| 11. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 12. |
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| 13. |
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| 14. |
- Hedelin, Maria, et al.
(författare)
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Association of frequent consumption of fatty fish with prostate cancer risk is modified by COX-2 polymorphism
- 2007
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Ingår i: International Journal of Cancer. - Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. No Calif Canc Ctr, Fremont, CA USA. Umea Univ, Dept Radiat Sci Oncol, Umea, Sweden. Univ Milan, Dept Stat, Milan, Italy. Karolinska Univ Hosp, Ctr Oncol, CLINTEC, Stockholm, Sweden. Wake Forest Univ, Ctr Human Genet, Sch Med, Winston Salem, NC USA. Harvard Univ, Dept Epidemiol, Boston, MA 02115 USA. : WILEY-LISS. - 0020-7136 .- 1097-0215. ; 120:2, s. 398-405
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Tidskriftsartikel (refereegranskat)abstract
- Dietary intake of marine fatty acids from fish may protect against prostate cancer development. We studied this association and whether it is modified by genetic variation in cyclooxygenase (COX)-2, a key enzyme in fatty acid metabolism and inflammation. We assessed dietary intake of fish among 1,499 incident prostate cancer cases and 1,130 population controls in Sweden. Five single nucleotide polymorphisms (SNPs) were identified and genotyped in available blood samples for 1,378 cases and 782 controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by multivariate logistic regression. Multiplicative and additive interactions between fish intake and COX-2 SNPs on prostate cancer risk were evaluated. Eating fatty fish (e.g. salmon-type fish) once or more per week, compared to never, was associated with reduced risk of prostate cancer (OR: 0.57, 95% CI: 0.43-0.76). The OR comparing the highest to the lowest quartile of marine fatty acids intake was 0.70 (95% CI: 0.51-0.97). We found a significant interaction (p < 0.001) between salmon-type fish intake and a SNP in the COX-2 gene (rs5275: +6365 T/C), but not with the 4 other SNPs examined. We found strong inverse associations with increasing intake of salmon-type fish among carriers of the variant allele (OR for once per week or more vs. never = 0.28, 95% CI: 0.18-0.45; p(trend) < 0.01), but no association among carriers of the more common allele. Frequent consumption of fatty fish and marine fatty acids appears to reduce the risk of prostate cancer, and this association is modified by genetic variation in the COX-2 gene.
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| 15. |
- Hong, Mun-Gwan, et al.
(författare)
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A genome-wide assessment of variability in human serum metabolism
- 2013
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 34:3, s. 515-524
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Tidskriftsartikel (refereegranskat)abstract
- The study of the genetic regulation of metabolism in human serum samples can contribute to a better understanding of the intermediate biological steps that lead from polymorphism to disease. Here, we conducted a genome-wide association study (GWAS) to discover metabolic quantitative trait loci (mQTLs) utilizing samples from a study of prostate cancer in Swedish men, consisting of 402 individuals (214 cases and 188 controls) in a discovery set and 489 case-only samples in a replication set. A global nontargeted metabolite profiling approach was utilized resulting in the detection of 6,138 molecular features followed by targeted identification of associated metabolites. Seven replicating loci were identified (PYROXD2, FADS1, PON1, CYP4F2, UGT1A8, ACADL, and LIPC) with associated sequence variants contributing significantly to trait variance for one or more metabolites (P = 10(-13) -10(-91)). Regional mQTL enrichment analyses implicated two loci that included FADS1 and a novel locus near PDGFC. Biological pathway analysis implicated ACADM, ACADS, ACAD8, ACAD10, ACAD11, and ACOXL, reflecting significant enrichment of genes with acyl-CoA dehydrogenase activity. mQTL SNPs and mQTL-harboring genes were over-represented across GWASs conducted to date, suggesting that these data may have utility in tracing the molecular basis of some complex disease associations.
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| 16. |
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| 17. |
- Hsu, Fang-Chi, et al.
(författare)
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A novel prostate cancer susceptibility locus at 19q13.
- 2009
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Ingår i: Cancer research. - 1538-7445. ; 69:7, s. 2720-3
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Tidskriftsartikel (refereegranskat)abstract
- A two-stage genome-wide association study (GWAS) of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative identified single nucleotide polymorphisms (SNP) in 150 regions across the genome that may be associated with prostate cancer (PCa) risk. We filtered these results to identify 43 independent SNPs where the frequency of the risk allele was consistently higher in cases than in controls in each of the five CGEMS study populations. Genotype information for 22 of these 43 SNPs was obtained either directly by genotyping or indirectly by imputation in our PCa GWAS of 500 cases and 500 controls selected from a population-based case-control study in Sweden [Cancer of the Prostate in Sweden (CAPS)]. Two of these 22 SNPs were significantly associated with PCa risk (P<0.05). We then genotyped these two SNPs in the remaining cases (n=2,393) and controls (n=1,222) from CAPS and found that rs887391 at 19q13 was highly associated with PCa risk (P=9.4 x 10(-4)). A similar trend of association was found for this SNP in a case-control study from Johns Hopkins Hospital (JHH), albeit the result was not statistically significant. Altogether, the frequency of the risk allele of rs887391 was consistently higher in cases than controls among each of seven study populations examined, with an overall P=3.2 x 10(-7) from a combined allelic test. A fine-mapping study in a 110-kb region at 19q13 among CAPS and JHH study populations revealed that rs887391 was the most strongly associated SNP in the region. Additional confirmation studies of this region are warranted.
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| 18. |
- Humphreys, Keith, et al.
(författare)
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The Genetic Structure of the Swedish Population
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:8, s. e22547-
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Tidskriftsartikel (refereegranskat)abstract
- Patterns of genetic diversity have previously been shown to mirror geography on a global scale and within continents and individual countries. Using genome-wide SNP data on 5174 Swedes with extensive geographical coverage, we analyzed the genetic structure of the Swedish population. We observed strong differences between the far northern counties and the remaining counties. The population of Dalarna county, in north middle Sweden, which borders southern Norway, also appears to differ markedly from other counties, possibly due to this county having more individuals with remote Finnish or Norwegian ancestry than other counties. An analysis of genetic differentiation (based on pairwise F(st)) indicated that the population of Sweden's southernmost counties are genetically closer to the HapMap CEU samples of Northern European ancestry than to the populations of Sweden's northernmost counties. In a comparison of extended homozygous segments, we detected a clear divide between southern and northern Sweden with small differences between the southern counties and considerably more segments in northern Sweden. Both the increased degree of homozygosity in the north and the large genetic differences between the south and the north may have arisen due to a small population in the north and the vast geographical distances between towns and villages in the north, in contrast to the more densely settled southern parts of Sweden. Our findings have implications for future genome-wide association studies (GWAS) with respect to the matching of cases and controls and the need for within-county matching. We have shown that genetic differences within a single country may be substantial, even when viewed on a European scale. Thus, population stratification needs to be accounted for, even within a country like Sweden, which is often perceived to be relatively homogenous and a favourable resource for genetic mapping, otherwise inferences based on genetic data may lead to false conclusions.
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| 19. |
- Jin, Guangfu, et al.
(författare)
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Genome-wide Association Study Identifies Loci at ATF7IP and KLK2 Associated with Percentage of Circulating Free PSA
- 2013
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Ingår i: Neoplasia. - : Elsevier BV. - 1522-8002 .- 1476-5586. ; 15:1, s. 95-95
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Percentage of free-to-total prostate-specific antigen (%fPSA) is an independent predictor of risk for prostate cancer among men with modestly elevated level of total PSA (tPSA) in blood. Physiological and pathological factors have been shown to influence the %fPSA value and diagnostic accuracy. MATERIALS/METHODS: To evaluate genetic determinants of %fPSA, we conducted a genome-wide association study of serum %fPSA by genotyping 642,584 single nucleotide polymorphisms (SNPs) in 3192 men of European ancestry, each with a tPSA level of 2.5 to 10 ng/ml, that were recruited in the REduction by DUtasteride of Prostate Cancer Events study. Single nucleotide polymorphisms (SNPs) with P < 10(-5) were further evaluated among the controls of a population-based case-control study in Sweden (2899 prostate cancer cases and 1722 male controls), including 464 controls having tPSA levels of 2.5 to 10 ng/ml. RESULTS: We identified two loci that were associated with %fPSA at a genome-wide significance level (P < 5 x 10(-8)). The first associated SNP was rs3213764 (P = 6.45 x 10(-10)), a nonsynonymous variant (K530R) in the ATF7IP gene at 12p13. This variant was also nominally associated with tPSA (P = .015). The second locus was rs1354774 (P = 1.25 x 10(-12)), near KLK2 at 19q13, which was not associated with tPSA levels, and is separate from the rs17632542 locus at KLK3 that was previously associated with tPSA levels and prostate cancer risk. Neither rs3213764 nor rs1354774 was associated with prostate cancer risk or aggressiveness. CONCLUSIONS: These findings demonstrate that genetic variants at ATF7IP and KLK2 contribute to the variance of %fPSA.
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| 20. |
- Jin, Guangfu, et al.
(författare)
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Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis : evidence from the International Consortium for Prostate Cancer Genetics (ICPCG)
- 2012
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 131:7, s. 1095-1103
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Tidskriftsartikel (refereegranskat)abstract
- Multiple prostate cancer (PCa) risk-related loci have been discovered by genome-wide association studies (GWAS) based on case-control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case-control GWAS are also associated with disease risk in HPC families.
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