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Hypertension and Genetic Variation in Endothelial-Specific Genes

Artikel i vetenskaplig tidskrift
Författare Erik Larsson
Björn Wahlstrand
B. Hedblad
Thomas Hedner
S. E. Kjeldsen
O. Melander
Per Lindahl
Publicerad i Plos One
Volym 8
Nummer/häfte 4
ISSN 1932-6203
Publiceringsår 2013
Publicerad vid Wallenberglaboratoriet
Institutionen för medicin
Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi
Institutionen för medicin, avdelningen för molekylär och klinisk medicin
Språk en
Länkar dx.doi.org/10.1371/journal.pone.006...
https://gup.ub.gu.se/file/118953
Ämnesord genome-wide association, blood-pressure, quantitative traits, risk, loci, polymorphism, cholesterol, populations, mortality, apoptosis
Ämneskategorier Medicinsk cellbiologi, Kardiologi

Sammanfattning

Genome-wide association (GWA) studies usually detect common genetic variants with low-to-medium effect sizes. Many contributing variants are not revealed, since they fail to reach significance after strong correction for multiple comparisons. The WTCCC study for hypertension, for example, failed to identify genome-wide significant associations. We hypothesized that genetic variation in genes expressed specifically in the endothelium may be important for hypertension development. Results from the WTCCC study were combined with previously published gene expression data from mice to specifically investigate SNPs located within endothelial-specific genes, bypassing the requirement for genome-wide significance. Six SNPs from the WTCCC study were selected for independent replication in 5205 hypertensive patients and 5320 population-based controls, and successively in a cohort of 16537 individuals. A common variant (rs10860812) in the DRAM (damage-regulated autophagy modulator) locus showed association with hypertension (P = 0.008) in the replication study. The minor allele (A) had a protective effect (OR = 0.93; 95% CI 0.88-0.98 per A-allele), which replicates the association in the WTCCC GWA study. However, a second follow-up, in the larger cohort, failed to reveal an association with blood pressure. We further tested the endothelial-specific genes for co-localization with a panel of newly discovered SNPs from large meta-GWAS on hypertension or blood pressure. There was no significant overlap between those genes and hypertension or blood pressure loci. The result does not support the hypothesis that genetic variation in genes expressed in endothelium plays an important role for hypertension development. Moreover, the discordant association of rs10860812 with blood pressure in the case control study versus the larger Malmo "Preventive Project-study highlights the importance of rigorous replication in multiple large independent studies.

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