Dyslipidemia in adults and genetic polymorphism in the mevalonate kinase gene, a systematic review

The presence of mutations in dyslipidemia-related genes is of great importance for the outcome of procedures on patients with elevated levels of HDL cholesterol. This systematic review aims to describe the genetic variants in the mevalonate kinase genes in adults with dyslipidemia. A systematic search of the following databases was conducted: Scopus, Web of Science, Google Scholar and Bireme, using the keywords: "Mevalonate Kinase Gene", "Dyslipidemia", "Genetic Polymorphism", linked using the term "AND". The inclusion criteria consisted of articles published between 2008 and 2018, written in Portuguese or English, while the exclusion criteria were the removal of duplicated articles, books, theses and bibliographic reviews, tests not conducted on humans, tests conducted on children and other genes evaluated. The articles listed in this review demonstrate the role of the genetic polymorphism of the mevalonate-kinase gene (MVK) in an adult population. A comparison of results from different studies is often complicated because of the diverse study variables such as: tests used, population studied. The studies described in this review demonstrated that there is an association between genetic profiles and dyslipidemia. Many studies have shown that, besides the external factors and individuals’ behavioral habits, the presence of mutations in the mevalonate kinase gene is associated with dyslipidemia.


Introduction
The mevalonate kinase gene, located in chromosome 12, encodes the mevalonate kinase (MVK) enzyme which is essential for the biosynthesis of cholesterol, exerting an influence over the metabolism of HDL cholesterol (L Miao et al., 2017) The symptoms of the modification of the mevalonate kinase function may manifest as hyperimmunoglobulinemia, which is associated with low levels of HDL, although it can be associated with Periodic Fever Syndrome and, when present in infancy to a severe degree, may lead to death (Browne & Timson, 2015). The presence of environmental factors has an influence on the appearance of particular symptoms. For example, the symptoms of individuals who have a deficiency in this enzyme are worse at low temperatures (Houten et al., 2002).
The monitoring of the plasmatic levels of cholesterol, evaluation and indications of lifestyle habits with a history of coronary heart disease, should be evaluated in conjunction with the molecular analysis of genes that induce alterations that are not modified by external factors (Sarzynski et al., 2011). Accordingly, genes related to the modulation of HDL cholesterol, such as the mevalonate kinase gene, should be determined for an evaluation of the risk of dyslipidemia associated with coronary heart disease (Sun et al., 2016).
The aim of this review is to present studies which compare external factors with the determination of mutations in the mevalonate kinase gene, in patients with dyslipidemia, by way of a systematic review.

Methodology
For the selection of the scientific articles, four electronic databases were queried: Scopus, Web of Science, Google Scholar and Bireme, conducted in April 2020.
For the selection of the articles, the following keywords were employed: "Mevalonate Kinase Gene", "Dyslipidemia", "Genetic Polymorphism", the terms being linked using the word "AND". The distribution of the results is exhibited in Figure 1. The inclusion criteria were defined as follows: the articles must have been published between January 2008 and December 2018 and written in Portuguese or English. Following this initial article triage, they were submitted for reading by two independent reviewers who selected the references in three stages: analysis of titles, abstracts and complete texts. The exclusion criteria were: removal of duplicate articles, books, theses and bibliographic reviews of related subjects. For the reading of the abstracts, the exclusion criteria were once again employed, eliminating articles that included tests not performed on humans, tests conducted on children and an evaluation of different genes.
Given this initial evaluation, the articles were submitted for a full-text reading, from which the data were extracted for the details of this review.

Results
The articles listed in this review demonstrate the role of the genetic polymorphism of the mevalonate kinase (MVK) gene in an adult population. The comparison of results from different studies is often complicated due to the variability of the diverse variables in the study, such as: tests used, population studied (men vs. women vs. children vs. those with a history of dyslipidemia; among others). In addition to these variables, those related to lifestyle and dietary habits also have an influence on results.

Discussion
The V377I genetic variant in the mevalonate kinase gene leads to two distinct forms: Hyperimmunoglobulinemia D and Periodic Fever, the latter being characterized by a fever with inflammatory symptoms which may be mild or severe (Messer et al., 2016). (Sun et al., 2016) found that alterations to genes MVK, MMAB and KCTD10 impact on the risk for dyslipidemia and coronary heart disease. Figuring among the associated alleles are rs11067233 in the gene MMAB, rs11066782 and rs11613718 in the gene KCTD10. It should be stressed that this study was performed on a Chinese population and this has to be taken into account as differences exist between ethnic groups. MVK and MMAB are responsible for controlling cholesterol while KCTD10 is linked to obesity, diabetes and atherosclerosis.
Studies conducted on two distinct ethnic groups in China produced interesting results when genetic factors were taken into account. Among other characteristics, these groups exhibited dietary habits, in marriage within the same ethnic group. The frequency of alleles that encode the mutations in the mevalonate kinase gene was different between the Maonan and Han groups, with rs3759387, rs877710, rs7134594 and rs9593 being detected in the two groups . In different genetic groups, these alleles point to a greater risk of coronary heart disease and cerebral ischemia (Liu Miao et al., 2017).
Some studies have reported that different levels of mevalonate kinase are found in different tissues, however it was ascertained that, in the presence of allele rs2287218, it suggests a predisposition to coronary heart disease and ischemic cerebral vascular accident (Wang et al., 2018).
European individuals homozygous for the mutation in the mevalonate kinase (V377I) are asymptomatic, while other individuals with the same mutation may present with severe alterations (Moura, Tricarico, Coelho, & Crovella, 2015). (Sarzynski et al., 2011), in their evaluation of the genetic profiles of patients subjected to bariatric surgery, found that the variations in the following loci of the studied genes: ABCA1, APOA5, CETP, GALNT2, LIPC, LIPG, LPL and MMAB / MVK, contribute significantly to the plasmatic levels of HDL-C in obese individuals, and that the associations persist even after considerable weight loss resulting from the bariatric surgery. However, they are not associated with alterations induced by surgery at HDL-C levels.
In the study conducted by (Fogarty, Xiao, Prokunina-Olsson, Scott, & Mohlke, 2010), the relative expression of the SNP allele transcription factors was investigated in 5 genes, using heterozygous, human hepatocyte cells for the genetic variants.
Variant rs7298565 of the gene MMAB (methylmalonic aciduria cblB type) features prominently, producing a regulatory effect to increase the levels of MMAB and reduce the levels of HDL-C, however, as far as the MVK gene is concerned, no significant differences were observed in the imbalance of allele-specific expression (Fogarty et al., 2010). Junyent et al. (2009) concluded that the association of genetic variations in the three main genes involved in the synthesis of cholesterol (KCDTD10 i5642G, MVK i851G and S52NG and MMAB 3U3527G), interact with the concentration of cholesterol in the plasma. The authors report that it is difficult to compare different ethnic groups, ages, sexes, dietary habits, since all these factors have an influence on the levels of cholesterol and the risk of disease related to the increase in the blood plasma (Junyent et al., 2009;.
In general, the majority of epidemiological studies only take into account individuals' normal external factors compared to the levels of cholesterol in the plasma as well as the risk of developing coronary heart disease, however it can be seen from these articles that genetic factors do influence these factors. Accordingly, in addition to eating and smoking habits, they must also be associated with the amount and intensity of physical exercise to which these individuals are accustomed.
Another important factor lies in the drug therapy since, when genetic factors are present, therapies should be reviewed to tailor them to each individual.

Conclusions
The studies described in this review show that there is an association between genetic profiles and dyslipidemia.
Many studies have shown that, besides the external factors and behavioral habits of individuals, the presence of mutations in the mevalonate-kinase gene is associated with dyslipidemia. Further studies evaluating the genetic profile of other populations must be performed in order to acquire a deeper understanding of the implications of this mutation. The role of physical activity in the population of diverse age groups should also be evaluated. Further studies are needed to confirm the present findings.
Declaration of the contribution of the authors: