Cardiovascular disease (CVD) is a major cause of death and disability in the United States. An individual's risk for CVD contains a substantial genetic component. Along with being highly heritable, plasma lipid concentrations are also strong determinants of CVD risk. Recently, there have been several large, concerted efforts to investigate the genetics of plasma lipid levels and CVD in population based studies. However successful these studies have been, approximately 70% of the genetic variance in plasma lipid levels remains unexplained. A popular hypothesis states that rare genetic variants that were un-assayed in previous studies may account for a significant portion of this unexplained variation. Sex steroid hormones and their receptors are also critical determinants of plasma lipid levels and CVD risk. An important unresolved question is whether genetic variability influences the effect of estrogen and/or progesterone in modifying lipid levels and risk for CVD. We will use genetic data, health histories, lipid concentrations, and data from a randomized clinical trial on hormone-therapy (HT) from the Women's Health Initiative (WHI) to: (1) identify rare genetic variants associated with plasma lipid levels in European America (EA) and African American (AA) postmenopausal women;and (2) identify rare genetic variants that interact with HT to modify plasma lipid levels and risk for CVD in EA and AA postmenopausal women. Information generated from this study will be critical in determining the impact of genetic variants on women's health and to prioritize them for intervention studies aimed to maximize overall clinical benefit of HT and minimize their associated cardiovascular risk. Findings may also provide valuable insights into disease pathways and mechanisms, and identify novel targets for screening, prevention, and treatment of dyslipidemia and CVD in postmenopausal women.
An individual's risk for developing cardiovascular disease contains a substantial genetic component. We will use data from the Women's Health Initiative to study the effects of genetic variation and hormone-therapy on cholesterol levels and risk for cardiovascular disease. Findings from this study may help maximize the benefit of hormone-therapy, minimize the associated risk for cardiovascular disease, and identify possible biological targets for therapeutic intervention.
|Turcot, Valérie (see original citation for additional authors) (2018) Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet 50:26-41|
|Liu, Dajiang J (see original citation for additional authors) (2017) Exome-wide association study of plasma lipids in >300,000 individuals. Nat Genet 49:1758-1766|
|Auer, Paul L; Reiner, Alex P; Leal, Suzanne M (2016) The effect of phenotypic outliers and non-normality on rare-variant association testing. Eur J Hum Genet 24:1188-94|
|Iotchkova, Valentina; Huang, Jie; Morris, John A et al. (2016) Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps. Nat Genet 48:1303-1312|
|Tajuddin, Salman M; Schick, Ursula M; Eicher, John D et al. (2016) Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. Am J Hum Genet 99:22-39|
|Chami, Nathalie; Chen, Ming-Huei; Slater, Andrew J et al. (2016) Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits. Am J Hum Genet 99:8-21|
|Auer, Paul L; Lettre, Guillaume (2015) Rare variant association studies: considerations, challenges and opportunities. Genome Med 7:16|
|Peloso, Gina M; Auer, Paul L; Bis, Joshua C et al. (2014) Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. Am J Hum Genet 94:223-32|
|Auer, Paul L; Teumer, Alexander; Schick, Ursula et al. (2014) Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits. Nat Genet 46:629-34|