title: Hypertension and genetic variation in endothelial-specific genes.
abstract: 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 16,537 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 Malmö Preventive Project-study highlights the importance of rigorous replication in multiple large independent studies.
authors: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. erik.larsson@gu.se
authors: Erik
authors: E
authors: Larsson
authors: Björn
authors: B
authors: Wahlstrand
authors: Bo
authors: B
authors: Hedblad
authors: Thomas
authors: T
authors: Hedner
authors: Sverre E
authors: SE
authors: Kjeldsen
authors: Olle
authors: O
authors: Melander
authors: Per
authors: P
authors: Lindahl
mesh_terms: D000818:Animals; D004727:Endothelium / Q000378:metabolism*; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008875:Middle Aged; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide
chemical_list: C512709:DRAM1 protein, human; D005819:Genetic Markers; D008565:Membrane Proteins
references: PLoS One. 2010 Aug 04;5(8):e11961
references: 20694148
references: Hum Genet. 2001 Oct;109(4):408-15
references: 11702222
references: Nat Genet. 2007 Oct;39(10):1181-6
references: 17898773
references: PLoS Genet. 2010 Oct 28;6(10):e1001177
references: 21082022
references: BMC Med Genet. 2009 May 19;10:43
references: 19454037
references: Hypertension. 2001 Sep;38(3 Pt 2):581-7
references: 11566935
references: Nucleic Acids Res. 2003 Aug 15;31(16):e93
references: 12907745
references: Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):226-31
references: 19114657
references: Science. 2007 Jun 1;316(5829):1331-6
references: 17463246
references: Hypertension. 1999 Apr;33(4):927-32
references: 10205225
references: Hypertension. 1999 May;33(5):1169-74
references: 10334806
references: Nature. 2007 Jun 7;447(7145):661-78
references: 17554300
references: BMC Med Genet. 2007 Sep 19;8 Suppl 1:S3
references: 17903302
references: PLoS One. 2012;7(2):e31489
references: 22384028
references: Circ J. 2012;76(4):907-13
references: 22322875
references: Nat Genet. 2011 Sep 11;43(10):1005-11
references: 21909110
references: Nucleic Acids Res. 2002 Jan 1;30(1):38-41
references: 11752248
references: Nat Genet. 2009 Jun;41(6):677-87
references: 19430479
references: Circulation. 2001 Apr 3;103(13):1721-6
references: 11282901
references: PLoS Genet. 2009 Feb;5(2):e1000365
references: 19197348
references: PLoS Genet. 2009 Jul;5(7):e1000564
references: 19609347
references: J Intern Med. 1996 Jun;239(6):489-97
references: 8656142
references: Hypertension. 2001 Dec 1;38(6):1321-4
references: 11751711
references: Nat Genet. 2009 May;41(5):527-34
references: 19396169
references: Genome Res. 2002 Jun;12(6):996-1006
references: 12045153
references: Hum Mol Genet. 2009 Jun 15;18(12):2288-96
references: 19304780
references: Nat Genet. 2011 Jun;43(6):531-8
references: 21572416
references: Nat Rev Genet. 2008 May;9(5):356-69
references: 18398418
references: Arterioscler Thromb Vasc Biol. 2008 Aug;28(8):1469-76
references: 18483404
references: Lancet. 2000 Jul 29;356(9227):359-65
references: 10972367
references: BMC Med Genet. 2007 Sep 19;8 Suppl 1:S4
references: 17903303
references: Endocr Rev. 2006 Feb;27(1):47-72
references: 16291870
references: Nat Genet. 2009 Jun;41(6):666-76
references: 19430483
references: Stat Med. 2005 Oct 15;24(19):2911-35
references: 16152135
references: Cell. 2006 Jul 14;126(1):121-34
references: 16839881
references: N Engl J Med. 2008 Mar 20;358(12):1240-9
references: 18354102
references: Nature. 2011 Sep 11;478(7367):103-9
references: 21909115