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Effect of SORT1 rs599839 Polymorphism on Lipid Profiles: A Single City Experience

Yıl 2022, Sayı: 17, 369 - 380, 29.08.2022
https://doi.org/10.38079/igusabder.987894

Öz

Aim: The SORT1 gene encoding Sortilin-1 (SORT1), a receptor of the VPS10p family, is localized at 1p13.3. SORT1 has been associated with the risk of developing coronary heart disease (CHD) in genome wide association studies (GWAS) due to its association with hepatic lipid metabolism and low-density lipoprotein-cholesterol (LDL-C) levels. Various variations on the SORT1 gene region cause different effects on lipid profiles. Our aim in this study; To determine whether the SORT1 rs599839 gene variants have an effect on CHD development and lipid parameters in the Giresun province of Turkey.
Method: In this case-control study, the study group consisting of 396 men (209 KKH / 187 controls) was genotyped in terms of SORT1 rs599839 polymorphism using TaqMan 5 'Allelic Discrimination Test.
Results: There is no statistically significant difference between the patient and control groups in terms of SORT1 rs599839 genotypes (p=0.81). The presence of the G allele caused lower Total-C (p=0.005, p=0.032, respectively) and LDL-C (respectively; p=0.005, p=0.040) levels in both patient and control groups, while higher HDL-Cholesterol (p=0.001, p=0.006) levels were observed, respectively.
Conclusion: Our findings suggest that the SORT1 rs599839 polymorphism does not contribute directly to the pathogenesis of CHD. However, the presence of the minor G allele lowered Total-cholesterol and LDL-cholesterol levels and caused an increase in HDL-cholesterol levels. This situation gave the impression that the presence of the minor G allele has a positive effect on the lipid profile and is protective against CHD.

Kaynakça

  • Mozaffarian D, Benjamin EJ, Alan SG, et al. Heart disease and stroke statistics-2016 update: A report from the American Heart Association. Circulation. 2016;133:e38–60.
  • Jia-Yin D, Meng-Lu D, Zong-Xin Z. ENPP1 K121Q (rs1044498C>A) genetic polymorphism confers a high risk of susceptibility to coronary heart disease. A PRISMA-Compliant Article Medicine. 2018;97:27(e11236).
  • Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: Update and therapeutic implications. Circulation. 2007;116:832-844.
  • Lıttle PJ, Chaıt A, Bobık A. Cellular and cytokinebased inflammatory processes as novel therapeutic targets for the prevention and treatment of atherosclerosis. Pharmacol Ther. 2011;131:255-268.
  • Kjolby M, Andersen OM, Breiderhoff T, et al. SORT1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export. Cell Metab. 2010;12:213–223.
  • Dube JB, Johansen CT, Hegele RA. Sortilin: An unusual suspect in cholesterol metabolism: From GWAS identification to in vivo biochemical analyses, sortilin has been identified as a novel mediator of human lipoprotein metabolism. BioEssays. 2011;33:430–437.
  • Strong A, Rader DJ. Sortilin as a regulator of lipoprotein metabolism. Curr Atheroscler Rep. 2012;14:211–218.
  • Ogawa K, Ueno T, Iwasaki T, et al. Soluble sortilin is released by activated platelets and its circulating levels are associated with cardiovascular risk factors. Atherosclerosis. 2016;249:110–115.
  • Anbo G, Francisco SC, Xi C, et al. Implications of Sortilin in Lipid Metabolism and Lipid Disorder Diseases. Dna and cell bıo. 2017;36:1050–1061.
  • Musunuru K, Strong A, Frank-Kamenetsky M, et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature. 2010;466:714-719.
  • Kjolby M, Nielsen MS, Petersen CM. Sortilin, encoded by the cardiovascular risk gene SORT1, and its suggested functions in cardiovascular disease. Curr Atheroscler Rep. 2015;17: 496–505.
  • Patel KM, Strong A, Tohyama J, et al. Macrophage sortilin promotes LDL uptake, foam cell formation, and atherosclerosis. Circ Res. 2015;116:789–796.
  • Guo J, Luo YX, Tao LX, Guo X.H. Association between 1p13.3 genomic markers and coronary artery disease: a meta-analysis involving patients and controls. GMR. 2015;14:9092–9102.
  • Sparks CE, Sparks RP, Sparks JD. The enigmatic role of sortilin in lipoprotein metabolism. Curr Opin Lipidol. 2015;26:598–600.
  • World Medical Association World Medical Association Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. JAMA. 2013;310:2191–2194.
  • Excoffier L, Laval G, Schneider S. Arlequin ver. 3.0: An integrated software package for population genetics data analysis. Evolutionary Bioinformatics Online 1. 2005;47-50.
  • Strong A, Patel K, Rader DJ. Sortilin and lipoprotein metabolism: Making sense out of complexity. Curr Opin Lipidol. 2014;25:350-357.
  • Strong A, Ding Q, Edmondson AC, et al. Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism. J Clin Invest. 2012;122:2807-2816.
  • Tauris J , Ellgaard L, Jacobsen C, et al.The carboxy-terminal domain of the receptor-associated protein binds to the Vps10p domain of sortilin. FEBS Lett. 1998; 429: 27-30.
  • Mortensen MB, Kjolby M, Gunnersen S, et al. Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis. J Clin Invest. 2014;124(12):5317-5322.
  • Marcus EK, Wilfried R, Tanja BG, et al. Association of the single nucleotide polymorphism rs599839 in the vicinity of the sortilin 1 gene with LDL and triglyceride metabolism, coronary heart disease and myocardial infarction. The Ludwigshafen risk and cardiovascular health Study. Atherosclerosis. 2010;209:492–497.
  • Matsuoka R, Abe S, Tokoro F, et al. Association of six genetic variants with myocardial infarction. Int J Mol Med. 2015;35:1451–1459.
  • Yi-Jiang Z, Shao-Cai H, Qian Y, Rui-Xing Y, Xiao-Li C, Wu-Xian C. Association of variants in CELSR2-PSRC1-SORT1 with risk of serum lipid traits, coronary artery disease and ischemic stroke. Int J Clin Exp Pathol. 2015;8:9543–9551.
  • Juan F, Sánchez MT, Maria DR , et al. Multivariate analysis for coronary heart disease in heterozygote familial hypercholesterolemia patients. Per Med. 2018;15:87-92.
  • Hao H , Lingai P, Li Z, Yucheng C, Zhi Z. Association of single nucleotide polymorphism rs599839 on chromosome 1p13.3 with premature coronary heart disease in a Chinese Han population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2008;25:686-689.
  • Willer CJ, Sanna S, Jackson AU, et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008;40:161–169.
  • Rizk NM, El Menya A, Egue H, et al. The association between serum LDL cholesterol and genetic variation in chromosomal locus 1p13.3 among coronary artery disease patients. BioMed Res Int. 2015;678924–36.
  • Linsel‐Nitschke P, Heeren J, Aherrahrou Z, et al. Genetic variation at chromosome 1p13.3 affects sortilin mRNA expression, cellular LDL‐uptake and serum LDL levels which translates to the risk of coronary artery disease. Atherosclerosis. 2009;08:183–189.
  • Eagle KA, Ginsburg GS, Musunuru K, et al. Identifying patients at high risk of a cardiovascular event in the near future: Current status and future directions: Report of a national heart, lung, and blood institute working group. Circulation. 2010;121:1447–1454.
  • Bruna G , Karin L, Max V, Shu Y, Ulf de F. Chromosome 1p13 genetic variants antagonize the risk of myocardial infarction associated with high ApoB serum levels. BMC Cardiovasc Disord. 2012;12:90.
  • Muendlein A, Geller-Rhomberg S, Saely CH, et al. Significant impact of chromosomal locus 1p13.3 on serum LDL cholesterol and on angiographically characterized coronary atherosclerosis. Atherosclerosis. 2009;206:494–499.
  • Walia GK, Gupta V, Aggarwal A,et al. Association of Common Genetic Variants with Lipid Traits in the Indian Population. PLoS One. 2014;9:e101688.
  • Nakayama K, Bayasgalan T, Yamanaka K et al. Jichi Community Genetics Team (JCOG) Large scale replication analysis of loci associated with lipid concentrations in a Japanese population. J Med Genet. 2009;46:370–374.
  • Zhou L, Ding H, Zhang X, et al. Genetic Variants at Newly Identified Lipid Loci Are Associated with Coronary Heart Disease in a Chinese Han Population. PLoS One. 2011;11:e27481.
  • Saleheen D, Soranzo N, Rasheed A, et al. Genetic determinants of major blood lipids in Pakistanis compared with Europeans. Circ Cardiovasc Genet. 2010;3(4):348-57.
  • Rodríguez-Arellano ME , Solares-Tlapechco J , Costa-Urrutia P, et al. Association of the PSRC1 rs599839 Variant with Coronary Artery Disease in a Mexican Population. Medicina (Kaunas). 2020;26:56(9):427.
  • Lu Y, Feskens EJ, Boer JM, et al. Exploring genetic determinants of plasma total cholesterol levels and their predictive value in a longitudinal study. Atherosclerosis. 2010; 213:200-215.
  • Zhou YJ, Hong SC, Yang Q, Yin RX, Cao XL, Chen WX. Association of variants in CELSR2-PSRC1-SORT1 with risk of serum lipid traits, coronary artery disease and ischemic stroke. Int J Clin Exp Pathol. 2015;8(8): 9543–9551.

SORT1 rs599839 Polimorfizminin Lipit Profillerine Olan Etkisi: Tek Şehir Deneyimi

Yıl 2022, Sayı: 17, 369 - 380, 29.08.2022
https://doi.org/10.38079/igusabder.987894

Öz

Amaç: VPS10p ailesinin bir reseptörü olan Sortilin-1(SORT1)’i kodlayan SORT1 geni 1p13.3’de lokalizedir. SORT1 genom çapında ilişkilendirme çalışmalarında (GWAS) hepatik lipit metabolizması ve düşük dansiteli lipoprotein-kolesterol (LDL-K) seviyeleri ile olan ilişkisinden dolayı koroner kalp hastalığı (KKH) oluşturma riski ile ilişkilendirilmiştir. SORT1 gen bölgesi üzerindeki çeşitli varyasyonlar lipit profilleri üzerinde farklı etkilere neden olmaktadır. Bizim bu çalışmadaki amacımız; Giresun ilinde SORT1 rs599839 gen varyantlarının KKH gelişimi ve lipit parametreleri üzerine bir etkisinin olup olmadığını belirlemektir.
Yöntem: Bu vaka-kontrol çalışmasında 396 kişiden oluşan erkek çalışma grubunda (209 KKH /187 kontrol) SORT1 rs599839 polimorfizmi için TaqMan 5’ Allelik Ayrım Testi ile genotipleme yapıldı.
Bulgular: Hasta ve kontrol grupları arasında SORT1 rs599839 genotip dağılımları açısından istatistiksel olarak fark bulunmamaktadır (p=0.81). G allel varlığı hem hasta hem de kontrol grubunda daha düşük Total-Kolesterol (TK) (sırasıyla; p=0.005,p=0.032) ve LDL-K (sırasıyla; p=0.005,p=0.040) seviyelerine sebep olurken daha yüksek yüksek dansiteli lipoprotein-kolesterol (HDL-K) (sırasıyla; p=0.001,p=0.006) seviyeleri gözlenmiştir.
Sonuç: Bulgularımız SORT1 rs599839 polimorfizminin direk olarak KKH patogenezine katkısının olmadığı yönündedir. Ancak, minör G allel varlığının TK ve LDL-K seviyelerini düşürürken, HDL-K seviyelerinde yükselmeye sebep olduğu görülmüştür. Bu durum minör G allel varlığının lipit profili üzerine olumlu etki gösterdiği ve KKH’a karşı koruyucu olduğu izlenimini vermiştir.

Kaynakça

  • Mozaffarian D, Benjamin EJ, Alan SG, et al. Heart disease and stroke statistics-2016 update: A report from the American Heart Association. Circulation. 2016;133:e38–60.
  • Jia-Yin D, Meng-Lu D, Zong-Xin Z. ENPP1 K121Q (rs1044498C>A) genetic polymorphism confers a high risk of susceptibility to coronary heart disease. A PRISMA-Compliant Article Medicine. 2018;97:27(e11236).
  • Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: Update and therapeutic implications. Circulation. 2007;116:832-844.
  • Lıttle PJ, Chaıt A, Bobık A. Cellular and cytokinebased inflammatory processes as novel therapeutic targets for the prevention and treatment of atherosclerosis. Pharmacol Ther. 2011;131:255-268.
  • Kjolby M, Andersen OM, Breiderhoff T, et al. SORT1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export. Cell Metab. 2010;12:213–223.
  • Dube JB, Johansen CT, Hegele RA. Sortilin: An unusual suspect in cholesterol metabolism: From GWAS identification to in vivo biochemical analyses, sortilin has been identified as a novel mediator of human lipoprotein metabolism. BioEssays. 2011;33:430–437.
  • Strong A, Rader DJ. Sortilin as a regulator of lipoprotein metabolism. Curr Atheroscler Rep. 2012;14:211–218.
  • Ogawa K, Ueno T, Iwasaki T, et al. Soluble sortilin is released by activated platelets and its circulating levels are associated with cardiovascular risk factors. Atherosclerosis. 2016;249:110–115.
  • Anbo G, Francisco SC, Xi C, et al. Implications of Sortilin in Lipid Metabolism and Lipid Disorder Diseases. Dna and cell bıo. 2017;36:1050–1061.
  • Musunuru K, Strong A, Frank-Kamenetsky M, et al. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature. 2010;466:714-719.
  • Kjolby M, Nielsen MS, Petersen CM. Sortilin, encoded by the cardiovascular risk gene SORT1, and its suggested functions in cardiovascular disease. Curr Atheroscler Rep. 2015;17: 496–505.
  • Patel KM, Strong A, Tohyama J, et al. Macrophage sortilin promotes LDL uptake, foam cell formation, and atherosclerosis. Circ Res. 2015;116:789–796.
  • Guo J, Luo YX, Tao LX, Guo X.H. Association between 1p13.3 genomic markers and coronary artery disease: a meta-analysis involving patients and controls. GMR. 2015;14:9092–9102.
  • Sparks CE, Sparks RP, Sparks JD. The enigmatic role of sortilin in lipoprotein metabolism. Curr Opin Lipidol. 2015;26:598–600.
  • World Medical Association World Medical Association Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. JAMA. 2013;310:2191–2194.
  • Excoffier L, Laval G, Schneider S. Arlequin ver. 3.0: An integrated software package for population genetics data analysis. Evolutionary Bioinformatics Online 1. 2005;47-50.
  • Strong A, Patel K, Rader DJ. Sortilin and lipoprotein metabolism: Making sense out of complexity. Curr Opin Lipidol. 2014;25:350-357.
  • Strong A, Ding Q, Edmondson AC, et al. Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism. J Clin Invest. 2012;122:2807-2816.
  • Tauris J , Ellgaard L, Jacobsen C, et al.The carboxy-terminal domain of the receptor-associated protein binds to the Vps10p domain of sortilin. FEBS Lett. 1998; 429: 27-30.
  • Mortensen MB, Kjolby M, Gunnersen S, et al. Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis. J Clin Invest. 2014;124(12):5317-5322.
  • Marcus EK, Wilfried R, Tanja BG, et al. Association of the single nucleotide polymorphism rs599839 in the vicinity of the sortilin 1 gene with LDL and triglyceride metabolism, coronary heart disease and myocardial infarction. The Ludwigshafen risk and cardiovascular health Study. Atherosclerosis. 2010;209:492–497.
  • Matsuoka R, Abe S, Tokoro F, et al. Association of six genetic variants with myocardial infarction. Int J Mol Med. 2015;35:1451–1459.
  • Yi-Jiang Z, Shao-Cai H, Qian Y, Rui-Xing Y, Xiao-Li C, Wu-Xian C. Association of variants in CELSR2-PSRC1-SORT1 with risk of serum lipid traits, coronary artery disease and ischemic stroke. Int J Clin Exp Pathol. 2015;8:9543–9551.
  • Juan F, Sánchez MT, Maria DR , et al. Multivariate analysis for coronary heart disease in heterozygote familial hypercholesterolemia patients. Per Med. 2018;15:87-92.
  • Hao H , Lingai P, Li Z, Yucheng C, Zhi Z. Association of single nucleotide polymorphism rs599839 on chromosome 1p13.3 with premature coronary heart disease in a Chinese Han population. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2008;25:686-689.
  • Willer CJ, Sanna S, Jackson AU, et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008;40:161–169.
  • Rizk NM, El Menya A, Egue H, et al. The association between serum LDL cholesterol and genetic variation in chromosomal locus 1p13.3 among coronary artery disease patients. BioMed Res Int. 2015;678924–36.
  • Linsel‐Nitschke P, Heeren J, Aherrahrou Z, et al. Genetic variation at chromosome 1p13.3 affects sortilin mRNA expression, cellular LDL‐uptake and serum LDL levels which translates to the risk of coronary artery disease. Atherosclerosis. 2009;08:183–189.
  • Eagle KA, Ginsburg GS, Musunuru K, et al. Identifying patients at high risk of a cardiovascular event in the near future: Current status and future directions: Report of a national heart, lung, and blood institute working group. Circulation. 2010;121:1447–1454.
  • Bruna G , Karin L, Max V, Shu Y, Ulf de F. Chromosome 1p13 genetic variants antagonize the risk of myocardial infarction associated with high ApoB serum levels. BMC Cardiovasc Disord. 2012;12:90.
  • Muendlein A, Geller-Rhomberg S, Saely CH, et al. Significant impact of chromosomal locus 1p13.3 on serum LDL cholesterol and on angiographically characterized coronary atherosclerosis. Atherosclerosis. 2009;206:494–499.
  • Walia GK, Gupta V, Aggarwal A,et al. Association of Common Genetic Variants with Lipid Traits in the Indian Population. PLoS One. 2014;9:e101688.
  • Nakayama K, Bayasgalan T, Yamanaka K et al. Jichi Community Genetics Team (JCOG) Large scale replication analysis of loci associated with lipid concentrations in a Japanese population. J Med Genet. 2009;46:370–374.
  • Zhou L, Ding H, Zhang X, et al. Genetic Variants at Newly Identified Lipid Loci Are Associated with Coronary Heart Disease in a Chinese Han Population. PLoS One. 2011;11:e27481.
  • Saleheen D, Soranzo N, Rasheed A, et al. Genetic determinants of major blood lipids in Pakistanis compared with Europeans. Circ Cardiovasc Genet. 2010;3(4):348-57.
  • Rodríguez-Arellano ME , Solares-Tlapechco J , Costa-Urrutia P, et al. Association of the PSRC1 rs599839 Variant with Coronary Artery Disease in a Mexican Population. Medicina (Kaunas). 2020;26:56(9):427.
  • Lu Y, Feskens EJ, Boer JM, et al. Exploring genetic determinants of plasma total cholesterol levels and their predictive value in a longitudinal study. Atherosclerosis. 2010; 213:200-215.
  • Zhou YJ, Hong SC, Yang Q, Yin RX, Cao XL, Chen WX. Association of variants in CELSR2-PSRC1-SORT1 with risk of serum lipid traits, coronary artery disease and ischemic stroke. Int J Clin Exp Pathol. 2015;8(8): 9543–9551.
Toplam 38 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Klinik Tıp Bilimleri
Bölüm Makaleler
Yazarlar

Ayşegül Başak Akadam-teker 0000-0003-3618-0560

Erhan Teker 0000-0002-0234-7548

Yayımlanma Tarihi 29 Ağustos 2022
Kabul Tarihi 9 Ağustos 2022
Yayımlandığı Sayı Yıl 2022 Sayı: 17

Kaynak Göster

JAMA Akadam-teker AB, Teker E. SORT1 rs599839 Polimorfizminin Lipit Profillerine Olan Etkisi: Tek Şehir Deneyimi. IGUSABDER. 2022;:369–380.

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