Citations 2
Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women
Grant, Delores J. , Alberg, Anthony J. , Barnholtz‐Sloan, Jill S. , Bondy, Melissa L. , Funkhouser, Ellen, Moorman, Patricia G. , Peres, Lauren C. , Peters, Edward , Schwartz, Ann G. , Terry, Paul , Wang, Xin‐Qun, Hoyo, Cathrine , Sandler, Dale P. , Taylor, Jack A. , Edwards, Todd L., Beeghly‐Fadiel, Alicia, Wentzensen, Nicolas , Pearce, Celeste Leigh , Wu, Anna H. , Whittemore, Alice S. , McGuire, Valerie , Sieh, Weiva , Rothstein, Joseph H. , Ness, Roberta B., Moysich, Kirsten B. , Rossing, Mary Anne, Sellers, Thomas A. , Monteiro, Álvaro N.A. , Levine, Douglas A. , Haiman, Christopher A. , Menon, Usha , Ramus, Susan J. , Gayther, Simon A. , Terry, Kathryn L. , Goode, Ellen L. , Cannioto, Rikki , Odunsi, Kunle , Etter, John Lewis , Huang, Ruea‐Yea , Bernardini, Marcus Q. , Tone, Alicia , May, Taymaa, Goodman, Marc T. , Thompson, Pamela J., Carney, Michael E. , Tworoger, Shelley S. , Lambrechts, Diether , Vergote, Ignace , Nieuwenhuysen, Els Van , Salvensen, Helga B., Massuger, Leon F.A.G. , Bruegl, Amanda , Moffitt, Melissa , Le, Nhu D. , Brooks‐Wilson, Angela , Kelemen, Linda E. , Song, Honglin , Eccles, Diana , DeFazio, Anna , Kennedy, Catherine J. , Schildkraut, Joellen M. , Lambrechts, Diether , Barnholtz-Sloan, Jill S , Moysich, Kirsten , Permuth, Jennifer B , Cramer, Daniel W , Fazio, Anna de , Lambrechts, Diether , Ramus, Susan J , Sandler, Dale P , Tworoger, Shelley S , Eccles, Diana , Menon, Usha , Monteiro, Alvaro N , Brooks-Wilson, Angela R , Kennedy, Catherine J , Lambrechts, Diether , Sieh, Weiva , Taylor, Jack A , Goodman, Marc T , Manichaikul, Ani , Bandera, Elisa V. , Coté, Michele L. , Keku, Temitope O , Berchuck, Andrew , O’Brien, Katie M. , Edwards, Digna R. Velez , Beeghly‐Fadiel, Alicia , Modugno, Francesmary , Doherty, Jennifer A. , Permuth, Jennifer B. , Setiawan, Veronica Wendy , Marchand, Loı̈c Le , Wilkens, Lynne R. , Karlan, Beth Y. , Gentry‐Maharaj, Aleksandra , Cramer, Daniel W. , Larson, Melissa C. , Kaufmann, Scott H. , Poole, Elizabeth M. , Vanderstichele, Adriaan , Anton‐Culver, Hoda , Ziogas, Argyrios , Brenton, James D. , Bjørge, Line , Kiemeney, Lambertus A. , Pejovic, Tanja B. , Cook, Linda S. , Pharoah, Paul D.P. , Campbell, Ian
Cancer Medicine | April 19, 2019 | Volume: 8 | Issue: 5 | Pages: 2503-2513
AbstractAn association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom‐designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high‐grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 1.2 × 10−6, BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6‐3.4, P = 1.6 × 10−5, BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 2.3 × 10−5, BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.
Lymphocyte activation gene 3 and coronary artery disease
Golden, D.A. , Kolmakova, Antonina, Sura, Sunitha R. , Vella, Anthony T. , Wang, Xin‐Qun, Chen, Yii-Der Ida , Rodríguez, Annabelle , Bielinski, Suzette J. , Manichaikul, Ani , Taylor, Kent D. , Rich, Stephen S.
JCI Insight | October 19, 2016 | Volume: 1 | Issue: 17 | Pages: No page available
BACKGROUND: The lipoprotein scavenger receptor BI ( SCARB1 ) rs10846744 noncoding variant is significantly associated with atherosclerotic disease independently of traditional cardiovascular risk factors. We identified a potentially novel connection between rs10846744, the immune checkpoint inhibitor lymphocyte activation gene 3 ( LAG3 ), and atherosclerosis. METHODS: In vitro approaches included flow cytometry, lipid raft isolation, phosphosignaling, cytokine measurements, and overexpressing and silencing LAG3 protein. Fasting plasma LAG3 protein was measured in hyperalphalipoproteinemic (HALP) and Multi-Ethnic Study of Atherosclerosis (MESA) participants. RESULTS: In comparison with rs10846744 reference (GG homozygous) cells, LAG3 protein levels by flow cytometry ( P < 0.001), in lipid rafts stimulated and unstimulated ( P = 0.03), and phosphosignaling downstream of B cell receptor engagement of CD79A ( P = 0.04), CD19 ( P = 0.04), and LYN ( P = 0.001) were lower in rs10846744 risk (CC homozygous) cells. Overexpressing LAG3 protein in risk cells and silencing LAG3 in reference cells confirmed its importance in phosphosignaling. Secretion of TNF-α was higher ( P = 0.04) and IL-10 was lower ( P = 0.04) in risk cells. Plasma LAG3 levels were lower in HALP carriers of the CC allele ( P < 0.0001) and by race ( P = 0.004). In MESA, race ( P = 0.0005), age ( P = 0.003), lipid medications ( P = 0.03), smoking history ( P < 0.0001), and rs10846744 genotype ( P = 0.002) were independent predictors of plasma LAG3. In multivariable regression models, plasma LAG3 was significantly associated with HDL-cholesterol (HDL-C) ( P = 0.007), plasma IL-10 ( P < 0.0001), and provided additional predictive value above the Framingham risk score ( P = 0.04). In MESA, when stratified by high HDL-C, plasma LAG3 was associated with coronary heart disease (CHD) (odds ratio 1.45, P = 0.004). CONCLUSION: Plasma LAG3 is a potentially novel independent predictor of HDL-C levels and CHD risk. FUNDING: This work was supported by an NIH RO1 grant (HL075646), the endowed Linda and David Roth Chair for Cardiovascular Research, and the Harold S. Geneen Charitable Trust Coronary Heart Disease Research award to Annabelle Rodriguez. MESA is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, and DK063491. Cardiometabochip genotyping data for the MESA samples was supported in part by grants and contracts R01HL98077, N02-HL-64278, HL071205, UL1TR000124, DK063491, RD831697, and P50 ES015915.