authors have declared that no competing interests exist.

Background: Cardiovascular disease (CVD) mortality varies across racial and ethnic groups in the U.S., and the extent that known risk factors can explain the differences has not been extensively explored., Methods: We examined the risk of dying from acute myocardial infarction (AMI) and other heart disease (OHD) among 139,406 African-American (AA), Native Hawaiian (NH), Japanese-American (JA), Latino and White men and women initially free from cardiovascular disease followed prospectively between 1993-1996 and 2003 in the Multiethnic Cohort Study (MEC). During this period, 946 deaths from AMI and 2,323 deaths from OHD were observed. Relative risks of AMI and OHD mortality were calculated accounting for established CVD risk factors: body mass index (BMI), hypertension, diabetes, smoking, alcohol consumption, amount of vigorous physical activity, educational level, diet and, for women, type and age at menopause and hormone replacement therapy (HRT) use., Results: Established CVD risk factors explained much of the observed racial and ethnic differences in risk of AMI and OHD mortality. After adjustment, NH men and women had greater risks of OHD than Whites (69% excess, P<0.001 and 62% excess, P = 0.003, respectively), and AA women had greater risks of AMI (48% excess, P = 0.01) and OHD (35% excess, P = 0.007). JA men had lower risks of AMI (51% deficit, P<0.001) and OHD (27% deficit, P = 0.001), as did JA women (AMI, 37% deficit, P = 0.03; OHD, 40% deficit, P = 0.001). Latinos had underlying lower risk of AMI death (26% deficit in men and 35% in women, P = 0.03)., Conclusion: Known risk factors explain the majority of racial and ethnic differences in mortality due to AMI and OHD. The unexplained excess in NH and AA and the deficits in JA suggest the presence of unmeasured determinants for cardiovascular mortality that are distributed unequally across these populations.