**6. Lp-PLA2 and genetic influences**

strongly and independently associated with 1-year mortality. Stankovic et al. [32] demon‐ strated that the Lp-PLA2 may have short-term predictive value in pure STEMI patients treated by primary percutaneous coronary intervention (PCI). They concluded that pre-interventional plasma Lp-PLA2 level is an independent predictor of 30-day MACE in patients with first anterior STEMI treated by primary PCI, and suggested that Lp-PLA2 level could help in very

Previously published studies examined and suggested the association between Lp-PLA2 and heart failure (HF) incidence in a population-based cohort of healthy individuals, and in people older than 65 years [60]. Baseline Lp-PLA2 levels are associated with a high risk of developing heart failure in 3,991 adults older than 65 years, independent of coronary risk factors [61]. Lp-PLA2 activity is significantly associated with congestive heart failure in 5,531 persons older than 65 years [62]. Gerber et al. [63] evaluated the association of Lp-PLA2 with mortality in subjects with diagnosed HF. Lp-PLA2 was strongly and independently associated with mortality in patients under 80 years of age. Moldoveanu et al.'s study [64] in 208 patients with HF found significantly increased Lp-PLA2 activity in HF patients with preserved ejection fraction (EF) than in HF with reduced EF. The literature data about the association of Lp-PLA2 and heart failure on admission in patients with acute myocardial infarction are missing. Stankovic et al. [32] suggested that patients with the first anterior STEMI who had higher levels of Lp-PLA2 had a worse prognosis, but not with a greater probability of developing HF. In Raichlin et al.'s [65] study in heart transplant patients, Lp-PLA2 correlated with the progression of cardiac allograft vasculopathy and increased risk of cardiovascular events/death suggesting

In 2005, the US Food and Drug Administration (FDA) approved Lp-PLA2 blood test for assessing patients at risk for ischemic stroke. The Rotterdam Study was the first populationbased study that determined the impact of elevated Lp-PLA2 on stroke. It identified that Lp-PLA2 activity was an independent predictor of ischemic stroke in the middle-aged healthy men and women population [31]**.** In the ARIC study, healthy middle-aged adults with increased levels of both Lp-PLA2 and hs-CRP had an 11-fold higher incidence of stroke than individuals with low Lp-PLA2 and hs-CRP levels [45]. This association between Lp-PLA2 mass/activity and first ischemic stroke was confirmed in the Malmo Diet and Cancer Study [66], Bruneck Study [67], and Cardiovascular Health Study [28]. The Tsekepis et al. study [68] showed that Lp-PLA2 correlated with the intima-media thickness in patients with beta-thalassemia, suggesting

Although some reports inconclusively found this positive association of Lp-PLA2 and firstever and recurrent stroke, little is known about its influence on stroke outcome. Elkind et al. [69] measured Lp-PLA2 mass and activity in relation to outcome in first ischemic stroke patients, determined as recurrent stroke, recurrence of vascular events, and mortality. Lp-PLA2 was a good predictor of recurrent stroke risk. Delgado et al. [70] investigated the temporal profile of Lp-PLA2 mass and activity within the first 24 hours after stroke and found significant changes in Lp-PLA2 concentrations early after stroke onset. Patients with higher Lp-PLA2 mass were more likely to be resistant to intravenous t-PA administration with very low early

early risk stratification of STEMI patients treated by PCI.

118 Lipoproteins - From Bench to Bedside

that it could be therapeutic target in heart transplant patients.

that Lp-PLA2 may be implicated in premature carotid atherosclerosis.

recanalization rates.

Several Lp-PLA2 gene polymorphisms and their role in affecting the regulation or production of LpPLA2 assessed as activity and mass were described; many in small studies and some in recently published genome-wide association studies. It is known that genetic factors account for 62% of the variation in Lp-PLA2 activity [76,77].

Although familial factors explain about one-half and one-quarter of the variance in Lp-PLA2 activity and mass, respectively [78,79], few genetic determinants of Lp-PLA2 have been identified. The first genome-wide association study using data from 6,668 Caucasian subjects in population-based Framingham Heart Study identified one locus associated with Lp-PLA2 mass, and four loci associated with Lp-PLA2 activity [80]. Twelve SNPs in the region of chromosome 6p12.3 near the gene for PLA2G7 were associated with Lp-PLA2 mass at a genome-wide level of significance. The top hit SNP rs1805017, is a nonsynonymous change (H92R) within the PLA2G7 gene. It was found that T allele that corresponds to the amino acid histidine was associated with higher Lp-PLA2 mass. On the other side, four loci achieving genome-wide significance for association with Lp-PLA2 activity was identified: a) first within the APOE/APOC1 gene cluster on chromosome 19q13.32 (rs41377151); b) second locus on chromosome 1p13.3, which includes the genes PSRC1 (rs599839), CELSR2 (rs4970834); c) third locus within an intron of SCARB1 on chromosome 12q24.31 (rs10846744); d) fourth locus in ZNF259 gene and BUD13 gene on chromosome 11q23.3 near the apolipoprotein gene cluster APOA5/APOA4/APOC3/APOA1 (rs12286037, rs11820589). Investigation from Suchindran's study was extended by Grallert et al. who made meta-analysis with additional four cohorts [81]. They performed genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium in five population-based studies with the aim to identify genetic loci related to Lp-PLA2 mass/activity [82]. This study, in the popoulation of 13,664 subjects, revealed the association of PLA2G7 loci variants with Lp-PLA2 mass/activity, and genetic variants (APOC1, CELSR2, LDL, ZNF259, SCARB1) related to low-density lipoprotein cholesterol levels with Lp-PLA2 activity.

Also, Lp-PLA2 mass was associated with SNP rs247616 on chromosome 16 within the choles‐ teryl ester transfer protein gene. The T allele of rs247616 was associated with higher HDL-C concentration and higher mean Lp-PLA2 mass [83]. The additional value of this study was the revealed significant association of four polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7 with coronary heart disease. Large-scale analysis focusing on variants in PLA2G7 did not identify any SNP that achieved experiment-wide statistical significance [79].

The most frequently studied SNPs within PLA2G7 are: variants in exon 9 (Val279Phe; rs45619133), exon 11 (Val379Ala; rs1051931), exon 7 (Ile198Thr, Iso195Thr; rs1805018), and exon 4 (Arg92His; rs1805017) [84-86].

The V279F SNP was found in subjects of Asian ancestry. The Val279Phe substitution is located within the catalytical domain of Lp-PLA2 and leads to reduction of enzyme activity in V/F heterozygous individuals or complete loss of enzymatic activity in homozygous F/F individ‐ uals. The 279F null allele is relatively frequent in Japan, with approximately 25% and 2% of the population carrying one or two copies. Its prevalence declines toward the West, has intermediate frequencies in China and Korea, is rare in the Middle East, and almost completely absent in European populations. The results from the association studies on this V279F variant and coronary artery disease have thus far been inconclusive. Li et al. [87] in Chinese Han population, found significant association of V279F and coronary artery disease, indicating that carrier of F allele increases the risk of coronary artery disease. This result was consistent with the Yamada et al. [88] study (850 cases/1,684 controls), which found that subjects carrying the mutant allele are at higher risk of arterial events (MI or stroke), and the Shimokata study (3,085 subjects with coronary artery disease/2,163 controls) [89]. The Jang et al. [90] study in two different patient sets (2,890 men diagnosed with CAD before age 60/3,128 male controls and 877 CAD cases/1,230 controls) confirmed that deficiency in Lp-PLA2 activity due to carriage of PLA2G7 279F allele protects from CAD in Korean men. Nevertheless, in the South Korean population (532 cases/670 controls) and Chinese study (827 cases/947 controls), V279F variant results in an unexpectedly opposite outcome [91,92]. Meta-analysis of 14 association studies focusing on R92H polymorphism in PLA2G7 gene and risk of CHD in 8,280 cases/5,656 controls indicate 92H allele had probably increased the risk of CHD [92]. The missense polymorphisms I198T and A379V are identified mainly in Caucasians. A379V variant in which alanine is substituted by valine is functional. Some studies explored the contribution of A379V to Lp-PLA2 activity with contradictory results; some found the association of A379V variant with increased [86,93] and some with decreased Lp-PLA2 activity [94].

There are also different reports about the association between the A379V variant and cardio‐ vascular disease [94-97]. A recent Taiwanese population study reported that subjects carrying the 379 V allele had increased severity of coronary atherosclerosis [94]; two studies in Cauca‐ sian subjects reported that the 379 V allele was associated with decreased atherosclerosis risk [93,96]; a large meta-analysis showed that the 379 V allele was associated with Lp-PLA2 activity, but not with cardiovascular risk markers [97]; and another study showed no associ‐ ation [95].

Intriguingly, in the study conducted by Liu and colleagues [94], the outcome was quite contradictory. They found that in the Chinese Taiwan Han population, A379V variant is significantly associated with Lp-PLA2 activity and the severity of coronary atherosclerosis. Recently, a meta-analysis including a total of 12 studies shows that in the populations from European ancestry, among the 7 SNPs, A379V variant shows the strongest association with Lp-PLA2 activity; however, no significant correlation is found between PLA2G7 variants and cardiovascular risk markers, coronary atheroma, or CHD [97].
