Cooper JA

References (5)

Title : PLA2G7 genotype, lipoprotein-associated phospholipase A2 activity, and coronary heart disease risk in 10 494 cases and 15 624 controls of European Ancestry - Casas_2010_Circulation_121_2284
Author(s) : Casas JP , Ninio E , Panayiotou A , Palmen J , Cooper JA , Ricketts SL , Sofat R , Nicolaides AN , Corsetti JP , Fowkes FG , Tzoulaki I , Kumari M , Brunner EJ , Kivimaki M , Marmot MG , Hoffmann MM , Winkler K , Marz W , Ye S , Stirnadel HA , Boekholdt SM , Khaw KT , Humphries SE , Sandhu MS , Hingorani AD , Talmud PJ
Ref : Circulation , 121 :2284 , 2010
Abstract : BACKGROUND: Higher lipoprotein-associated phospholipase A(2)(Lp-PLA2) activity is associated with increased risk of coronary heart disease (CHD), making Lp-PLA2 a potential therapeutic target. PLA2G7 variants associated with Lp-PLA2 activity could evaluate whether this relationship is causal. METHODS AND RESULTS: A meta-analysis including a total of 12 studies (5 prospective, 4 case-control, 1 case-only, and 2 cross-sectional studies; n=26 118) was undertaken to examine the association of the following: (1) Lp-PLA2 activity versus cardiovascular biomarkers and risk factors and CHD events (2 prospective studies; n=4884); (2) PLA2G7 single-nucleotide polymorphisms and Lp-PLA2 activity (3 prospective, 2 case-control, 2 cross-sectional studies; up to n=6094); and (3) PLA2G7 single-nucleotide polymorphisms and angiographic coronary artery disease (2 case-control, 1 case-only study; n=4971 cases) and CHD events (5 prospective, 2 case-control studies; n=5523). Lp-PLA2 activity correlated with several CHD risk markers. Hazard ratios for CHD events for the top versus bottom quartile of Lp-PLA2 activity were 1.61 (95% confidence interval, 1.31 to 1.99) and 1.17 (95% confidence interval, 0.91 to 1.51) after adjustment for baseline traits. Of 7 single-nucleotide polymorphisms, rs1051931 (A379V) showed the strongest association with Lp-PLA2 activity, with VV subjects having 7.2% higher activity than AAs. Genotype was not associated with risk markers, angiographic coronary disease (odds ratio, 1.03; 95% confidence interval, 0.80 to 1.32), or CHD events (odds ratio, 0.98; 95% confidence interval, 0.82 to 1.17). CONCLUSIONS: Unlike Lp-PLA2 activity, PLA2G7 variants associated with modest effects on Lp-PLA2 activity were not associated with cardiovascular risk markers, coronary atheroma, or CHD. Larger association studies, identification of single-nucleotide polymorphisms with larger effects, or randomized trials of specific Lp-PLA2 inhibitors are needed to confirm or refute a contributory role for Lp-PLA2 in CHD.
ESTHER : Casas_2010_Circulation_121_2284
PubMedSearch : Casas_2010_Circulation_121_2284
PubMedID: 20479152
Gene_locus related to this paper: human-PLA2G7

Title : Effects of six APOA5 variants, identified in patients with severe hypertriglyceridemia, on in vitro lipoprotein lipase activity and receptor binding - Dorfmeister_2008_Arterioscler.Thromb.Vasc.Biol_28_1866
Author(s) : Dorfmeister B , Zeng WW , Dichlberger A , Nilsson SK , Schaap FG , Hubacek JA , Merkel M , Cooper JA , Lookene A , Putt W , Whittall R , Lee PJ , Lins L , Delsaux N , Nierman M , Kuivenhoven JA , Kastelein JJ , Vrablik M , Olivecrona G , Schneider WJ , Heeren J , Humphries SE , Talmud PJ
Ref : Arterioscler Thromb Vasc Biol , 28 :1866 , 2008
Abstract : OBJECTIVE: The purpose of this study was to identify rare APOA5 variants in 130 severe hypertriglyceridemic patients by sequencing, and to test their functionality, since no patient recall was possible. METHODS AND RESULTS: We studied the impact in vitro on LPL activity and receptor binding of 3 novel heterozygous variants, apoAV-E255G, -G271C, and -H321L, together with the previously reported -G185C, -Q139X, -Q148X, and a novel construct -Delta139 to 147. Using VLDL as a TG-source, compared to wild type, apoAV-G255, -L321 and -C185 showed reduced LPL activation (-25% [P=0.005], -36% [P<0.0001], and -23% [P=0.02]), respectively). ApoAV-C271, -X139, -X148, and Delta139 to 147 had little affect on LPL activity, but apoAV-X139, -X148, and -C271 showed no binding to LDL-family receptors, LR8 or LRP1. Although the G271C proband carried no LPL and APOC2 mutations, the H321L carrier was heterozygous for LPL P207L. The E255G carrier was homozygous for LPL W86G, yet only experienced severe hypertriglyceridemia when pregnant. CONCLUSIONS: The in vitro determined function of these apoAV variants only partly explains the high TG levels seen in carriers. Their occurrence in the homozygous state, coinheritance of LPL variants or common APOA5 TG-raising variant in trans, appears to be essential for their phenotypic expression.
ESTHER : Dorfmeister_2008_Arterioscler.Thromb.Vasc.Biol_28_1866
PubMedSearch : Dorfmeister_2008_Arterioscler.Thromb.Vasc.Biol_28_1866
PubMedID: 18635818

Title : The lipoprotein lipase gene serine 447 stop variant influences hypertension-induced left ventricular hypertrophy and risk of coronary heart disease - Talmud_2007_Clin.Sci.(Lond)_112_617
Author(s) : Talmud PJ , Flavell DM , Alfakih K , Cooper JA , Balmforth AJ , Sivananthan M , Montgomery HE , Hall AS , Humphries SE
Ref : Clinical Science (Lond) , 112 :617 , 2007
Abstract : LVH [LV (left ventricular) hypertrophy] is an independent risk factor for CHD (coronary heart disease). During LVH, the preferred cardiac energy substrate switches from FAs (fatty acids) to glucose. LPL (lipoprotein lipase) is the key enzyme in triacylglycerol (triglyceride) hydrolysis and supplies FAs to the heart. To investigate whether substrate utilization influences cardiac growth and CHD risk, we examined the association between the functional LPL S447X (rs328) variant and hypertension-induced LV growth and CHD risk. LPL-X447 has been shown to be more hydrolytically efficient and would therefore release more free FAs than LPL-S477. In a cohort of 190 hypertensive subjects, LPL X447 was associated with a greater LV mass index [85.2 (1.7) in S/S compared with 91.1 (3.4) in S/X+X/X; P=0.01], but no such association was seen in normotensive controls (n=60). X447 allele frequency was higher in hypertensives with than those without LVH {0.14 [95% CI (confidence interval), 0.08-0.19] compared with 0.07 (95% CI, 0.05-0.10) respectively; odds ratio, 2.52 (95% CI, 1.17-5.40), P=0.02}. The association of LPL S447X with CHD risk was then examined in a prospective study of healthy middle-aged U.K. men (n=2716). In normotensive individuals, compared with S447 homozygotes, X447 carriers were protected from CHD risk [HR (hazard ratio), 0.48 (95% CI, 0.23-1.00); P=0.05], whereas, in the hypertensives, X447 carriers had increased risk [HR, 1.54 (95% CI, 1.13-2.09) for S/S (P=0.006) and 2.30 (95% CI, 1.53-3.45) for X447+ (P<0.0001)] and had a significant interaction with hypertension in CHD risk determination (P=0.007). In conclusion, hypertensive LPL X447 carriers have increased risk of LVH and CHD, suggesting that altered FA delivery constitutes a mechanism through which LVH and CHD are associated in hypertensive subjects.
ESTHER : Talmud_2007_Clin.Sci.(Lond)_112_617
PubMedSearch : Talmud_2007_Clin.Sci.(Lond)_112_617
PubMedID: 17291198

Title : Candidate gene genotypes, along with conventional risk factor assessment, improve estimation of coronary heart disease risk in healthy UK men - Humphries_2007_Clin.Chem_53_8
Author(s) : Humphries SE , Cooper JA , Talmud PJ , Miller GJ
Ref : Clinical Chemistry , 53 :8 , 2007
Abstract : BACKGROUND: One of the aims of cardiovascular genetics is to test the efficacy of the use of genetic information to predict cardiovascular risk. We therefore investigated whether inclusion of a set of common variants in candidate genes along with conventional risk factor (CRF) assessment enhanced coronary heart disease (CHD)-risk algorithms.
METHODS: We followed middle-aged men in the prospective Northwick Park Heart Study II (NPHSII) for 10.8 years and analyzed complete trait and genotype information available on 2057 men (183 CHD events).
RESULTS: Of the 12 genes previously associated with CHD risk, in stepwise multivariate risk analysis, uncoupling protein 2 (UCP2; P = 0.0001), apolipoprotein E (APOE; P = 0.0003), lipoprotein lipase (LPL; P = 0.007), and apolipoprotein AIV (APOA4; P = 0.04) remained in the model. Their combined area under the ROC curve (A(ROC)) was 0.62 (0.58-0.66) [12.6% detection rate for a 5% false positive rate (DR(5))]. The A(ROC) for the CRFs age, triglyceride, cholesterol, systolic blood pressure, and smoking was 0.66 (0.61-0.70) (DR(5) = 14.2%). Combining CRFs and genotypes significantly improved discrimination (P = 0.001). Inclusion of previously demonstrated interactions of smoking with LPL, interleukin-6 (IL6), and platelet/endothelial cell adhesion molecule (PECAM1) genotypes increased the A(ROC) to 0.72 (0.68-0.76) for a DR(5) of 19.1% (P = 0.01 vs CRF combined with genotypes).
CONCLUSIONS: For a modest panel of selected genotypes, CHD-risk estimates incorporating CRFs and genotype-risk factor interactions were more effective than risk estimates that used CRFs alone.
ESTHER : Humphries_2007_Clin.Chem_53_8
PubMedSearch : Humphries_2007_Clin.Chem_53_8
PubMedID: 17130180

Title : A common mutation in the lipoprotein lipase gene promoter, -93T\/G, is associated with lower plasma triglyceride levels and increased promoter activity in vitro - Hall_1997_Arterioscler.Thromb.Vasc.Biol_17_1969
Author(s) : Hall S , Chu G , Miller G , Cruickshank K , Cooper JA , Humphries SE , Talmud PJ
Ref : Arterioscler Thromb Vasc Biol , 17 :1969 , 1997
Abstract : Single-strand conformational polymorphism analysis of the lipoprotein lipase promoter identified a T-->G transition at position -93. The frequency in healthy white men was 3.4% (n = 1575). There was an 83% allelic association between -93T-->G and Asp9-->Asn (D9N); all N9 mutations occurred on a -93G allele, but not all -93G mutations occurred on an N9 allele. It was thus possible to assess the effect on plasma triglyceride (Tg) levels of the rare -93G mutation in the presence of the wild-type D9. Carriers of the -93G, with genotype TG/DD, had significantly lower Tg levels than TT/DD individuals (1.36 versus 1.78 mmol/L, P = .01); carriers of both mutations (TG/DN) had the highest Tg levels (1.93 mmol/L). When the group was stratified above and below the sample mean for body mass index (BMI), carriers of the -93G on a D9 allele (TG/DD) were "protected" against the Tg-raising effect of obesity, as assessed by BMI. In Afro-Caribbeans (n = 91), the carrier frequency of -93G was 18-fold higher (63%), with weaker (17%) allelic association between -93G and N9. In vitro, the -93G promoter had 24% higher activity than the -93T in a rat smooth muscle cell line and 18% higher activity in a human adrenal cell line. A protein identified by band-shift assays bound to the -93G but not to the -93T allele, which may explain the lower Tg levels in -93G carriers.
ESTHER : Hall_1997_Arterioscler.Thromb.Vasc.Biol_17_1969
PubMedSearch : Hall_1997_Arterioscler.Thromb.Vasc.Biol_17_1969
PubMedID: 9351361