@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 {6138, title = {Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy.}, journal = {Circ Cardiovasc Genet}, volume = {6}, year = {2013}, month = {2013 Apr}, pages = {144-53}, abstract = {

BACKGROUND- Familial dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with >30 known genes. TTN truncating variants were recently implicated in a candidate gene study to cause 25\% of familial and 18\% of sporadic DCM cases. METHODS AND RESULTS- We used an unbiased genome-wide approach using both linkage analysis and variant filtering across the exome sequences of 48 individuals affected with DCM from 17 families to identify genetic cause. Linkage analysis ranked the TTN region as falling under the second highest genome-wide multipoint linkage peak, multipoint logarithm of odds, 1.59. We identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Nucleotide diversity at the TTN locus, including missense variants, was comparable with 5 other known DCM genes. The average number of missense variants in the exome sequences from the DCM cases or the ≈5400 cases from the Exome Sequencing Project was ≈23 per individual. The average number of TTN truncating variants in the Exome Sequencing Project was 0.014 per individual. We also identified a region (chr9q21.11-q22.31) with no known DCM genes with a maximum heterogeneity logarithm of odds score of 1.74. CONCLUSIONS- These data suggest that TTN truncating variants contribute to DCM cause. However, the lack of segregation of all identified TTN truncating variants illustrates the challenge of determining variant pathogenicity even with full exome sequencing.

}, keywords = {Adolescent, Adult, Aged, Cardiomyopathy, Dilated, Chromosomes, Human, Pair 9, Connectin, Exome, Female, Genetic Heterogeneity, Genetic Linkage, Genetic Loci, Genome, Human, Humans, Male, Middle Aged, Muscle Proteins, Mutation, Missense, Odds Ratio, Pedigree, Protein Kinases, Sequence Analysis, DNA, Young Adult}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.111.000062}, author = {Norton, Nadine and Li, Duanxiang and Rampersaud, Evadnie and Morales, Ana and Martin, Eden R and Zuchner, Stephan and Guo, Shengru and Gonzalez, Michael and Hedges, Dale J and Robertson, Peggy D and Krumm, Niklas and Nickerson, Deborah A and Hershberger, Ray E} }