Balkan Journal of Medical Genetics

RTN4 AND FBXL17 GENES ARE ASSOCIATED WITH CORONARY HEART DISEASE IN GENOME-WIDE ASSOCIATION ANALYSIS OF LITHUANIAN FAMILIES
Domarkienė I1,*, Pranculis A1, Germanas Š1, Jakaitienė A1, Vitkus D2, Dženkevičiūtė V3, Kučinskienė ZA2, Kučinskas V1
*Corresponding Author: Ingrida Domarkienė, Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Santariškių str. 2, 08661 Vilnius, Lithuania; Tel.: +370-52501788; E-mail: ingrida.domarkiene@ mf.vu.lt
page: 17

DISCUSSION

Our aim was to identify the particular genetic factors for Lihuanian CHD patients. In order to avoid population stratification we planned the familial GWAS and subsequently performed TDT analysis. Out of 12 significant SNPs, at least two (italicized and bold rows in Table 1) had promising OR values in addition to power and p values. Despite relatively wide OR intervals, caused by a modest sample size, these SNPs may indicate the potential genes that could be involved in CHD pathogenesis. The SNP rs17046570 is located in an intron of the reticulon 4 coding gene (RTN4) on chromosome 2. Retic-ulons are associated with endoplasmic reticulum, and are involved in neuroendocrine secretion or membrane trafficking and apoptotic processes. In particular, reticulon 4 has been identified as a potential inhibitor of central nervous system regeneration by means of the inhibition of neuron outgrowth [11,12]. Common RTN4 variants that are associated with schizophrenia in the Japanese population [13] and also blood lipid phenotypes [14], are cited. RTN4 is a candidate gene associated with vascular cell apoptosis and AS modulation [12]. It is thought to participate in vascular remodeling and is a considerable new factor for atherogenesis process [15-17]. It was also stated that reticulons may be factors that mediate between the apoptosis and AS processes [12]. Thus, our results are consistent with these findings. Another SNP on chromosome 5, rs11743737, is located in an intron of the F-box and leucine-rich repeat protein 17 coding gene FBXL17. The FBXL17 protein has an F-box that is a 40 amino acid motif typical for F-box containing proteins. F-box containing proteins together with culin and SKP1 (S-phase kinase-associated protein 1) make up the SCF complex (SKP1, cullin, F-box containing complex) that is a protein ubiquitine ligase [18]. The SCF is a key complex in the ubiquitine-proteosome system (UPS) that is involved in 70.0-90.0% of protein degradation processes including the degradation of a number of proteins important for the cardiovascular system. The UPS is also important in the regulation of endothelial cell cycle. The effect of oxidative stress on the SCF complex may disrupt the function of UPS and in turn the function of the endothelium that is regulated the by UPS [19]. According to the NCBI Gene database review of association results [from National Human Genome Research Institute (NHGRI) Catalogue and association results submitted to the database of Genotypes and Phenotypes (dbGaP)] there are many SNPs in the FBXL17 gene region associated with the various phenotypes including cholesterol, high-density lipoproteins, body mass index. These findings do not compromise our findings either. Moreover, these summarized results might show us the complexity and universality of the FBXL17 protein function in the pathogenesis of different diseases. It is possible that other SNPs that are in linkage disequilibrium with the identified CHD associated SNPs were not identified during this TDT analysis but may also be involved in the development of the disease. Conclusions. Our results suggest that the RTN4 and FBXL17 genes may be the susceptibility loci for the CHD in the Lithuanian male population. In addition, the genotypes of the significantly associated SNPs with OR >7 may prove to be informative and specific for the genetic risk of CHD evaluation in the Lithuanian population and could be taken under consideration in further hypothesis validation.

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