@article {985, title = {USF1 gene variants, cardiovascular risk, and mortality in European Americans: analysis of two US cohort studies.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {27}, year = {2007}, month = {2007 Dec}, pages = {2736-42}, abstract = {

OBJECTIVE: A common haplotype of the upstream transcription factor 1 gene (USF1) has been associated with decreased susceptibility to familial combined hyperlipidemia (FCHL) and, paradoxically, with increased risk of cardiovascular disease (CVD) and all-cause mortality.

METHODS AND RESULTS: We assessed associations between USF1 tagSNPs, CVD risk factors, and aging-related phenotypes using data from 2 large population-based cohorts, Coronary Artery Risk Development in Young Adults (CARDIA) and the Cardiovascular Health Study (CHS), comprising younger and older adults, respectively. In CARDIA, each additional copy of the FCHL low-risk allele was associated with 2.4 mg/dL lower levels of LDL cholesterol (P=0.01) and decreased risk of subclinical atherosclerosis as assessed by coronary artery calcium (odds ratio 0.79; 95\%CI 0.63 to 0.98). Whereas there was little association between USF1 genotype and metabolic or CVD traits in older adults from CHS, the USF1 low-risk dyslipidemia allele was associated with higher plasma C-reactive protein and interleukin (IL)-6 levels and with increased risk of mortality, particularly attributable to noncardiovascular causes.

CONCLUSIONS: There appears to be a complex and possibly age-dependent relationship between USF1 genotype, atherosclerosis phenotypes, and CVD risk. USF1 may influence mortality through pathways distinct from atherosclerosis. Alternatively, linkage disequilibrium with neighboring polymorphisms in other genes such as F11R may be responsible for the observed USF1 genotype-phenotype associations in older adults.

}, keywords = {Adult, Age Factors, Aged, Aged, 80 and over, Aging, Blood Glucose, C-Reactive Protein, Calcium, Cardiovascular Diseases, Carotid Artery, Common, Cohort Studies, Coronary Artery Disease, Coronary Vessels, European Continental Ancestry Group, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Hyperlipidemia, Familial Combined, Insulin, Interleukin-6, Linkage Disequilibrium, Lipids, Male, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Risk Assessment, Risk Factors, Time Factors, United States, Upstream Stimulatory Factors}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.107.154559}, author = {Reiner, Alexander P and Carlson, Christopher S and Jenny, Nancy S and Durda, J Peter and Siscovick, David S and Nickerson, Deborah A and Tracy, Russell P} } @article {6289, title = {Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study.}, journal = {PLoS Biol}, volume = {11}, year = {2013}, month = {2013 Sep}, pages = {e1001661}, abstract = {

The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25\% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.

}, keywords = {African Americans, Asian Americans, Body Mass Index, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Hispanic Americans, Humans, Indians, North American, Lipids, Metagenomics, Oceanic Ancestry Group, Polymorphism, Single Nucleotide}, issn = {1545-7885}, doi = {10.1371/journal.pbio.1001661}, author = {Carlson, Christopher S and Matise, Tara C and North, Kari E and Haiman, Christopher A and Fesinmeyer, Megan D and Buyske, Steven and Schumacher, Fredrick R and Peters, Ulrike and Franceschini, Nora and Ritchie, Marylyn D and Duggan, David J and Spencer, Kylee L and Dumitrescu, Logan and Eaton, Charles B and Thomas, Fridtjof and Young, Alicia and Carty, Cara and Heiss, Gerardo and Le Marchand, Lo{\"\i}c and Crawford, Dana C and Hindorff, Lucia A and Kooperberg, Charles L} }