| 1. |
- Wheeler, Eleanor, et al.
(författare)
-
Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations : A transethnic genome-wide meta-analysis
- 2017
-
Ingår i: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 14:9
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findings: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 x 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI0.55-0.74) of African American adults with T2Dto remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.Conclusions: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
|
|
| 2. |
- Haiman, Christopher A., et al.
(författare)
-
A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer
- 2011
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:12, s. 61-1210
-
Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 x 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 x 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 x 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
|
|
| 3. |
- Cox, David G., et al.
(författare)
-
A comprehensive analysis of the androgen receptor gene and risk of breast cancer: results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3)
- 2006
-
Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 8:5
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction Androgens have been hypothesised to influence risk of breast cancer through several possible mechanisms, including their conversion to estradiol or their binding to the oestrogen receptor and/ or androgen receptor ( AR) in the breast. Here, we report on the results of a large and comprehensive study of the association between genetic variation in the AR gene and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium ( BPC3). Methods The underlying genetic variation was determined by first sequencing the coding regions of the AR gene in a panel of 95 advanced breast cancer cases. Second, a dense set of markers from the public database was genotyped in a panel of 349 healthy women. The linkage disequilibrium relationships ( blocks) across the gene were then identified, and haplotypetagging single nucleotide polymorphisms ( htSNPs) were selected to capture the common genetic variation across the locus. The htSNPs were then genotyped in the nested breast cancer cases and controls from the Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study, and Women's Health Study cohorts ( 5,603 breast cancer cases and 7,480 controls). Results We found no association between any genetic variation ( SNP, haplotype, or the exon 1 CAG repeat) in the AR gene and risk of breast cancer, nor were any statistical interactions with known breast cancer risk factors observed. Conclusion Among postmenopausal Caucasian women, common variants of the AR gene are not associated with risk of breast cancer.
|
|
| 4. |
- Cox, David G, et al.
(författare)
-
Haplotypes of the estrogen receptor beta gene and breast cancer risk
- 2008
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 122:2, s. 387-392
-
Tidskriftsartikel (refereegranskat)abstract
- Exposure to exogenous (oral contraceptives, postmenopausal hormone therapy) and endogenous (number of ovulatory cycles, adiposity) steroid hormones is associated with breast cancer risk. Breast cancer risk associated with these exposures could hypothetically be modified by genes in the steroid hormone synthesis, metabolism and signaling pathways. Estrogen receptors are the first step along the path of signaling cell growth and development upon stimulation with estrogens. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium has systematically selected haplotype tagging SNPs in genes along the steroid hormone synthesis, metabolism and binding pathways, including the estrogen receptor beta (ESR2) gene. Four htSNPs tag the 6 major (>5% frequency) haplotypes of the ESR2 gene. These polymorphisms have been genotyped in 5,789 breast cancer cases and 7,761 controls nested within the American Cancer Society Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study and Women's Health Study cohorts. None of the SNPs were independently associated with breast cancer risk. One haplotype of the ESR2 gene was associated with breast cancer risk before correction for multiple testing (OR 1.17, 95% CI 1.07-1.28, p = 0.0007). This haplotype remained associated with breast cancer risk after adjustment for multiple testing using a permutation procedure. There was no statistically significant heterogeneity in SNP or haplotype odds ratios across cohorts. These data suggest that inherited variants in ESR2 (while possibly conferring a small increased risk of breast cancer) are not associated with appreciable (OR > 1.2) changes in breast cancer risk among Caucasian women.
|
|
| 5. |
- de Bakker, Paul I. W., et al.
(författare)
-
Transferability of tag SNPs in genetic association studies in multiple populations
- 2006
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 38:11, s. 1298-1303
-
Tidskriftsartikel (refereegranskat)abstract
- A general question for linkage disequilibrium-based association studies is how power to detect an association is compromised when tag SNPs are chosen from data in one population sample and then deployed in another sample. Specifically, it is important to know how well tags picked from the HapMap DNA samples capture the variation in other samples. To address this, we collected dense data uniformly across the four HapMap population samples and eleven other population samples. We picked tag SNPs using genotype data we collected in the HapMap samples and then evaluated the effective coverage of these tags in comparison to the entire set of common variants observed in the other samples. We simulated case-control association studies in the non-HapMap samples under a disease model of modest risk, and we observed little loss in power. These results demonstrate that the HapMap DNA samples can be used to select tags for genome-wide association studies in many samples around the world.
|
|
| 6. |
- Haiman, Christopher A, et al.
(författare)
-
Levels of Beta-Microseminoprotein in Blood and Risk of Prostate Cancer in Multiple Populations.
- 2012
-
Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874.
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundA common genetic variant (rs10993994) in the 5' region of the gene encoding β-microseminoprotein (MSP) is associated with circulating levels of MSP and prostate cancer risk. Whether MSP levels are predictive of prostate cancer risk has not been evaluated.MethodsWe investigated the prospective relationship between circulating plasma levels of MSP and prostate cancer risk in a nested case-control study of 1503 case subjects and 1503 control subjects among black, Latino, Japanese, Native Hawaiian, and white men from the Multiethnic Cohort study. We also examined the ability of MSP to serve as a biomarker for discriminating prostate cancer case subjects from control subjects. All statistical tests are two-sided.ResultsIn all racial and ethnic groups, men with lower MSP levels were at greater risk of developing prostate cancer (odds ratio = 1.02 per one unit decrease in MSP, P < .001 in the prostate-specific antigen [PSA]-adjusted analysis). Compared with men in the highest decile of MSP, the multivariable PSA-adjusted odds ratio was 3.64 (95% confidence interval = 2.41 to 5.49) for men in the lowest decile. The positive association with lower MSP levels was observed consistently across racial and ethnic populations, by disease stage and Gleason score, for men with both high and low levels of PSA and across all genotype classes of rs10993994. However, we did not detect strong evidence of MSP levels in improving prostate cancer prediction beyond that of PSA.ConclusionsRegardless of race and ethnicity or rs10993994 genotype, men with low blood levels of MSP have increased risk of prostate cancer.
|
|
| 7. |
- Kato, Norihiro, et al.
(författare)
-
Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation
- 2015
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 47:11, s. 1282-1293
-
Tidskriftsartikel (refereegranskat)abstract
- We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
|
|
| 8. |
- McKay, James D., et al.
(författare)
-
Vitamin D Receptor Polymorphisms and Breast Cancer Risk: Results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium
- 2009
-
Ingår i: Cancer Epidemiology Biomarkers & Prevention. - 1538-7755. ; 18:1, s. 297-305
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Vitamin D is hypothesized to lower the risk of breast cancer by inhibiting cell proliferation via the nuclear vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNP) in the VDR gene (VDR), rs154441.0 (BsmI), and rs2228570 (FokI), have been inconsistently associated with breast cancer risk. Increased risk has been reported for the FokIff genotype, which encodes a less transcriptionally active isoform of VDR, and reduced risk has been reported for the BsmI BB genotype, a SNP in strong linkage disequilibrium with a 3'-untranslated region, which may influence VDR mRNA stability. Methods: We pooled data from 6 prospective studies in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium to examine associations between these SNPs and breast cancer among >6,300 cases and 8,100 controls for each SNP using conditional logistic regression. Results: The odds ratio (OR) for the rs2228570 (FokI) ff versus FF genotype in the overall population was statistically significantly elevated [OR, 1-1.6; 95% confidence interval (95% CI), 1.04-1.28] but was weaker once data from the cohort with previously published positive findings were removed (OR, 1.1.0; 95% CI, 0.981.24). No association was noted between rs1544410 (Bsm I) BB and breast cancer risk overall (OR, 0.98; 95% CI, 0.89-1.09), but the BB genotype was associated with a significantly lower risk of advanced breast cancer (OR, 0.74; 95% CI, 0.60-0.92). Conclusions: Although the evidence for independent contributions of these variants to breast cancer susceptibility remains equivocal, future large studies should integrate genetic variation in VDR with biomarkers of vitamin D status. (Cancer Epidemiol Biomarkers Prev 2009;18(1):297-305)
|
|
| 9. |
- Schumacher, Fredrick R., et al.
(författare)
-
A comprehensive analysis of common IGF1, IGFBP1 and IGFBP3 genetic variation with prospective IGF-I and IGFBP-3 blood levels and prostate cancer risk among
- 2010
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:15, s. 3089-3101
-
Tidskriftsartikel (refereegranskat)abstract
- The insulin-like growth factor (IGF) pathway has been implicated in prostate development and carcinogenesis. We conducted a comprehensive analysis, utilizing a resequencing and tagging single-nucleotide polymorphism (SNP) approach, between common genetic variation in the IGF1, IGF binding protein (BP) 1, and IGFBP3 genes with IGF-I and IGFBP-3 blood levels, and prostate cancer (PCa) risk, among Caucasians in the NCI Breast and Prostate Cancer Cohort Consortium. We genotyped 14 IGF1 SNPs and 16 IGFBP1/IGFBP3 SNPs to capture common [minor allele frequency (MAF) >= 5%] variation among Caucasians. For each SNP, we assessed the geometric mean difference in IGF blood levels (N = 5684) across genotypes and the association with PCa risk (6012 PCa cases/6641 controls). We present two-sided statistical tests and correct for multiple comparisons. A non-synonymous IGFBP3 SNP in exon 1, rs2854746 (Gly32Ala), was associated with IGFBP-3 blood levels (P-adj = 8.8 x 10(-43)) after adjusting for the previously established IGFBP3 promoter polymorphism A-202C (rs2854744); IGFBP-3 blood levels were 6.3% higher for each minor allele. For IGF1 SNP rs4764695, the risk estimates among heterozygotes was 1.01 (99% CI: 0.90-1.14) and 1.20 (99% CI: 1.06-1.37) for variant homozygotes with overall PCa risk. The corrected allelic P-value was 8.7 x 10(-3). IGF-I levels were significantly associated with PCa risk (P-trend = 0.02) with a 21% increase of PCa risk when compared with the highest quartile to the lowest quartile. We have identified SNPs significantly associated with IGFBP-3 blood levels, but none of these alter PCa risk; however, a novel IGF1 SNP, not associated with IGF-I blood levels, shows preliminary evidence for association with PCa risk among Caucasians.
|
|
| 10. |
- Setiawan, Veronica Wendy, et al.
(författare)
-
CYP17 genetic variation and risk of breast and prostate cancer from the national Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3)
- 2007
-
Ingår i: Cancer Epidemiology Biomarkers & Prevention. - 1538-7755. ; 16:11, s. 2237-2246
-
Tidskriftsartikel (refereegranskat)abstract
- CYP17 encodes cytochrome p450c17 alpha, which mediates activities essential for the production of sex steroids. Common germ line variation in the CYP17 gene has been related to inconsistent results in breast and prostate cancer, with most studies focusing on the nonsynonymous single nucleotide polymorphism (SNP) T27C (rs743572). We comprehensively characterized variation in CYP17 by direct sequencing of exons followed by dense genotyping across the 58 kb region around CYP17 in five racial/ethnic populations. Two blocks of strong linkage disequilibrium were identified and nine haplotype-tagging SNPs, including T27C, were chosen to predict common haplotypes (R-h(2) >= 0.85). These haplotype-tagging SNPs were genotyped in 8,138 prostate cancer cases and 9,033 controls, and 5,333 breast cancer cases and 7,069 controls from the Breast and Prostate Cancer Cohort Consortium. We observed borderline significant associations with prostate cancer for rs2486758 [TC versus TT, odds ratios (OR), 1.07; 95% confidence intervals (95% Cl), 1.00-1.14; CC versus TT, OR, 1.09; 95% CI, 0.95-1.26; P trend = 0.04] and rs6892 (AG versus AA, OR, 1.08; 95% CI, 1.00-1.15; GG versus AA, OR, 1.11; 95% CI, 0.95-1.30; P trend = 0.03). We also observed marginally significant associations with breast cancer for rs4919687 (GA versus GG, OR, 1.04; 95% CI, 0.97-1.12, AA versus GG, OR, 1.17; 95% CI, 1.03-1.34; P trend = 0.03) and rs4919682 (CT versus CC, OR, 1.04; 95% CI, 0.97-1.12; TT versus CC, OR, 1.16; 95% CI, 1.01-1.33; P trend = 0.04). Common variation at CYP17 was not associated with circulating sex steroid hormones in men or postmenopausal women. Our findings do not support the hypothesis that common germ line variation in CYP17 makes a substantial contribution to postmenopausal breast or prostate cancer susceptibility.
|
|
