[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: MD2 has been recognized as polyorganic AD disease with predominant muscle involvement and overall, a milder course than MD1. While peripheral nerve involvement (neuropathy) has been documented in MD1, it could be also the feature of MD2, regarding its pathophysiology and/or disturbed glucose or thyroid metabolism.
AIM: To determine the frequency and type of neuropathy in MD2 patients, particularly in relation to the presence of diabetes mellitus/glucose intolerance (DM) and thyroid disease (TD).
MATERIALS AND METHODS: Medical records including history, neurological and EMG examination and laboratory tests for endocrinopathy have been reviewed in 30 Croatian patients (25F + 5M, 22 families) with symptomatic heterozygote CCTG expansion in ZNF9. Physical examination included semiquantitative estimate of limb force, tendon reflexes and sensory testing. EMG reports of MUPs sampling, nerve conduction velocities (NCV), the latency and amplitude of motor and neural potentials from 2-6 peripheral nerves were matched with 30 paired controls.
MAIN RESULTS: Proximal muscle weakness and/or intermittent myotonic symptoms were present each in 26/30 patients. In 12/30 patients the vibration sense was altered or absent in feet, and in 17/30, the ankle reflexes were reduced or absent without distal sensory complaints. EMG results were supportive for axonal polyneuropathy in 19/30 patients and a carpal tunnel neuropathy in 10/30. Both conditions overlapped in 8/30 patients. Endocrinopathy was detected in 14/30 (7 DM, 7 TD). Out of 21 patients with either neuropathy, DM or TD signs were present each in 6 patients.
CONCLUSION: We found physical and/or electrophysiological signs of neuropathy in up to two thirds of MD2 patients. Only one half of all patients demonstrated the laboratory signs of endocrinopathy. We conclude that peripheral nerve involvement is a common inherent feature of MD2, irrespective of featured metabolic abnormalities.
International Myotonic Dystrophy Consortium Meeting (IDMC 10), Paris, France; 06/2015
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION
In heterogeneous group of hereditary motor and sensory CMT neuropathies, GJB1 mutations causing M.Charcot-Marie-Tooth X type 1 (CMTX1) are considered to be second most common, following PMP22 variants. The disease is most often characterized by severe distal muscles weakness and atrophy, sensory loss and foot deformity. Female carriers can be mildly affected or asymptomatic. The diagnosis is suspected on NCV profile, featuring an intermediate velocity range. We report the results of GJB1 clinical and molecular study in the first series of Croatian CMT patients.
The detection and phenotypic characterization of GJB1 mutations in Croatian CMT patients.
MATERIALS AND METHODS
Following clinical and EMG examination, 22 suspected samples from 18 families, negative for PMP dupl/del, were analyzed for the mutations in GJB1 coding region. Applied Biosystems 3130xl Genetic analyzer and BigDye® Terminator v3.1 Cycle Sequencing Kit were used. The prediction of new variants pathogenicity was made with PolyPhen-2 software.
GJB1 missense point mutations were found in 12 patients from 9 families (7 heterozygous, 5 hemizygous). In 3 unrelated families p.Val170Asp was found. In each of the remaining 6 families different mutations were found (p.Leu108Pro, p.Val13Met, p.Ser49Pro, p.Arg183His). Two mutations
were not described previously: p.Phe141Ser (c.422T>C) and p.Val177Met (c.529G>A). Very severe phenotype was characteristic of novel p.Phe141Ser in hemizygous and also heterozygous state. Cardinal phenotypic features are compared.
GJB1 mutations were found in one half of CMTX1 suspected patients/ families. In hemizygous and also heterozygous patients, phenotype is often severe, yet varies from mild/asymptomatic to devastating, with earliest distal sensory involvement.
European Human Genetics Conference 2015, Glasgow, Scotland, UK; 06/2015
[Show abstract][Hide abstract] ABSTRACT: Objective: Several studies showed that leptin may be associated with faster heart rate (HR) and it was questioned whether this could be associated with increased cardiovascular risk. Our goal was to examine the possible association of leptin and HR in subjects with low cardiovascular risk. Design and method: Participants (N = 208; 135 females; 137 normotensives, 34 prehypertensives and 37 untreated hypertensives) were selected from a random sample of 2487 subjects enrolled in an observational study. Subjects with diabetes, chronic kidney disease, pregnancy, terminal illness and treated hypertensives were excluded. BP was measured using Omron M6 device following ESH/ESC guidelines. Leptin concentration was determined by ELISA. Results: In the whole group leptin concentration was higher (12.10 (6.12-17.50) vs. 4.01 (1.70-8.17), p < 0.001) in women than in men. There were no significant differences in leptin concentrations between normotensives (NT), prehypertensives (PHT) and untreated hypertensives (uHT). However, uHT (11.20 (6.00-16.90)) had significantly higher leptin concentration than NT (8.60 (3.60-14.65);p < 0.05) and non-significantly higher than PHT (8.04 (3.60-12.60;p > 0.05)). There were no differences between NT and PHT (p > 0.05). HR was similar in all three BP groups (p = 0.82). Leptin was positively correlated with BMI, albuminuria, CRP and insulin concentrations (p < 0.05). HR was positively correlated with eGFR and insulin and negatively with HDL. There were no significant correlations of leptin and HR in any of three BP groups. In multivariate analysis leptin was not a significant predictor of HR (Beta = -0.01, p = 0.90), systolic (Beta = -0.06, p = 0.27) or diastolic BP (Beta = 0.03, p = 0.58). BMI and female sex were positively associated with leptin concentration in multivariate analysis (p < 0.05). Conclusions: In our group of subjects with low cardiovascular risk leptin was not associated with HR. Hypertensive patients had higher leptin concentrations than NT and non-significantly higher than PHT subjects, latter two having similar leptin concentrations. Copyright
Journal of Hypertension 06/2015; 33:e170. DOI:10.1097/01.hjh.0000467847.10365.66 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction: Severe congenital neutropenia (SCN) is an autosomal dominant disease characterized by chronic neutropenia which leads to severe recurrent bacterial or mycotic infections. Shwachman- Diamond syndrome (SDS) is an autosomal recessive disease that is characterized by exocrine pancreatic insufficiency, dysfunction of the bone marrow and predisposition to develop myelodysplastic syndrome or leukemia. Objective: The objective was to confirm clinical diagnosis in several Croatian families at genetic level by analyzing their DNA samples. Methods: 20 samples of genomic DNA were analyzed: 7 samples of patients with clinical diagnosis of SCN or SDS and 13 samples of their family members. Coding regions of ELANE and SBDS gene were amplified by PCR with specific primers. PCR fragments were bidirecty sequenced using Big Dye® Terminator v3.1 Cycle Sequencing Kit and Applied Biosystems 3130xl Genetic analyzer. Results: In all 4 patients with SCN, mutations were found in ELANE gene. These mutations were de novo, because in their parents' samples mutations were not found. In all 3 patients with SDS, mutations were found on both alleles, which were inherited from their parents. Two new variants were found, one in ELANE gene (c.213C>G ; p.Cys71Trp) and one in SBDS gene (c.41A>G ; p.Asn14Ser). Both variants were analyzed with PolyPhen-2 software and were predicted as probably damaging. Conclusion: Mutations in ELANE gene were reported in 38-80% of individuals with SCN, and in SBDS gene in more that 90% of individuals with SDS. In our case, clinical diagnoses of SCN or SDS were confirmed in all analyzed patients.
The 16th Biennial Meeting of the European Society for Immunodeficiencies, Prague, Czech Republic; 10/2014
[Show abstract][Hide abstract] ABSTRACT: Aim
To determine the association between the number of thymine-adenine (TA)n dinucleotide repeats in the promoter region of the gene coding for the estrogen receptor alpha (ESR1) and the prevalence of lone atrial fibrillation (AF) in men.
We conducted a case-control study involving 89 men with lone AF and 166 healthy male controls. The ESR1 genotype was established by polymerase chain reaction and capillary electrophoresis. To assess the association of ESR1 genotype with AF, logistic regression models were built with AF as outcome.
Men with lone AF had significantly greater number of (TA)n repeats of single alleles than controls (mean ± standard deviation, 19.2 ± 4.2 vs 18 ± 4.3, P = 0.010). After adjustment for other factors, a unit-increase in (TA)n repeat number was associated with a significantly greater likelihood of AF (odds ratio 1.069; 95% confidence interval 1.024-1.116, P = 0.002).
Our results indicate that a greater number of (TA)n repeats in the promoter region of ESR1 is associated with a significantly increased likelihood of lone atrial fibrillation in men.
Croatian Medical Journal 02/2014; 55(1):38-44. DOI:10.3325/cmj.2014.55.38 · 1.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim:
The aim of the study was to estimate the influence of interactions between peroxisome proliferator-activated receptor γ (PPARγ) and target genes lipoprotein lipase (LPL), interleukin 6 (IL6), angiotensin converting enzyme (ACE), and angiotensin II type 1 receptor (AT1R) on metabolic syndrome (MetSy) and its traits.
The study included 527 participants (263 with MetSy and 264 controls). Genotyping of PPARγ Pro12Ala, LPL PvuII (-/+), IL6 -174G>C, ACE I/D and AT1R 1166A>C was performed using polymerase chain reaction-restriction fragment length polymorphism-based methods.
Interaction between PPARγ Pro12Ala and LPL Pvu(-/+) improved prediction of MetSy over and above prediction based on a model containing no interactions (χ(2)=7.22; df=1; p=0.007). In the group of participants with PPARγ Pro12Ala or Ala12Ala genotypes, those with the LPL Pvu (-/+) or (+/+) genotype had greater odds for MetSy (odds ratio OR=5.98; 95% confidence interval CI: 1.46-24.47, p=0.013). Interaction between PPARγ Pro12Ala and IL6 -174G>C improved prediction of high fasting blood glucose (χ(2)=13.99; df=1; p<0.001). PPARγ Ala12 variant was found protective in patients with IL6 -174GG genotype (OR=0.10; 95% CI: 0.02-0.57, p=0.01), while in the case of IL6 -174C allele carriers, for PPARγ Ala12 carriers, larger odds for high glucose levels compared with Pro12 variant were observed (OR=2.39; 95% CI: 1.11-5.17, p=0.026). Interactions of PPARγ and ACE were significant for BMI. In the group with ACE DD genotype, those with PPARγ Pro12Ala or Ala12Ala genotype have greater odds for obesity (OR=9.98; 95% CI: 1.18-84.14, p=0.034).
PPARγ gene variants can, in interaction with some of its target genes, modulate physiological processes leading to the development of MetSy.
[Show abstract][Hide abstract] ABSTRACT: Peroxisome proliferator activated receptor-gamma (PPARG) and lipoprotein lipase (LPL) play important role in lipid homeostasis, insulin resistance and adipogenesis, and their gene variability could be considered as predictive genetic markers for metabolic syndrome (MetSy). The aim of the study was to estimate possible associations of PPARG (Pro12Ala) and LPL PvuII (+/-) polymorphisms with MetSy and its traits. Study included 527 subjects. According to the modified National Cholesterol Education Program Adult Treatment Panel III definitions, subjects were classified into the metabolic syndrome group and control group. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism methods. In the total sample, LPL variants were associated with waist circumference (chi2 = 7.263, d.f = 2, p = 0.026) and with BMI (chi2 = 6.549, d.f = 2, p = 0.038), where PvuII (+/+) genotype carriers had the highest risk for increased waist circumference (specific PvuII (+/+) vs. others analysis chi2 = 7.033, p = 0.008) and increased BMI (specific PvuII( +/+) vs. others analysis chi2 = 5.154, p = 0.023). LPL gene variants were also associated with HDL-C levels (chi2 = 6.901, d.f = 2, p = 0.032), where PvuII (-/-) genotype carriers had higher HDL-C values in comparison to others (specific Pvu (+/+) vs. others analysis chi2 = 6.504, p = 0.011). Furthermore, PvuII (-) allele carriers had significantly lower glucose (allele based analysis Add Value = -0.0878, chi2 = 5.878, d.f. = 1, p = 0.015). Significant interaction was detected between PPARG and LPL that affected HDL-C levels in male population (chi2 = 11.790, d.f = 1, p = 0.0006) in the manner that Ala/PvuII(+) contributed to the lowest HDL-C values (Specific Ala/ Pvu(+) vs. others analysis was chi2 = 11.750, p = 0.0006). According to obtained results LPL and PPARG gene variants could be susceptibility factors of obesity and lipid status, contributing to development of MetSy, particularly in males. Because of antiatherogenic function of HDL-C, the identification of genetic variants associated with HDL-C can provide useful information related to genotype-phenotype relationships. Since the interplay between PPARG and LPL gene and gender seems to be significant it could point to the personalized behavioural recommendations for prevention of metabolic and cardiovascular diseases.
Collegium antropologicum 09/2013; 37(3):801-8. · 0.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Romani, the largest European minority group with approximately 11 million people , constitute a mosaic of languages, religions, and lifestyles while sharing a distinct social heritage. Linguistic  and genetic [3-8] studies have located the Romani origins in the Indian subcontinent. However, a genome-wide perspective on Romani origins and population substructure, as well as a detailed reconstruction of their demographic history, has yet to be provided. Our analyses based on genome-wide data from 13 Romani groups collected across Europe suggest that the Romani diaspora constitutes a single initial founder population that originated in north/northwestern India ∼1.5 thousand years ago (kya). Our results further indicate that after a rapid migration with moderate gene flow from the Near or Middle East, the European spread of the Romani people was via the Balkans starting ∼0.9 kya. The strong population substructure and high levels of homozygosity we found in the European Romani are in line with genetic isolation as well as differential gene flow in time and space with non-Romani Europeans. Overall, our genome-wide study sheds new light on the origins and demographic history of European Romani.
Current biology: CB 12/2012; 22(24). DOI:10.1016/j.cub.2012.10.039 · 9.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Familial hypercholesterolemia (FH) is caused by mutations in the genes for LDLR, APOB or PCSK9, and identification of the causative mutation provides definitive diagnosis so that the patient can be treated, their relatives tested and, therefore, premature heart disease prevented.
DNA of eight unrelated individuals with clinically diagnosed FH were analyzed using a High-Resolution Melting method (HRM) for the LDLR gene (coding region, promoter and intron/exon boundaries), the APOB gene (part exon 26) and the PCSK9 gene (exon7). Variations found were sequenced and the effect on function of confirmed variants examined using predictive algorithms. Gross deletions and insertions were analysed using MLPA.
Three novel LDLR variants were found, p.(S470C), p.(C698R) and c.2312–2A>C. All were predicted to be pathogenic using predictive algorithms. Three previously reported disease-causing mutations were identified (p.(G20R), p.(N272T) and p.(S286R); the latter was also carried by a hypercholesterolaemic relative. One patient carried the pathogenic APOB variant p.(R3527Q). No large LDLR deletions nor insertions were found, neither were any PCSK9 variants identified.
HRM is a sensitive method for screening for mutations. While the causative mutation has been identified in 88% of these clinically defined FH patients, there appears to be a high degree of allelic heterogeneity in Croatian patients.
Annals of Human Genetics 11/2012; 77(1). DOI:10.1111/j.1469-1809.2012.00735.x · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to identify KRAS and BRAF gene mutations in colorectal cancer patients and to assess whether they are linked with clinicopathological features. The results of KRAS and BRAF mutation analysis could be used in the selection of patients for anti-EGFR therapy. All specimens were obtained during routine surgery of patients with colorectal carcinoma. The diagnoses were established by standard procedures and confirmed histopathologically. After DNA extraction, KRAS mutations were analyzed using quantitative real-time PCR and BRAF mutations were analyzed using real-time PCR by fluorescence melting curve analysis. Our results show that KRAS gene mutations were detected in 35.6% samples and the most frequent mutation was Gly12Val. BRAF gene mutation Val600Glu was detected in 8.5% samples. Statistical analysis revealed a significant association between the KRAS mutation and Dukes' stage (p=0.034), with the lowest frequency in Dukes'A, and between the KRAS mutation and histological grade (p=0.044), with no KRAS mutation found in poor differentiated tumors. The first data about KRAS and BRAF mutational status in the sample of Croatian population with colorectal cancer shows that the incidence of KRAS and BRAF mutations is within generally valid limits. Prospective studies are to be continued in order to determine whether these mutations contribute to progression of colorectal cancer.
[Show abstract][Hide abstract] ABSTRACT: Human obesity is accepted as an important risk factor for development of MetS. Adiponectin is linked to central obesity and ADIPOQ variants are promising markers for understanding the genetic base of obesity-related disorders. We performed analyses of adiponectin concentrations and ADIPOQ variants and tested their associations with obesity and MetS in young subjects of Croatian origin.
Biochemical and anthropometric parameters of MetS were obtained for 149 unrelated subjects. Adiponectin levels were measured by ELISA assay. ADIPOQ -11391G>A and -11377C>G were genotyped by real-time PCR.
BMI and WC, TG and GLUC showed inverse correlation, whereas HDL-C showed a positive correlation with adiponectin concentrations. For central obesity, we found association with -11377C>G and with -11391G>A polymorphisms. ADIPOQ -11377GG and -11391GA significantly increased the risk for the development of central obesity (OR 5.57 and OR 3.37, respectively). Significant association was found between -11391A, -11377G allele and haplotype and increased TG. -11377C>G and -11391G>A variant were significantly associated with the incidence of MetS. C>G mutation at position -11377 significantly increased the risk of MetS development (OR = 2.93). Compared with the -11391G homozygotes, carriers of the A allele had a significantly increased risk for the development of MetS (OR = 3.15). The test of overall association showed a statistically significant correlation of MetS with -11377C>G and -11391G>A haplotypes (p = 0.008).
Analysis of adiponectin concentration and ADIPOQ -11391G>A and -11377C>G gene variants may be clinically meaningful for estimation of MetS risk in a young population.
Archives of medical research 02/2012; 43(2):145-53. DOI:10.1016/j.arcmed.2012.02.004 · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Activation of KRAS oncogene has been implicated in colorectal carcinogenesis. KRAS mutations can be detected in more than 30% of all patients with colorectal cancer (CRC). Most recently, regimens that include anti-epidermal growth factor receptor (EGFR) targeted antibodies, cetuximab and panitumumab, for metastatic CRC have been developed. Several recent studies have shown that patients with KRAS mutations in codons 12 and 13 in metastatic CRC do not benefit from anti-EGFR therapy. With the aim to determine KRAS status as predictive biomarker, 7 known mutations ofKRAS gene in codons 12 or 13 on 44 CRC samples were tested. After DNA extraction from paraffin-embedded tumor tissue blocks, KRAS mutations were analysed using quantitative real-time PCR with internationally certified method, for the first time in Croatia. Mutations were detected in 12 tumor samples: five patients with Gly12Val (GGT>GTT), three with Gly12Asp (GGT>GAT), two patients with Gly13Asp (GGC>GAC), one patient with Gly12Ser (GGT>AGT) and one with Gly12Cys (GGT>TGT) mutation in tumor. Our data about KRAS mutational status in the sample of Croatian population diagnosed with CRC have shown that incidence of KRAS mutation is 27%, which is consistent with results already reported worldwide. The final result must be a proper selection of the correct therapy with EGFR inhibitors for the patients with CRC which is critical for improving clinical outcomes, unnecessary toxicities, side effects and financial cost.
[Show abstract][Hide abstract] ABSTRACT: There is accumulating evidence for an increased prevalence of metabolic syndrome (MetS) in bipolar patients, which is comparable to the prevalence of MetS in patients with schizophrenia. Hyperhomocysteinaemia has emerged as an independent and graded risk factor for the development of cardiovascular disease (CVD), which is, at the same time, the primary clinical outcome of MetS. The aim of this study was to ascertain if the presence of MetS was associated with hyperhomocysteinaemia in patients with bipolar disorder (N=36) and schizophrenia (N=46) treated with second-generation antipsychotics (SGA). MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III) criteria and the cut-off point for hyperhomocysteinaemia was set up at 15 μmoll(-1). Results of the study indicated that the presence of the MetS is statistically significantly associated with the elevated serum homocysteine in all participants. As hyperhomocysteinaemia has emerged as an independent risk factor for psychiatric disorder and CVD, it could be useful to include fasting homocysteine serum determination in the diagnostic panels of psychiatric patients to obtain a better assessment of their metabolic risk profile.
Psychiatry Research 08/2011; 189(1):21-5. DOI:10.1016/j.psychres.2010.11.021 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tubular proteinuria and enzymuria are hallmarks of endemic nephropathy (EN). The role of I/D angiotensin convertase (ACE) gene polymorphism has not yet been elucidated in this peculiar chronic tubulointerstitial nephritis, and our aim was to investigate the role of this polymorphism in EN focusing on the urinary N-acetyl-β-D-glucosaminidase (NAG) excretion, a biomarker of proximal tubular damage.
ACE genotype and allele frequencies were determined in 229 farmers (147 women and 82 men) from an endemic Croatian village. The farmers were stratified according to the WHO criteria into the following subgroups: those 'at risk' for EN (n = 37), 'suspected of having EN' (n = 57), and 'others' (n = 135).
There were 74 (32.3%) subjects homozygous for the D allele, 99 (43.2%) heterozygous (ID genotype) and 56 (24.4%) homozygous for the I allele. No differences in allele frequency were found between the established WHO subgroups (p > 0.05). In the whole group, DD subjects had significantly higher values of diastolic blood pressure (p = 0.003) and urinary NAG than subjects with ID and II genotype (5.5 ± 1.2 vs. 4.0 ± 3.0 vs. 3.8 ± 4.2, respectively; p = 0.023). The highest values of serum creatinine (p = 0.02), proteinuria (p = 0.03) and urinary NAG (6.0 ± 3.7 vs. 3.7 ± 2.1 vs. 3.0 ± 1.6, respectively; p = 0.008) were observed in those suspected of having EN group with the DD genotype.
ACE gene polymorphism is not a risk factor for EN. However, it might influence the clinical course of EN, and increased excretion of NAG might be a prognostic marker of this chronic tubulointerstitial nephritis.
Nephron Clinical Practice 07/2011; 119(2):c105-12. DOI:10.1159/000327528 · 1.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: P-glycoprotein (Pgp) is a drug e ux transporter and is the encoded product of the human multidrug resistance gene ABCB1 (MDR1). Pgp is expressed in the blood-brain barrier (BBB) and blood-cerebrospinal uid (CSF) barrier, and reduces the brain penetration of antiepileptic drugs (AEDs). Functio-nal polymorphism or overexpression of Pgp in the BBB of patients with epilepsy may play a role in pharma-coresistance. e aim of this study was to investigate the possible association of ABCB1 gene polymorphisms C1236T in exon 12, G2677T in exon 21, and C3435T in exon 26 with the development of resistance to anti-epileptic therapy. All patients enrolled in the study had an established diagnosis of partial complex epilepsy with or without secondary generalisation and have been su ering from it for more than two years. Patients were devided into two groups. e rst group comprised 57 patients refractory to the current therapy, while group 2 consisted of 48 patients with well-controled seizures. Results of our study showed statistically sig-nii cant di erence in the allele and genotype frequency of ABCB1 G2677T between resistant and nonresis-tant patients. Haplotype G2677/C3435/C1236 was overrepresented among resistant patients. According to our results, ABCB1 variants C1236T, G2677T and C3435T might be associated with therapeutic response to AED in patients with partial epilepsy with or without secondary generalization and represent a possible pre-dictive factor for pharmacoresistance.
[Show abstract][Hide abstract] ABSTRACT: Thorough control of risk factors is pivotal for cardiocerebrovascular diseases. As classic risk assessment accounts for only 50% of risk variability and due to the role of inflammatory processes in endothelial dysfunction and atherosclerotic plaque rupture, it is necessary to identify new biomarkers for risk prediction. In addition to the inflammatory marker high sensibility C-reactive protein (hs-CRP), lipoprotein associated phospholipase A2 (Lp-PLA2) is gaining increasing significance, since it is directly involved in the pathogenesis of atherosclerotic plaque progression. Lp-PLA2 is highly specific for vascular inflammation, has low biological variability, and plays a causative role in atherosclerotic plaque inflammation. It belongs to the group of intracellular and secretory phospholipase enzymes that can hydrolyze sn-2 phospholipid ester bond of cellular membranes and lipoproteins. Lp-PLA2 enzyme is formed by macrophages and foam cells in atherosclerotic plaque, and is associated primarily with LDL particles in blood. Lp-PLA2 that is bound to LDL is the sole enzyme responsible for hydrolysis of oxidized phospholipids (oxPL) on LDL particles. Lp-PLA2 hydrolyzes oxPL at the surface of lipoproteins, but has weak activity against non-oxPL. Lp-PLA2 is also the enzyme that hydrolyzes oxPL on HDL particles, where it may have a role in the antioxidative function of HDL. The distribution of Lp-PLA2 between LDL and HDL particles depends on the extent of Lp-PLA2 glycosylation, which may affect the activity of Lp-PLA2 in plasma. Stable atherosclerotic plaques contain few inflammatory cells and a small amount of Lp-PLA2. In contrast, unstable plaques most often do not have significant impact on arterial lumen but may be detected by its thin connective tissue cap, low collagen and high lipid content. A distinguishing factor between stable and unstable atherosclerotic plaque may also be the presence of activated inflammatory cells and increased Lp-PLA2 concentration in unstable plaque. These new insights indicate that Lp-PLA2 may be a risk factor, which is important for the formation of atherosclerotic plaque but also for its rupture. The purpose of applying markers of inflammation is to improve stratification of patients at risk, so that treatment intensity may be adjusted to the risk level. Lp-PLA2 inhibition is associated with decreased cytokines. Lipid-affecting drugs stabilize atherosclerotic plaque by reducing the central lipid core, decreasing macrophage infiltration, and thickening of the connective tissue cap. These drugs reduce Lp-PLA2 concentration and the frequency of cardiocerebrovascular events as well. Besides acting as a specific marker of atherosclerotic plaque inflammation, Lp-PLA2 has a significant prognostic value because of its direct role in the formation of rupture-prone atherosclerotic plaque, unlike classic risk factors, for example lipid measurement or vascular imaging, which do not directly estimate acute ischemic potential in the arterial wall. Studies have demonstrated correlation between increased Lp-PLA2 concentrations and enhanced risk of cardiocerebrovascular events, even after multivariate adjustment to classic risk factors. In addition to its high specificity for vascular inflammation, Lp-PLA2 concentration is stable in terms of time, unlike, for instance, CRP levels. Lp-PLA2 has been confirmed as an independent risk predictor, which is complementary to hsCRP. It could be used in clinical practice for improved risk assessment in patients with transient cardiocerebrovascular risk, particularly in those with metabolic syndrome (obese patients with mixed dyslipidemia, hyperglycemia, insulin resistance, and arterial hypertension). Lp-PLA2 levels allow for further risk stratification of high-risk patients into a very high risk group where more aggressive therapy is recommended, as well as the achievement of LDL-cholesterol levels < 2.5 or, even better, < 2.0 mmol/L as a feasible therapeutic target. Similar to hsCRP, the levels of Lp-PLA2 are reduced by lipid-affecting drugs, while its low concentrations are associated with a very low risk of cardiocerebrovascular events both in low- and high-risk population. According to recent American guidelines for assessing the risk of cardiovascular disease, Lp-PLA2 determination is recommended as an additional marker to the classic risk assessment in patients with moderate and high risk.
Acta medica Croatica: c̆asopis Hravatske akademije medicinskih znanosti 10/2010; 64(4):237-45.