title: Sequencing of Lp-PLA2-encoding PLA2G7 gene in 2000 Europeans reveals several rare loss-of-function mutations.
abstract: Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA2) activity have been shown to be associated with increased risk of coronary heart disease and an inhibitor of this enzyme is under development for the treatment of that condition. A Val279Phe null allele in this gene, that may influence patient eligibility for treatment, is relatively common in East Asians but has not been observed in Europeans. We investigated the existence and functional effects of low frequency alleles in a Western European population by re-sequencing the exons of PLA2G7 in 2000 samples. In all, 19 non-synonymous single-nucleotide polymorphisms (nsSNPs) were found, 14 in fewer than four subjects (minor allele frequency <0.1%). Lp-PLA2 activity was significantly lower in rare nsSNP carriers compared with non-carriers (167.8±63.2 vs 204.6±41.8, P=0.01) and seven variants had enzyme activities consistent with a null allele. The cumulative frequency of these null alleles was 0.25%, so <1 in 10,000 Europeans would be expected to be homozygous, and thus not potentially benefit from treatment with an Lp-PLA2 inhibitor.
authors: Department of Genetics, GlaxoSmithKline, Upper Merion, PA, USA.
authors: K
authors: K
authors: Song
authors: M R
authors: MR
authors: Nelson
authors: J
authors: J
authors: Aponte
authors: E S
authors: ES
authors: Manas
authors: S-A
authors: SA
authors: Bacanu
authors: X
authors: X
authors: Yuan
authors: X
authors: X
authors: Kong
authors: L
authors: L
authors: Cardon
authors: V E
authors: VE
authors: Mooser
authors: J C
authors: JC
authors: Whittaker
authors: D M
authors: DM
authors: Waterworth
references: Nat Genet. 2006 Mar;38(3):375-81
references: 16493422
references: BMC Psychiatry. 2009 Mar 17;9:9
references: 19292899
references: Nat Genet. 2007 Apr;39(4):513-6
references: 17322881
references: J Biol Chem. 2008 Nov 14;283(46):31617-24
references: 18784071
references: Nucleic Acids Res. 2002 Sep 1;30(17):3894-900
references: 12202775
references: Nature. 2008 Nov 6;456(7218):98-101
references: 18758442
references: Annu Rev Genomics Hum Genet. 2006;7:61-80
references: 16824020
references: PLoS Genet. 2006 Dec;2(12):e190
references: 17194218
references: Circulation. 2008 Sep 9;118(11):1172-82
references: 18765397
references: Hum Genet. 2009 Feb;125(1):11-20
references: 19034521
references: PLoS Genet. 2009 May;5(5):e1000481
references: 19436704
references: Am J Hum Genet. 2006 Sep;79(3):514-23
references: 16909389
references: Circulation. 2010 Jun 1;121(21):2284-93
references: 20479152
references: Lancet. 2008 Feb 9;371(9611):483-91
references: 18262040
references: Hum Mol Genet. 2001 Mar 15;10(6):591-7
references: 11230178
references: Nat Genet. 2005 Feb;37(2):161-5
references: 15654334
references: J Clin Endocrinol Metab. 2006 Sep;91(9):3521-7
references: 16787988
references: Nucleic Acids Res. 2003 Jul 1;31(13):3812-4
references: 12824425
references: Nat Genet. 2008 May;40(5):592-599
references: 18391953
references: Hum Mol Genet. 2004 Jul 1;13(13):1341-51
references: 15115767
references: Nat Genet. 2008 Jun;40(6):768-75
references: 18454148
references: N Engl J Med. 2006 Mar 23;354(12):1264-72
references: 16554528
references: Nat Genet. 2006 Dec;38(12):1457-62
references: 17115056
references: BMC Cardiovasc Disord. 2008 Mar 17;8:6
references: 18366642
references: Lancet. 2010 May 1;375(9725):1536-44
references: 20435228