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- Wild, Philipp S., et al.
(författare)
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A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease
- 2011
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Ingår i: Circulation: Cardiovascular Genetics. - : American Heart Association/Lippincott, Williams & Wilkins. - 1942-325X .- 1942-3268. ; 4:4, s. 203-403
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Tidskriftsartikel (refereegranskat)abstract
- Background-eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results-In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7 x 10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3 x 10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4 x 10(-3)). Conclusions-The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD. (Circ Cardiovasc Genet. 2011;4:403-412.)
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- Lucas, Gavin, et al.
(författare)
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Post-Genomic Update on a Classical Candidate Gene for Coronary Artery Disease: ESR1
- 2011
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Ingår i: Circulation: Cardiovascular Genetics. - 1942-325X. ; 4:6, s. 357-647
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Tidskriftsartikel (refereegranskat)abstract
- Background-After age, sex is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed sex difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene-encoding Estrogen Receptor alpha (ESR1) have shown conflicting results, although only a limited range of variation in the gene has been investigated. Methods and Results-We exploited information made available by advanced new methods and resources in complex disease genetics to revisit the question of ESR1's role in risk of CAD. We performed a meta-analysis of 14 genome-wide association studies (CARDIoGRAM discovery analysis, N = approximate to 87 000) to search for population-wide and sex-specific associations between CAD risk and common genetic variants throughout the coding, noncoding, and flanking regions of ESR1. In addition to samples from the MIGen (N = approximate to 6000), WTCCC (N = approximate to 7400), and Framingham (N = approximate to 3700) studies, we extended this search to a larger number of common and uncommon variants by imputation into a panel of haplotypes constructed using data from the 1000 Genomes Project. Despite the widespread expression of ER alpha in vascular tissues, we found no evidence for involvement of common or low-frequency genetic variation throughout the ESR1 gene in modifying risk of CAD, either in the general population or as a function of sex. Conclusions-We suggest that future research on the genetic basis of sex-related differences in CAD risk should initially prioritize other genes in the reproductive steroid hormone biosynthesis system. (Circ Cardiovasc Genet. 2011;4:647-654.)
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- Zöller, Bengt, et al.
(författare)
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Venous Thromboembolism Does Not Share Strong Familial Susceptibility with Ischemic Stroke: A Nationwide Family Study in Sweden.
- 2011
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Ingår i: Circulation: Cardiovascular Genetics. - 1942-325X. ; 4:5, s. 484-490
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: -Coagulation allelic variants associated with venous thromboembolism (VTE) have been suggested to be involved in the pathogenesis of ischemic stroke. This nationwide study aimed at determining whether VTE shares familial susceptibility with ischemic stroke. Method and Results-The Swedish Multigeneration Register of 0-75-year-old subjects was linked to the Swedish Hospital Discharge Register and the Cause of Death Register for the period 1987-2007. Odds ratios (OR), for VTE, and ischemic stroke were determined in two ways: odds of ischemic stroke in offspring whose parents had been diagnosed with VTE, and odds of VTE in offspring whose parents had been diagnosed with ischemic stroke. The analyses were repeated for siblings and spouses. Offspring of parents with VTE (n=25 929) were at increased risk for ischemic stroke (n=5595): OR 1.10 (95% CI 1.06-1.14). Siblings of probands with VTE (n=45 132) had no increased risk of ischemic stroke (n=1716): OR 1.05 (95% CI 1.00-1.11). Spouses of probands with VTE (n=24 106) were at increased risk for ischemic stroke (n=940): OR 1.18 (95% CI 1.10-1.27). The risks for VTE in relatives of probands with ischemic stroke were: OR 1.15, 95% CI 1.10-1.21 (offspring), OR 1.07, 95% CI 1.02-1.12 (siblings), and OR 1.21, 95% CI 1.11-1.32 (spouses). CONCLUSIONS: -Venous thromboembolism does not share strong familial susceptibility with ischemic stroke in the Swedish population. Moreover, familial non-genetic factors contribute to the observed weak familial associations. The present study suggests that it is unlikely that strong shared disease-causing mutations exist to a large extent in the Swedish population.
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