RESUMEN
BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.
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Población Negra , Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Femenino , Humanos , Población Negra/genética , Neoplasias de la Mama/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Polygenic risk scores (PRSs) have been demonstrated to identify women of European, Asian, and Latino ancestry at elevated risk of developing breast cancer (BC). We evaluated the performance of existing PRSs trained in European ancestry populations among women of African ancestry. METHODS: We assembled genotype data for women of African ancestry, including 9241 case subjects and 10 193 control subjects. We evaluated associations of 179- and 313-variant PRSs with overall and subtype-specific BC risk. PRS discriminatory accuracy was assessed using area under the receiver operating characteristic curve. We also evaluated a recalibrated PRS, replacing the index variant with variants in each region that better captured risk in women of African ancestry and estimated lifetime absolute risk of BC in African Americans by PRS category. RESULTS: For overall BC, the odds ratio per SD of the 313-variant PRS (PRS313) was 1.27 (95% confidence interval [CI] = 1.23 to 1.31), with an area under the receiver operating characteristic curve of 0.571 (95% CI = 0.562 to 0.579). Compared with women with average risk (40th-60th PRS percentile), women in the top decile of PRS313 had a 1.54-fold increased risk (95% CI = 1.38-fold to 1.72-fold). By age 85 years, the absolute risk of overall BC was 19.6% for African American women in the top 1% of PRS313 and 6.7% for those in the lowest 1%. The recalibrated PRS did not improve BC risk prediction. CONCLUSION: The PRSs stratify BC risk in women of African ancestry, with attenuated performance compared with that reported in European, Asian, and Latina populations. Future work is needed to improve BC risk stratification for women of African ancestry.
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Neoplasias de la Mama , Anciano de 80 o más Años , Pueblo Asiatico , Población Negra/genética , Neoplasias de la Mama/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Factores de RiesgoRESUMEN
African American women are disproportionately affected by type 2 diabetes. Genetic factors may explain part of the excess risk. More than 100 genetic variants have been associated with risk of type 2 diabetes, but most studies have been conducted in white populations. Two genome-wide association studies (GWAS) in African Americans have identified three novel genetic variants only. We conducted admixture mapping using 2918 ancestral informative markers in 2632 cases of type 2 diabetes, and 2596 controls nested in the ongoing Black Women's Health Study cohort, with the goal of identifying genomic loci with local African ancestry associated with type 2 diabetes. In addition, we performed replication analysis of 71 previously identified index SNPs, and fine-mapped those genetic loci to identify better or new genetic variants associated with type 2 diabetes in African Americans. We found that individual African ancestry was associated with higher risk of type 2 diabetes. In addition, we identified two genomic regions, 3q26 and 12q23, with excess of African ancestry associated with higher risk of type 2 diabetes. Lastly, we replicated 8 out of 71 index SNPs from previous GWAS, including, for the first time in African Americans, the X-linked rs5945326 SNP near the DUSP9 gene. In addition, our fine-mapping efforts suggest independent signals at five loci. Our detailed analysis identified two genomic regions associated with risk of type 2 diabetes, and showed that many genetic risk variants are shared across ancestries.
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Negro o Afroamericano/genética , Mapeo Cromosómico , Diabetes Mellitus Tipo 2/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 3/genética , Fosfatasas de Especificidad Dual/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Persona de Mediana Edad , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genéticaRESUMEN
Several genome-wide association studies (GWAS) have identified genetic variants associated with birth weight. To date, however, most GWAS of birth weight have focused primarily on European ancestry samples even though prevalence of low birth weight is higher among African-Americans. We conducted admixture mapping using 2918 ancestral informative markers in 2596 participants of the Black Women's Health Study, with the goal of identifying novel genomic regions where local African ancestry is associated with birth weight. In addition, we performed a replication analysis of 11 previously identified index single nucleotide polymorphisms (SNPs), and fine-mapped those genetic loci to identify better or new genetic variants associated with birth weight in African-Americans. We found that high African ancestry at 12q14 was associated with low birth weight, and we identified multiple independent birth weight-lowering variants in this genomic region. We replicated the association of a previous GWAS SNP in ADRB1 and our fine-mapping efforts suggested the presence of new birth weight-associated variants in ADRB1, HMGA2, and SLC2A4. Further studies are needed to determine whether birth weight-associated loci can in part explain race-associated birth weight disparities.
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Peso al Nacer/genética , Negro o Afroamericano/genética , Sitios Genéticos , Polimorfismo de Nucleótido Simple , Adulto , Femenino , Estudio de Asociación del Genoma Completo , Transportador de Glucosa de Tipo 4/genética , Proteína HMGA2/genética , Humanos , Persona de Mediana Edad , Receptores Adrenérgicos beta 1/genéticaRESUMEN
BACKGROUND: MicroRNAs (miRNAs) regulate gene expression and influence cancer. Primary transcripts of miRNAs (pri-miRNAs) are poorly annotated and little is known about the role of germline variation in miRNA genes and breast cancer (BC). We sought to identify germline miRNA variants associated with BC risk and tumor subtype among African-American (AA) women. METHODS: Under the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, genotyping and imputed data from four studies on BC in AA women were combined into a final dataset containing 224,188 miRNA gene single nucleotide polymorphisms (SNPs) for 8350 women: 3663 cases and 4687 controls. The primary miRNA sequence was identified for 566 miRNA genes expressed in Encyclopedia of DNA Elements (ENCODE) Tier 1 cell types and human pancreatic islets. Association analysis was conducted using logistic regression for BC status overall and by tumor subtype. RESULTS: A novel BC signal was localized to an 8.6-kb region of 17q25.3 by four SNPs (rs9913477, rs1428882938, rs28585511, and rs7502931) and remained statistically significant after multiple test correction (odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.26-1.65; p = 3.15 × 10-7; false discovery rate (FDR) = 0.03). These SNPs reside in a genomic location that includes both the predicted primary transcript of the noncoding miRNA gene MIR3065 and the first intron of the gene for brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2). Furthermore, miRNA-associated SNPs on chromosomes 1p32.3, 5q32, and 3p25.1 were the strongest signals for hormone receptor, luminal versus basal-like, and HER2 enrichment status, respectively. A second phase of genotyping (1397 BC cases, 2418 controls) that included two SNPs in the 8.6-kb region was used for validation and meta-analysis. While neither rs4969239 nor rs9913477 was validated, when meta-analyzed with the original dataset their association with BC remained directionally consistent (OR = 1.29, 95% CI = 1.16-1.44 (p = 4.18 × 10-6) and OR = 1.33, 95% CI = 1.17-1.51 (p = 1.6 × 10-5), respectively). CONCLUSION: Germline genetic variation indicates that MIR3065 may play an important role in BC development and heterogeneity among AA women. Further investigation to determine the potential functional effects of these SNPs is warranted. This study contributes to our understanding of BC risk in AA women and highlights the complexity in evaluating variation in gene-dense regions of the human genome.
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Neoplasias de la Mama/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , MicroARNs/genética , Negro o Afroamericano/genética , Anciano , Femenino , Regulación Neoplásica de la Expresión Génica , Genoma Humano/genética , Mutación de Línea Germinal , Humanos , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple/genética , Receptor ErbB-2/genéticaRESUMEN
Circulating levels of vitamin D are generally lower in African Americans than in US whites, and 1 prior analysis carried out in a small number of African Americans suggested that, within this population, vitamin D levels may be related to the degree of genetic admixture. We assessed the association between percentage of European ancestry and serum vitamin D level (assessed in 2013-2015) among 2,183 African-American women from the Black Women's Health Study whose DNA had been genotyped for ancestry-informative markers. ADMIXMAP software was used to estimate the percentage of European ancestry versus African ancestry in each individual. In linear regression analyses with adjustment for genotype batch, age, body mass index, supplemental vitamin D use, ultraviolet B radiation flux in the participant's state of residence, and season of blood draw, each 10% increase in European ancestry was associated with a 0.67-ng/mL increase in serum vitamin D concentration (95% confidence interval: 0.17, 1.17). The association was statistically significant only among women who were not taking vitamin D supplements (for each 10% increase in European ancestry, ß = 0.86, 95% confidence interval: 0.14, 1.57). Among African Americans, use of vitamin D supplements may help to reduce vitamin D deficiency associated with genetic ancestry.
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Negro o Afroamericano/genética , Predisposición Genética a la Enfermedad/etnología , Deficiencia de Vitamina D/genética , Vitamina D/sangre , Población Blanca/genética , Adulto , Anciano , Suplementos Dietéticos , Femenino , Humanos , Modelos Lineales , Persona de Mediana Edad , Estaciones del Año , Estados Unidos , Deficiencia de Vitamina D/etnología , Salud de la Mujer/etnología , Adulto JovenRESUMEN
Background: Constitutional immunity shaped by exposure to endemic infectious diseases and parasitic worms in Sub-Saharan Africa may play a role in the etiology of breast cancer among African American (AA) women.Methods: A total of 149,514 gene variants in 433 genes across 45 immune pathways were analyzed in the AMBER consortium among 3,663 breast cancer cases and 4,687 controls. Gene-based pathway analyses were conducted using the adaptive rank truncated product statistic for overall breast cancer risk, and risk by estrogen receptor (ER) status. Unconditional logistic regression analysis was used to estimate ORs and 95% confidence intervals (CIs) for single variants.Results: The top pathways were Interleukin binding (P = 0.01), Biocarta TNFR2 (P = 0.005), and positive regulation of cytokine production (P = 0.024) for overall, ER+, and ER- cancers, respectively. The most significant gene was IL2RB (P = 0.001) for overall cancer, with rs228952 being the top variant identified (OR = 0.85; 95% CI, 0.79-0.92). Only BCL3 contained a significant variant for ER+ breast cancer. Variants in IL2RB, TLR6, IL8, PRKDC, and MAP3K1 were associated with ER- disease. The only genes showing heterogeneity between ER- and ER+ cancers were TRAF1, MAP3K1, and MAPK3 (P ≤ 0.02). We also noted genes associated with autoimmune and atopic disorders.Conclusions: Findings from this study suggest that genetic variants in immune pathways are relevant to breast cancer susceptibility among AA women, both for ER+ and ER- breast cancers.Impact: Results from this study extend our understanding of how inherited genetic variation in immune pathways is relevant to breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 27(3); 321-30. ©2018 AACR.
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Enfermedades Autoinmunes/epidemiología , Negro o Afroamericano/genética , Neoplasias de la Mama/epidemiología , Predisposición Genética a la Enfermedad , Mapas de Interacción de Proteínas/genética , Adulto , Anciano , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Proteína Quinasa Activada por ADN/genética , Proteína Quinasa Activada por ADN/inmunología , Proteína Quinasa Activada por ADN/metabolismo , Femenino , Humanos , Subunidad beta del Receptor de Interleucina-2/genética , Subunidad beta del Receptor de Interleucina-2/inmunología , Subunidad beta del Receptor de Interleucina-2/metabolismo , Interleucina-8/genética , Interleucina-8/inmunología , Interleucina-8/metabolismo , Quinasa 1 de Quinasa de Quinasa MAP/genética , Quinasa 1 de Quinasa de Quinasa MAP/inmunología , Quinasa 1 de Quinasa de Quinasa MAP/metabolismo , Persona de Mediana Edad , Proteínas Nucleares/genética , Proteínas Nucleares/inmunología , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleótido Simple , Mapas de Interacción de Proteínas/inmunología , Receptores de Estrógenos/metabolismo , Factores de Riesgo , Receptor Toll-Like 6/genética , Receptor Toll-Like 6/inmunología , Receptor Toll-Like 6/metabolismoRESUMEN
Background: Vitamin D may have anticancer activities. The high prevalence of vitamin D deficiency in African Americans (AAs) may be a contributing factor to the cancer health disparities between AAs and European Americans (EAs).Objectives: We compared concentrations of 25(OH)D and vitamin D-binding protein (VDBP) in AA and EA women and investigated determinants of the vitamin D-biomarker concentrations in both populations.Design: We used data and biospecimens from 909 AA and 847 EA healthy control subjects from the Carolina Breast Cancer Study (CBCS) and the Women's Circle of Health Study (WCHS) in the African American Breast Cancer Epidemiology and Risk Consortium. We measured plasma 25(OH)D and VDBP concentrations in all participants and genotyped 67 vitamin D-related genes in AA women only.Results: AA women had lower 25(OH)D concentrations than did EA women (mean ± SD: 14.2 ± 8.1 compared with 21.1 ± 11.5 ng/mL, respectively; P < 0.0001) but similar concentrations of VDBP (mean ± SD: 344 ± 133 compared with 336 ± 124 µg/mL, respectively; P = 0.25). With VDBP and other factors controlled for, the observed racial difference in 25(OH)D concentrations did not diminish. Relations of demographic and lifestyle factors with 25(OH)D were similar between AA and EA women. Although none of the genetic variants that have been identified in previous genome-wide association studies of 25(OH)D concentrations in EAs were significant (P > 0.05) in AAs, AA women who carried the allele of a functional single nucleotide polymorphism rs4988235, which has been previously associated with lactase expression and lactose tolerance, had higher dietary vitamin D intake and higher measured 25(OH)D concentrations.Conclusions: AA women have lower concentrations of total 25(OH)D than EA women do, but both groups have similar VDBP concentrations, suggesting that there are lower concentrations of free 25(OH)D in AAs. Although demographic and lifestyle determinants of 25(OH)D concentrations are similar between the 2 groups, genetic determinants may be ethnicity specific. Larger studies in AAs will be needed to fully elucidate the underlying determinants of low vitamin D concentrations in AA populations.
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Negro o Afroamericano/genética , Dieta , Genotipo , Deficiencia de Vitamina D/sangre , Proteína de Unión a Vitamina D/sangre , Vitamina D/análogos & derivados , Población Blanca/genética , Adulto , Demografía , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Lactasa/sangre , Intolerancia a la Lactosa/genética , Estilo de Vida , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estados Unidos , Vitamina D/sangre , Deficiencia de Vitamina D/genéticaRESUMEN
Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry.Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT).Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant (P < 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality.Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry.Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016-26. ©2017 AACR.
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Biomarcadores de Tumor/genética , Negro o Afroamericano/genética , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Alelos , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Mapeo Cromosómico , Femenino , Sitios Genéticos , Humanos , Polimorfismo de Nucleótido Simple , Receptores de Estrógenos/metabolismo , Factores de RiesgoRESUMEN
SNP rs7903146 in the Wnt pathway's TCF7L2 gene is the variant most significantly associated with type 2 diabetes to date, with associations observed across diverse populations. We sought to determine whether variants in other Wnt pathway genes are also associated with this disease. We evaluated 69 genes involved in the Wnt pathway, including TCF7L2, for associations with type 2 diabetes in 2632 African American cases and 2596 controls from the Black Women's Health Study. Tag SNPs for each gene region were genotyped on a custom Affymetrix Axiom Array, and imputation was performed to 1000 Genomes Phase 3 data. Gene-based analyses were conducted using the adaptive rank truncated product (ARTP) statistic. The PSMD2 gene was significantly associated with type 2 diabetes after correction for multiple testing (corrected p = 0.016), based on the nine most significant single variants in the +/- 20 kb region surrounding the gene, which includes nearby genes EIF4G1, ECE2, and EIF2B5. Association data on four of the nine variants were available from an independent sample of 8284 African American cases and 15,543 controls; associations were in the same direction, but weak and not statistically significant. TCF7L2 was the only other gene associated with type 2 diabetes at nominal p <0.01 in our data. One of the three variants in the best gene-based model for TCF7L2, rs114770437, was not correlated with the GWAS index SNP rs7903146 and may represent an independent association signal seen only in African ancestry populations. Data on this SNP were not available in the replication sample.
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Negro o Afroamericano/genética , Mapeo Cromosómico , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleótido Simple , Proteína 2 Similar al Factor de Transcripción 7/genética , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Adulto JovenRESUMEN
Leveraging population-distinct linkage equilibrium (LD) patterns, trans-ethnic follow-up of variants discovered from genome-wide association studies (GWAS) has proved to be useful in facilitating the identification of bona fide causal variants. We previously developed the preferential LD approach, a novel method that successfully identified causal variants driving the GWAS signals within European-descent populations even when the causal variants were only weakly linked with the GWAS-discovered variants. To evaluate the performance of our approach in a trans-ethnic setting, we applied it to follow up breast cancer GWAS hits identified mostly from populations of European ancestry in African Americans (AA). We evaluated 74 breast cancer GWAS variants in 8,315 AA women from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. Only 27% of them were associated with breast cancer risk at significance level α=0.05, suggesting race-specificity of the identified breast cancer risk loci. We followed up on those replicated GWAS hits in the AMBER consortium utilizing the preferential LD approach, to search for causal variants or better breast cancer markers from the 1000 Genomes variant catalog. Our approach identified stronger breast cancer markers for 80% of the GWAS hits with at least nominal breast cancer association, and in 81% of these cases, the marker identified was among the top 10 of all 1000 Genomes variants in the corresponding locus. The results support trans-ethnic application of the preferential LD approach in search for candidate causal variants, and may have implications for future genetic research of breast cancer in AA women.
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Biomarcadores de Tumor/genética , Negro o Afroamericano/genética , Neoplasias de la Mama/etnología , Neoplasias de la Mama/genética , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Anciano , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Persona de Mediana Edad , Fenotipo , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Estados Unidos/epidemiologíaRESUMEN
The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. Dysfunction of the Hippo pathway components has been linked with breast cancer stem cell regulation, as well as breast tumor progression and metastasis. TAZ, a key component of the Hippo pathway, is highly expressed in triple negative breast cancer; however, the associations of genetic variations in this important pathway with breast cancer risk remain largely unexplored. Here, we analyzed 8309 germline variants in 15 genes from the Hippo pathway with a total of 3663 cases and 4687 controls from the African American Breast Cancer Epidemiology and Risk Consortium. Odds ratios (ORs) were estimated using logistic regression for overall breast cancer, by estrogen receptor (ER) status (1983 ER positive and 1098 ER negative), and for case-only analyses by ER status. The Hippo signaling pathway was significantly associated with ER-negative breast cancer (pathway level P = 0.02). Gene-based analyses revealed that CDH1 was responsible for the pathway association (P < 0.01), with rs4783673 in CDH1 statistically significant after gene-level adjustment for multiple comparisons (P = 9.2×10(-5), corrected P = 0.02). rs142697907 in PTPN14 was associated with ER-positive breast cancer and rs2456773 in CDK1 with ER-negativity in case-only analysis after gene-level correction for multiple comparisons (corrected P < 0.05). In conclusion, common genetic variations in the Hippo signaling pathway may contribute to both ER-negative and ER+ breast cancer risk in AA women.
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Proteína Quinasa CDC2/genética , Cadherinas/genética , Receptor alfa de Estrógeno/genética , Proteínas Tirosina Fosfatasas no Receptoras/genética , Neoplasias de la Mama Triple Negativas/genética , Antígenos CD , Femenino , Regulación Neoplásica de la Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Vía de Señalización Hippo , Humanos , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Factores de Riesgo , Transducción de Señal , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
BACKGROUND: Vitamin D deficiency, which has been linked to an increased risk of colorectal cancer, is particularly common among African Americans. Previous studies of vitamin D status and breast cancer risk, mostly conducted in white women, have had conflicting results. We examined the relationship between predicted vitamin D status and incidence of breast cancer in a cohort of 59,000 African American women. METHODS: Participants in the Black Women's Health Study have been followed by biennial mail questionnaires since 1995, with self-reported diagnoses of cancer confirmed by hospital and cancer registry records. Repeated five-fold cross-validation with linear regression was used to derive the best 25-hydroxyvitamin D (25(OH)D) prediction model based on measured 25(OH)D in plasma specimens obtained from 2856 participants in 2013-2015 and questionnaire-based variables from the same time frame. In the full cohort, including 1454 cases of incident invasive breast cancer, Cox proportional hazards models were used to compute the incidence rate ratio (IRR) for each quartile of predicted vitamin D score relative to the highest quartile. Predicted vitamin D score for each two-year exposure period was a cumulative average of predicted scores from all exposure periods up to that time. RESULTS: Twenty-two percent of women with measured 25(OH)D were categorized as "deficient" (<20 ng/mL) and another 25 % as "insufficient" (20-29 ng/mL). The prediction model explained 25 % of variation in measured 25(OH)D and the correlation coefficient for predicted versus observed 25(OH)D averaged across all cross-validation runs was 0.49 (SD 0.026). Breast cancer risk increased with decreasing quartile of predicted 25(OH)D, p for trend 0.015; the IRR for the lowest versus highest quartile was 1.23 (95 % confidence interval 1.04, 1.46). CONCLUSIONS: In prospective data, African American women in the lowest quartile of cumulative predicted 25(OH)D were estimated to have a 23 % increased risk of breast cancer relative to those with relatively high levels. Preventing vitamin D deficiency may be an effective means of reducing breast cancer incidence in African American women.
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Negro o Afroamericano , Neoplasias de la Mama/sangre , Neoplasias de la Mama/epidemiología , Vitamina D/análogos & derivados , Adulto , Anciano , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Vigilancia de la Población , Estudios Retrospectivos , Encuestas y Cuestionarios , Estados Unidos/epidemiología , Estados Unidos/etnología , Vitamina D/sangre , Adulto JovenRESUMEN
OBJECTIVE: To replicate results from a previous genome-wide association study of European ancestry women, in which a positive association was found between uterine leiomyomata (UL) and rs4247357, a single-nucleotide polymorphism located near the fatty acid synthase (FASN) gene. DESIGN: Prospective cohort study. SETTING: Not applicable. PATIENT(S): African-American women aged 23-50 years, who were premenopausal and had an intact uterus in 1997. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We genotyped rs4247357 among 2,301 incident UL cases and 3,005 controls from the Black Women's Health Study (1997-2011). Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression with control for age, geographic region of residence, and percent European ancestry using a panel of validated ancestry informative markers. RESULT(S): Overall, rs4247357 was not associated with UL risk. Relative to the CC genotype, ORs were 1.04 (95% CI 0.92-1.19) for the AC genotype and 1.09 (95% CI 0.93-1.29) for the AA genotype. A positive association was found, however, among those with higher European ancestry (≥40%). Relative to the CC genotype, ORs were 2.03 (95% CI 1.12-3.69) for the AC genotype and 2.44 (95% CI 1.20-4.96) for the AA genotype. Dietary fat intake also appeared to modify the FASN-UL association. CONCLUSION(S): Although there was little overall association between rs4247357 and UL risk, a positive association was observed among women with ≥40% European ancestry. Direct sequencing of this genomic region might be warranted to determine whether rs4247357, or some other variant, is causally related to UL.
Asunto(s)
Negro o Afroamericano/genética , Grasas de la Dieta/efectos adversos , Acido Graso Sintasa Tipo I/genética , Leiomioma/etnología , Polimorfismo de Nucleótido Simple , Neoplasias Uterinas/etnología , Salud de la Mujer/etnología , Adulto , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Conducta Alimentaria/etnología , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Heterocigoto , Homocigoto , Humanos , Incidencia , Leiomioma/diagnóstico , Leiomioma/genética , Modelos Logísticos , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Fenotipo , Estudios Prospectivos , Salud Reproductiva/etnología , Medición de Riesgo , Factores de Riesgo , Estados Unidos/epidemiología , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Adulto JovenRESUMEN
A large percentage of breast cancer heritability remains unaccounted for, and most of the known susceptibility loci have been established in European and Asian populations. Rare variants may contribute to the unexplained heritability of this disease, including in women of African ancestry (AA). We conducted an exome-wide analysis of rare variants in relation to risk of overall and subtype-specific breast cancer in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, which includes data from four large studies of AA women. Genotyping on the Illumina Human Exome Beadchip yielded data for 170 812 SNPs and 8287 subjects: 3629 cases (1093 estrogen receptor negative (ER-), 1968 ER+, 568 ER unknown) and 4658 controls, the largest exome chip study to date for AA breast cancer. Pooled gene-based association analyses were performed using the unified optimal sequence kernel association test (SKAT-O) for variants with minor allele frequency (MAF) ≤ 5%. In addition, each variant with MAF >0.5% was tested for association using logistic regression. There were no significant associations with overall breast cancer. However, a novel gene, FBXL22 (P = 8.2×10(-6)), and a gene previously identified in GWAS of European ancestry populations, PDE4D (P = 1.2×10(-6)), were significantly associated with ER- breast cancer after correction for multiple testing. Cases with the associated rare variants were also negative for progesterone and human epidermal growth factor receptors-thus, triple-negative cancer. Replication is required to confirm these gene-level associations, which are based on very small counts at extremely rare SNPs.
Asunto(s)
Negro o Afroamericano/genética , Neoplasias de la Mama/genética , Adulto , Anciano , Neoplasias de la Mama/química , Neoplasias de la Mama/etiología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Exoma , Proteínas F-Box/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Modelos Logísticos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptores de Estrógenos/análisis , RiesgoRESUMEN
We conducted gene-based analysis in 26 genes in the FGFR signaling pathway to identify genes carrying genetic variation affecting risk of breast cancer and the specific estrogen receptor (ER) subtypes. Tagging single-nucleotide polymorphisms (SNPs) for each gene were selected and genotyped on a customized Illumina Exome Array. Imputation was carried out using 1000 Genomes haplotypes. The analysis included 3237 SNPs in 3663 breast cancer cases (including 1983 ER-positive, and 1098 ER-negative) and 4687 controls from the African American Breast Cancer Epidemiology and Risk consortium, a collaborative project of four large studies of breast cancer in African American women (Carolina Breast Cancer Study, Black Women's Health Study, Women's Circle of Health Study, and Multiethnic Cohort). We used a multi-locus adaptive joint (AdaJoint) test to determine the association of each gene in the FGFR signaling pathway with overall breast cancer and ER subtypes. The FGF1 gene was significantly associated with risk of ER-negative breast cancer (P = 0.001). The FGFR2 gene was associated with risk of overall breast cancer (P = 0.002) and ER-positive breast cancer (P = 0.002). The FGF1 gene affects risk of ER-negative breast cancer in African American women. We confirmed the association of the FGFR2 gene with risk of overall and ER-positive breast cancer. These results highlight the importance of the FGFR signaling pathway in the pathogenesis of breast cancer, and suggest that different genes in the same pathway may be associated with different ER breast cancer subtypes.
Asunto(s)
Negro o Afroamericano/genética , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Transducción de Señal/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Factor 1 de Crecimiento de Fibroblastos/genética , Pruebas Genéticas/métodos , Genotipo , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Receptores de Estrógenos/genética , Factores de Riesgo , Adulto JovenRESUMEN
Studies of genetic variations in vitamin D-related pathways and breast cancer risk have been conducted mostly in populations of European ancestry, and only sparsely in African Americans (AA), who are known for a high prevalence of vitamin D deficiency. We analyzed 24,445 germline variants in 63 genes from vitamin D-related pathways in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium, including 3,663 breast cancer cases and 4,687 controls. Odds ratios (OR) were derived from logistic regression models for overall breast cancer, by estrogen receptor (ER) status (1,983 ER positive and 1,098 ER negative), and for case-only analyses of ER status. None of the three vitamin D-related pathways were associated with breast cancer risk overall or by ER status. Gene-level analyses identified associations with risk for several genes at a nominal p ≤ 0.05, particularly for ER- breast cancer, including rs4647707 in DDB2. In case-only analyses, vitamin D metabolism and signaling pathways were associated with ER- cancer (pathway-level p = 0.02), driven by a single gene CASR (gene-level p = 0.001). The top SNP in CASR was rs112594756 (p = 7 × 10(-5), gene-wide corrected p = 0.01), followed by a second signal from a nearby SNP rs6799828 (p = 1 × 10(-4), corrected p = 0.03). In summary, several variants in vitamin D pathways were associated with breast cancer risk in AA women. In addition, CASR may be related to tumor ER status, supporting a role of vitamin D or calcium in modifying breast cancer phenotypes.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad/genética , Vitamina D/metabolismo , Adolescente , Adulto , Negro o Afroamericano , Anciano , Femenino , Variación Genética , Genotipo , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Receptores Sensibles al Calcio/genética , Receptores de Estrógenos/biosíntesis , Factores de Riesgo , Adulto JovenRESUMEN
Genome wide association studies have identified ~100 loci associated with body mass index (BMI). Persons with low birth weight have an increased risk of metabolic disorders. We postulate that normal mechanisms of body weight regulation are disrupted in subjects with low birth weight. The present analyses included 2215 African American women from the Black Women's Health Study, and were based on genotype data on 20 BMI-associated loci and self-reported data on birth weight, weight at age 18 and adult weight. We used general linear models to assess the association of individual single-nucleotide polymorphisms (SNPs) with BMI at age 18 and later in adulthood within strata of birth weight (above and below the median, 3200 g). Three SNPs (rs1320330 near TMEM18, rs261967 near PCSK1 and rs17817964 in FTO), and a genetic score combining these three variants, showed significant interactions with birth weight in relation to BMI. Among women with birth weight <3200 g, there was an inverse association between genetic score and BMI; beta-coefficient=-0.045 (95% confidence intervals (CI) -0.104, 0.013) for BMI at age 18, and -0.055 (95% CI -0.112, 0.002) for adult BMI. Among women with birth weight ⩾3200 g, genetic score was positively associated with BMI: beta-coefficient=0.110 (95% CI 0.051, 0.169) for BMI at age 18 (P for interaction=0.0002), and 0.112 (95% CI 0.054, 0.170) for adult BMI (P for interaction<0.0001). Because TMEM18, PCSK1 and FTO are highly expressed in the central nervous system (CNS), our results suggest that low-birth weight may disrupt mechanisms of CNS body weight regulation.
Asunto(s)
Peso al Nacer , Índice de Masa Corporal , Sistema Nervioso Central/metabolismo , Variación Genética , Adulto , Anciano , Población Negra , Femenino , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
We sought to investigate genetic variation in hormone pathways in relation to risk of overall and subtype-specific breast cancer in women of African ancestry (AA). Genotyping and imputation yielded data on 143,934 SNPs in 308 hormone-related genes for 3663 breast cancer cases (1098 ER-, 1983 ER+, 582 ER unknown) and 4687 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. AMBER includes data from four large studies of AA women: the Carolina Breast Cancer Study, the Women's Circle of Health Study, the Black Women's Health Study, and the Multiethnic Cohort Study. Pathway- and gene-based analyses were conducted, and single-SNP tests were run for the top genes. There were no strong associations at the pathway level. The most significantly associated genes were GHRH, CALM2, CETP, and AKR1C1 for overall breast cancer (gene-based nominal p ≤ 0.01); NR0B1, IGF2R, CALM2, CYP1B1, and GRB2 for ER+ breast cancer (p ≤ 0.02); and PGR, MAPK3, MAP3K1, and LHCGR for ER- disease (p ≤ 0.02). Single-SNP tests for SNPs with pairwise linkage disequilibrium r (2) < 0.8 in the top genes identified 12 common SNPs (in CALM2, CETP, NR0B1, IGF2R, CYP1B1, PGR, MAPK3, and MAP3K1) associated with overall or subtype-specific breast cancer after gene-level correction for multiple testing. Rs11571215 in PGR (progesterone receptor) was the SNP most strongly associated with ER- disease. We identified eight genes in hormone pathways that contain common variants associated with breast cancer in AA women after gene-level correction for multiple testing.
Asunto(s)
Neoplasias de la Mama/genética , Hormonas Esteroides Gonadales/genética , Proteínas de Neoplasias/genética , Receptores de Progesterona/genética , Adulto , Negro o Afroamericano/genética , Anciano , Neoplasias de la Mama/patología , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Redes y Vías Metabólicas/genética , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptores de Estrógenos/genética , Factores de Riesgo , Población Blanca/genéticaRESUMEN
OBJECTIVE: To investigate uterine leiomyomata (UL) incidence in relation to polymorphisms in genes involved in vitamin D metabolism and skin pigmentation. Rates of UL are 2-3 times higher in African Americans than in European Americans. Recent studies suggest that vitamin D deficiency is associated with an increased risk of UL. DESIGN: Nested case-control study. SETTING: Not applicable. PATIENT(S): Two thousand two hundred thirty-two premenopausal women first diagnosed with UL confirmed by ultrasound or surgery during 1997-2011 (cases) and 2,432 premenopausal women never diagnosed with UL through 2011 (controls). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Self-reported UL. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between each polymorphism and UL, controlling for age, geographic region, and ancestry. RESULT(S): Three of 12 polymorphisms were associated with UL at the nominal significance level: rs4944957 and rs12800438 near DHCR7 and rs6058017 in ASIP. After correction for multiple hypothesis testing, two single nucleotide polymorphisms remained significantly associated with UL (rs12800438 and rs6058017). Compared with the AA genotype for rs12800438 (correlated with higher serum 25[OH]D levels), ORs were 1.09 (95% CI, 0.92, 1.29) and 1.23 (95% CI, 1.03, 1.47) for the GA and GG genotypes, respectively. Compared with the AA genotype for rs6058017 (correlated with lighter skin pigmentation), ORs were 1.01 (95% CI, 0.83, 1.22) and 1.18 (95% CI, 0.97, 1.44) for the GA and GG genotypes, respectively. CONCLUSION(S): Our data support the hypothesis that vitamin D deficiency is involved in UL etiology.