Balkan Journal of Medical Genetics

THE LRP1 GENE POLYMORPHISM IS ASSOCIATED WITH INCREASED RISK OF METABOLIC SYNDROME PREVALENCE IN THE SERBIAN POPULATION
Vučinić N1,*, Stokić E1,2, Djan I3,4, Obreht D5, Veličković N5, Stankov K6, Djan M5
*Corresponding Author: Nataša Vučinić, Ph.D., University of Novi Sad, Faculty of Medicine, Department of Pharmacy, Hajduk Veljkova 3, 21000 Novi Sad, Serbia. Tel: +38121422760. Mobile: +381652452456. Fax: +38121450620. E-mail: natasa.vucinic@mf.uns.ac.rs
page: 51

INTRODUCTION

During the past 50 years, numerous dramatic changes in human environment as well as behavioral and lifestyle changes, have led to a global increase in obesity and type 2 diabetes mellitus (T2DM). Both diseases are reaching epidemic proportions in developed and developing countries and their co-occurrence represents one of the biggest health threats in the 21st century [1,2]. Metabolic syndrome (MetS) has been described as a cluster of risk factors for cardiovascular diseases (CVDs) and T2DM, primarily due to the existence of abdominal obesity and insulin resistance [3]. Patients with MetS have a 3-fold higher risk of experiencing a heart attack or stroke and a 2-fold higher risk of fatal outcome compared to the general population. Recent findings revealed that MetS increases the risk for the prevalence of microalbuminuria, which is crucial in this syndrome because it accelerates the progression of chronic kidney disease and increases the prevalence of cardiovascular events [4]. Fujita [5] recently demonstrated the possible involvement of aldosterone/ mineralocorticoid receptor activation in hypertension development and renal injury in obesity-induced hypertension with MetS. Pathophysiological abnormalities that contribute to the development of MetS include impaired mitochondrial oxidative phosphorylation and mitochondrial biogenesis, dampened insulin metabolic signaling, endothelial dysfunction, and associated myocardial functional abnormalities [6]. Introduction of drug therapy for MetS should not be delayed, as adherence to lifestyle modifications such as dietary changes, weight reduction, and exercise is not achieved in most cases [7]. All components of MetS are considered to be multifactorial traits. The identification of a genetic component of MetS is difficult due to the complexity of MetS and variability of lifestyle factors. However, linkage analysis, candidate gene approach and genome-wide association studies (GWAS) suggested that MetS is a polygenic and multifactorial disease, developing as a result of complex interactions of many genes and environmental factors [8]. Investigations of the genetic basis of this syndrome represent a major challenge [2-4]. Metabolic syndrome is a complex polygenetic disorder of metabolism including central obesity, dyslipidemia, hypertension, and hyperglycemia. Genetic predisposition is one of the risk factors that cannot be controlled, but the knowledge of genetic basis allows us to correct other, modifying, environmental factors, thereby disease can be delayed or prevented. Understanding the importance of genetic and environmental factors, as well as their interactions is critical for finding specific treatments and identifying individuals at high risk of becoming ill. Determining the genetic basis of MetS is one of the necessary steps in disease prevention, and in designing targeted therapies [9]. The LRP1 gene is located on human chromosome 12q13-14 and encodes low-density lipoprotein receptorrelated protein [5]. To date, several known mutations of this gene are: intron 2 (C>T), exon 3 (C>T), exon 6 (C>T), intron 6 (G>C), intron 19 (C>T), exon 22 (C>T), intron 38 (C>T), exon 61 (G>A) and intron 83 (G>A). Protein LRP1 is a multifunctional receptor with two main biological functions: endocytosis of many ligands and control and integration of intracellular signaling pathways that are essential for the survival of the cells themselves, but are also essential for the maintenance of basal cell function and development and survival of the organism. Because of its importance, LRP1 is expressed in almost all cells [10]. Mutation within exon 3 of the LRP1 gene, C>T at position 667 that does not change the amino acid sequence of the protein, is associated with Alzheimer’s disease [6,11], cerebral amyloid angiopathy [12], increased factor VIII (FVIII) level in plasma and the risk of venous thromboembolism [13]. It also affects the expression of markers for adipocyte differentiation and the maintenance of lipid levels in mature adipocytes, and has a key role in lipid metabolism [14,15]. Liu et al. [16] found that LRP1, which is critical in lipid metabolism, also regulates food intake and energy homeostasis in adult central nervous system. The investigation of Niemeier et al. [17] showed that among the low-density lipoprotein receptor (LDLR) family in human osteoblasts, LRP1 plays a predominant role in vitamin K1 uptake through chylomicron remnants endocytosis. Association between LRP1 and lung cancer was investigated in study of Meng et al. [18] pointing out that LRP1 expression is associated with improved lung cancer outcomes. The LRP1 gene is highly variable in different populations. Looking at the entire human population, frequency of the T allele of exon 3 LRP1 gene was 22.0%, and the C allele was 78.0%. To date, frequency of LRP1 exon 3 alleles have not been analyzed in the Serbian population. The LRP1 receptor is one of the major ApoE binding receptors in the liver, muscles, heart and adipose tissue. As participating in such a large number of physiological processes, functional clarification of these mechanisms and further identification of LRP1 partners can open up new aspects in the treatment of metabolic diseases, such as lipid metabolism disorders, atherosclerosis, obesity, Alzheimer’s disease and inflammatory processes [9,19,20]. Diet-induced obesity and its serious consequences, such as diabetes, cardiovascular disease and cancer, rapidly became one of the biggest global health problems. Thus, the clarification and understanding of the cellular and molecular mechanisms by which fat food intake causes obesity and diabetes is essential to identify preventive and therapeutic strategies [21]. Data findings identify LRP1 as a critical regulator of adipocyte energy homeostasis, where functional impairment of LRP1 leads to reduced lipid transport, increased insulin sensitivity and muscle power consumption [22]. Thanks to its role in these processes, associations of the LRP1 gene and various pathological conditions was investigated. Although a 667 (C>T) polymorphism does not change an amino acid sequence, this polymorphism influences the splicing efficiency of exon 3 in an exon-trapping assay, leading to a small, but still significant decrease in full-length LRP mRNA produced form the LRP gene with the C allele [23]. As far as we know, none of the diseases are associated with mutations in the LRP1 gene coding region [15]. The main goals of the present study were to determine the association between individual alleles of the exon 3 LRP1 gene and MetS development and correlation analyses between the LRP1 gene polymorphism and individual anthropometric and biochemical parameters. To the best of our knowledge, this is the first study demonstrating the association of the LRP1 gene polymorphisms with MetS incidence as well as with the individual components of MetS.

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