Association between the DOCK7, PCSK9 and GALNT2 Gene Polymorphisms and Serum Lipid levels

Cardiovascular disease (CVD) remains as the leading cause of morbidity and mortality worldwide, and its prevalence is expected to increase further, which exerts a significant economic burden1,2. Most of the current prevention strategies are focused on identifying and managing the established risk factors including hyperlipidemia3 that can be effectively addressed for individuals and populations suffering from atherosclerosis. It is generally agreed that dyslipidemia is complex and the result of the interactions4,5 of multiple genes6,7,8 and multiple environmental factors9,10. Statins are highly effective for lowering low-density lipoprotein (LDL) cholesterol levels and, consequently, cardiovascular event rates. However, statins do not eliminate cardiovascular risk. High triglyceride (TG) level is a significant risk factor for independent cardiovascular disease and is a marker for atherogenic remnant lipoproteins, such as very low-density lipoprotein (VLDL) cholesterol. Additionally, with elevated TG levels, a combination of LDL cholesterol with VLDL cholesterol in the measure of non-high-density lipoprotein (HDL) cholesterol may be a better predictor of cardiovascular risk than LDL cholesterol alone. Therefore, improved understanding of TG-related loci may optimize patient management strategies, provide potential new targets for future individual therapy, and thereby improve patients’ chances for survival. Candidate gene and genome-wide association studies (GWASs)11,12,13 have identified a number of sequence variants that explain some of the individual variation in the susceptibility for high TG levels. The dedicator of cytokinesis 7 (DOCK7; Gene ID: 85440; MIM: 615730) formerly known as ZIR2 and EIEE23, is located on chromosome 1p31.3 and the protein encoded by this gene is a guanine nucleotide exchange factor (GEF) that plays a role in axon formation and neuronal polarization. The encoded protein displays GEF activity toward RAC1 and RAC3 Rho small GTPases but not toward CDC42. Several transcript variants encoding different isoforms have been found for this gene. The proprotein convertase subtilisin/kexin type 9 (PCSK9; Gene ID: 255738; MIM: 607786) gene, also known as FH3, PC9, NARC1, LDLCQ1, NARC-1 and HCHOLA3, is located on 1p32.3 and this gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing can result in multiple transcript variants. The polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2; Gene ID: 2590; MIM: 602274) gene, formerly known as GalNAc-T2, is located on chromosome 1q41-q42 and encodes a member of the glycosyltransferase 2 protein family. Members of this family initiate mucin-type O-glycoslation of peptides in the Golgi apparatus. The encoded protein may be involved in O-linked glycosylation of the immunoglobulin A1 hinge region. This gene may influence TG levels, and may be involved type 2 diabetes, as well as several types of cancer. Alternative splicing can also result in multiple transcript variants (http://www.ncbi.nlm.nih.gov/gene/). Human genetic studies of lipid levels can identify targets for new therapies for cholesterol management and prevention of heart disease especially monoclonal anti-PCSK9 antibodies are already on the market to significantly reduced levels of LDL cholesterol when added to statin therapy administered at the maximum tolerated dose14. For comparison with the nonsynonymous single nucleotide polymorphisms (SNPs) in known drug therapies genes, we scored point mutations at synonymous point mutations in housekeeping genes or genes of unknown function on the approximate locations of the chromosome 1. The exact positions of the PCSK9 SNPs were located in the similar position area of the DOCK7 and GLANT2 SNPs (http://hapmap.ncbi.nlm.nih.gov/). Several genetic variants in the DOCK7, PCSK9 and GLANT2 have been associated with serum lipid parameters, especially with TG in Western populations15, e.g. the SNPs of DOCK7 rs1167998, rs1088935316, PCSK9 rs1159114717 and GALNT2 rs484691413 were associated with TG levels in European and PCSK9 rs50515118 and GALNT2 rs2144300 and rs484691419 in the Asian populations. However, the association of the DOCK7 (rs1168013 and rs10889332), PCSK9 (rs615563, rs7552841 and rs1126517) and GALNT2 (rs1997947, rs2760537, rs4846913 and rs11122316) SNPs and serum lipid levels has not been previously reported. Since ancient times China is a multi-ethnic country. Among 56 nationalities in China, the Han nationality is the biggest one. Jing is one of the smallest population of ethnic minorities in southern China with a population of 22,517 (in 2000 the fifth national census statistics of China), China’s only a coastal fishery ethnic minority, and China’s only national ocean at the same time20. Jing populations live in Dongxing city, Guangxi Zhuang Autonomous Region. Diet to rice is given priority to, fresh fish and shrimp more, like to use fish sauce to taste. The history of Jing ethnic minority shows Jing nationality is a relatively conservative and isolated minority, and preserves their custom of intra-ethnic marriage21. Thus, their genetic background may be less heterogeneous within the population. Little is known about the association of SNPs and lipid phenotypes in the Jing population. Therefore, this research was undertaken to detect the association of the DOCK7 rs1168013, DOCK7 rs10889332, PCSK9 rs615563, PCSK9 rs7552841, PCSK9 rs11206517, GALNT2 rs1997947, GALNT2 rs2760537, GALNT2 rs4846913, and GALNT2 rs11122316 SNPs and lipid profiles in the two ethnic groups.