Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study

KURNAZ GÖMLEKSİZ, Özlem; ÇOŞKUNPINAR, Ender; KANCA, Deniz; Ozkara, Gulcin; ÖZTÜRK, OĞUZ; YILMAZ AYDOĞAN, Hülya; DEMİRCAN, Aslıhan; Buğra, Zehra; Yanar, Fatih

doi:10.1515/tjb-2018-0546

Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study

Aslıhan DEMİRCAN, (İstanbul Üniversitesi, Aziz Sancar Deneysel Tıp Enstitüsü, Moleküler Tıp Anabilim Dalı, İstanbul, Türkiye)

Ender ÇOŞKUNPINAR, (İstanbul Üniversitesi, Aziz Sancar Deneysel Tıp Enstitüsü, Moleküler Tıp Anabilim Dalı, İstanbul, Türkiye)

Deniz KANCA, (İstanbul Üniversitesi, Aziz Sancar Deneysel Tıp Enstitüsü, Moleküler Tıp Anabilim Dalı, İstanbul, Türkiye)

Gülçin ÖZKARA, (İstanbul Üniversitesi, Aziz Sancar Deneysel Tıp Enstitüsü, Moleküler Tıp Anabilim Dalı, İstanbul, Türkiye)

Fatih YANAR, (İstanbul Üniversitesi, Aziz Sancar Deneysel Tıp Enstitüsü, Moleküler Tıp Anabilim Dalı, İstanbul, Türkiye)

Özlem KURNAZ GÖMLEKSİZ, (Altınbaş Üniversitesi, Tıp Fakültesi, Tıbbi Biyoloji Anabilim Dalı, İstanbul, Türkiye)

Zehra BUĞRA, (İstanbul Üniversitesi, İstanbul Tıp Fakültesi, Kardiyoloji Anabilim Dalı, İstanbul, Türkiye)

Oğuz ÖZTÜRK, (İstanbul Üniversitesi, Aziz Sancar Deneysel Tıp Enstitüsü, Moleküler Tıp Anabilim Dalı, İstanbul, Türkiye)

Hülya YILMAZ AYDOĞAN (İstanbul Üniversitesi, Aziz Sancar Deneysel Tıp Enstitüsü, Moleküler Tıp Anabilim Dalı, İstanbul, Türkiye)

Türk Biyokimya Dergisi

3 1

Yıl: 2019 Cilt: 44 Sayı: 6 Sayfa Aralığı: 822 - 830 Metin Dili: İngilizce DOI: 10.1515/tjb-2018-0546 İndeks Tarihi: 06-06-2020

Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study

Öz:

Objective: Fatty acid β-oxidation defects can lead to difficulties at covering energy requirement of heart. Thecarnitine-shuttle is responsible for the transfering oflong-chain fatty acids from the internal mitochondrialmembrane. The role of genetic variants of the enzymes inthe carnitine shuttle in coronary artery disease (CAD) hasnot been studied. Therefore, we performed a case-controlstudy investigating the possible relation between theCPTIA-rs3019613 and CROT-rs2214930 gene variationslocated carnitine shuttle and CAD risk.Materials and methods: Study groups were comprisedof 96 CAD patients and 85 controls. CPTIA-rs3019613G > A and CROT-rs2214930 T > C polymorphisms weredetermined by real-time-PCR.Results: The CROT-rs2214930-CC genotype was found tobe associated with decreased HDL-cholesterol (HDL-C) incontrols (p = 0.029). In patients with CPTIA-rs3019613-Aallele, body mass index (BMI) (p = 0.016) and BMI threshold-value (p = 0.030) were found be higher compared tothose with GG-genotype, while HDL-C threshold-value(HDL-C ≤ 0.90 mmol/L) was found to be lower (p = 0.015).Regression analysis confirmed CPTIA-rs3019613-A allelehas a significant relationship with decreased HDL-C(p = 0.009) in patients.Conclusion: Our study indicated that the polymorphismsof the CROT and CPTIA genes related to β-oxidation oflong-chain fatty acids had an important effect on serumHDL-C levels and may be a potential risk for CAD.

Anahtar Kelime:

Koroner arter hastalığında karnitin mekiği CPTIA ve CROT genlerinde genetik varyasyonlarının rolü: Vaka – kontrol çalışması

Öz:

maç: Yağ asit β oksidasyonundaki defektler kardiyovasküler problemlere ve kalbin ihtiyacı olan enerjinin karşılanmasında güçlüklere yol açabilir. Karnitin mekiği, uzun zincirli yağ asitlerinin iç mitokondriyal zardan transferinden sorumludur. Koroner arter hastalığında (KAH) karnitin mekiğindeki enzimlerin genetik varyantlarının rolü henüz çalışılmamıştır. Bu nedenle karnitin mekiğinde yer alan CPTIA rs3019613 G > A ve CROT rs2214930 T > C gen varyasyonları ile KAH riski arasındaki olası ilişkiyi araştıran bir vaka kontrol çalışması yaptık. Gereç ve yöntem: Çalışma grupları 96 KAH hastası ve 85 kontrolden oluşturulmuştur. CPTIA rs3019613-G > A ve CROT rs2214930 T > C polimorfizmleri gerçek zamanlı PZR ile tespit edilmiştir. Bulgular: Kontrol grubunda CROT rs2214930 CC genotipi düşük HDL-Kolesterol (HDL-K) düzeyleri ile ilişkili bulunmuştur (p = 0.029). CPTIA rs3019613 A aleli olan hastalarda GG genotipli olanlara göre, vücut kitle indeksi (VKİ) (p = 0.016) ve VKİ eşik değeri (p = 0.030) daha yüksek iken, HDL-K eşik değeri (HDL-C ≤ 0.90 mmol/1) daha düşük bulundu (p = 0.015). Regresyon analizi, CPTIA rs3019613 A alelinin, hastalarda azalmış HDL-K (p = 0.009) ile ilişkisini doğrulamıştır. Sonuç: Çalışmamız uzun-zincirli yağ asitlerinin β oksidasyonu ile ilişkili olan CROT ve CPTIA gen polimorfizmlerinin serum HDL-K düzeylerine önemli etkisi olduğunu ve KAH için potansiyel risk olabileceğine işaret etmektedir.

Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

1. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev 2010;90:207–58.
2. Young ME, Guthrie PH, Razeghi P, Leighton B, Abbasi S, Patil S, et al. Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese zucker rat heart. Diabetes 2002;51:2587–95.
3. Sharma S, Adrogue JV, Golfman L, Uray I, Lemm J, Youker K, et al. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J 2004;18:1692–700.
4. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, et al. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA 2000;97:1784–9.
5. Essop MF, Camp HS, Choi CS, Sharma S, Fryer RM, Reinhart GA, et al. Reduced heart size and increased myocardial fuel substrate oxidation in ACC2 mutant mice. Am J Physiol Heart Circ Physiol 2008;295:H256–65.
6. Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 2006;142:77–85.
7. Bonnefont JP, Djouadi F, Prip-Buus C, Gobin S, Munnich A, Bastin J. Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol Aspects Med 2004;25:495–520.
8. Lemas DJ, Wiener HW, O’Brien DM, Hopkins S, Stanhope KL, Havel PJ, et al. Genetic polymorphisms in carnitine palmitoyltransferase 1A gene are associated with variation in body composition and fasting lipid traits in Yup’ik Eskimos. J Lipid Res 2012;53:175–84.
9. Van der Leij FR, Huijkman NC, Boomsma C, Kuipers JR, Bartelds B. Genomics of the human carnitine acyltransferase genes. Mol Genet Metab 2000;71:139–53.
10. Rao JN, Warren GZ, Estolt-Povedano S, Zammit VA, Ulmer TS. An environment-dependent structural switch underlies the regulation of carnitine palmitoyltransferase 1A. J Biol Chem 2011;286:42545–54.
11. Nyman LR, Cox KB, Hoppel CL, Kerner J, Barnoski BL, Hamm DA, et al. Homozygous carnitine palmitoyltransferase 1a (liver isoform) deficiency is lethal in the mouse. Mol Genet Metab 2005;86:179–87.
12. Ji S, You Y, Kerner J, Hoppel CL, Schoeb TR, Chick WS, et al. Homozygous carnitine palmitoyltransferase 1b (muscle isoform) deficiency is lethal in the mouse. Mol Genet Metab 2008;93:314–22.
13. Gao X, Li K, Hui X, Kong X, Sweeney G, Wang Y, et al. Carnitine palmitoyltransferase 1A prevents fatty acid-induced adipocyte dysfunction through suppression of c-Jun N-terminal kinase. Biochem J 2011;435:723–32.
14. Zhang L, Keung W, Samokhvalov V, Wang W, Lopaschuk GD. Role of fatty acid uptake and fatty acid β-oxidation in mediating insulin resistance in heart and skeletal muscle. BBA–Mol Cell Biol Lipids 2010;1801:1–22.
15. Robitaille J, Houde A, Lemieux S, Pérusse L, Gaudet D, Vohl MC. Variants within the muscle and liver isoforms of the carnitine palmitoyltransferase I (CPT1) gene interact with fat intake to modulate indices of obesity in French-Canadians. J Mol Med 2007;85:129–37.
16. Rajakumar C, Ban MR, Cao H, Young TK, Bjerregaard P, Hegele RA. Carnitine palmitoyltransferase IA polymorphism P479L is common in Greenland Inuit and is associated with elevated plasma apolipoprotein A-I. J Lipid Res 2009;50:1223–8.
17. Martin MA, Gomez MA, Guillen F, Bornstein B, Campos Y, Rubio JC, et al. Myocardial carnitine and carnitine palmitoyltransferase deficiencies in patients with severe heart failure. Biochim Biophys Acta 2000;1502:330–6.
18. Beltrame JF, Dreyer R, Tavella R. Epidemiology of coronary artery disease, coronary artery disease-current concepts in epidemiology, pathophysiology, diagnostics and treatment, Dr. David Gaze (ED.), ISBN: 978-953-51-0262-5, 2012.
19. Lusis AJ. Atherosclerosis. Nature 2000;407:233–41.
20. Crowther MA. Pathogenesis of atherosclerosis. Hematol Am Soc Hematol Educ Program 2005;2005:436–41.
21. Fillmore N, Mori J, Lopaschuk GD. Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy. Br J Pharmacol 2014;171: 2080–90.
22. He L, Kim T, Long Q, Liu J, Wang P, Zhou Y, et al. Carnitine palmitoyltransferase-1b deficiency aggravates pressure overload– induced cardiac hypertrophy caused by lipotoxicity. Circulation 2012;126:1705–16.
23. Hirota Y, Ohara T, Zenibayashi M, Kuno S, Fukuyama K, Teranishi T, et al. Lack of association of CPT1A polymorphisms or haplotypes on hepatic lipid content or insulin resistance in Japanese individuals with type 2 diabetes mellitus. Metabolism 2007;56:656–61.

APA	DEMİRCAN A, ÇOŞKUNPINAR E, KANCA D, Ozkara G, Yanar F, KURNAZ GÖMLEKSİZ Ö, Buğra Z, ÖZTÜRK O, YILMAZ AYDOĞAN H (2019). Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study. , 822 - 830. 10.1515/tjb-2018-0546
Chicago	DEMİRCAN Aslıhan,ÇOŞKUNPINAR Ender,KANCA Deniz,Ozkara Gulcin,Yanar Fatih,KURNAZ GÖMLEKSİZ Özlem,Buğra Zehra,ÖZTÜRK OĞUZ,YILMAZ AYDOĞAN Hülya Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study. (2019): 822 - 830. 10.1515/tjb-2018-0546
MLA	DEMİRCAN Aslıhan,ÇOŞKUNPINAR Ender,KANCA Deniz,Ozkara Gulcin,Yanar Fatih,KURNAZ GÖMLEKSİZ Özlem,Buğra Zehra,ÖZTÜRK OĞUZ,YILMAZ AYDOĞAN Hülya Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study. , 2019, ss.822 - 830. 10.1515/tjb-2018-0546
AMA	DEMİRCAN A,ÇOŞKUNPINAR E,KANCA D,Ozkara G,Yanar F,KURNAZ GÖMLEKSİZ Ö,Buğra Z,ÖZTÜRK O,YILMAZ AYDOĞAN H Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study. . 2019; 822 - 830. 10.1515/tjb-2018-0546
Vancouver	DEMİRCAN A,ÇOŞKUNPINAR E,KANCA D,Ozkara G,Yanar F,KURNAZ GÖMLEKSİZ Ö,Buğra Z,ÖZTÜRK O,YILMAZ AYDOĞAN H Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study. . 2019; 822 - 830. 10.1515/tjb-2018-0546
IEEE	DEMİRCAN A,ÇOŞKUNPINAR E,KANCA D,Ozkara G,Yanar F,KURNAZ GÖMLEKSİZ Ö,Buğra Z,ÖZTÜRK O,YILMAZ AYDOĞAN H "Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study." , ss.822 - 830, 2019. 10.1515/tjb-2018-0546
ISNAD	DEMİRCAN, Aslıhan vd. "Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study". (2019), 822-830. https://doi.org/10.1515/tjb-2018-0546

APA	DEMİRCAN A, ÇOŞKUNPINAR E, KANCA D, Ozkara G, Yanar F, KURNAZ GÖMLEKSİZ Ö, Buğra Z, ÖZTÜRK O, YILMAZ AYDOĞAN H (2019). Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study. Türk Biyokimya Dergisi, 44(6), 822 - 830. 10.1515/tjb-2018-0546
Chicago	DEMİRCAN Aslıhan,ÇOŞKUNPINAR Ender,KANCA Deniz,Ozkara Gulcin,Yanar Fatih,KURNAZ GÖMLEKSİZ Özlem,Buğra Zehra,ÖZTÜRK OĞUZ,YILMAZ AYDOĞAN Hülya Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study. Türk Biyokimya Dergisi 44, no.6 (2019): 822 - 830. 10.1515/tjb-2018-0546
MLA	DEMİRCAN Aslıhan,ÇOŞKUNPINAR Ender,KANCA Deniz,Ozkara Gulcin,Yanar Fatih,KURNAZ GÖMLEKSİZ Özlem,Buğra Zehra,ÖZTÜRK OĞUZ,YILMAZ AYDOĞAN Hülya Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study. Türk Biyokimya Dergisi, vol.44, no.6, 2019, ss.822 - 830. 10.1515/tjb-2018-0546
AMA	DEMİRCAN A,ÇOŞKUNPINAR E,KANCA D,Ozkara G,Yanar F,KURNAZ GÖMLEKSİZ Ö,Buğra Z,ÖZTÜRK O,YILMAZ AYDOĞAN H Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study. Türk Biyokimya Dergisi. 2019; 44(6): 822 - 830. 10.1515/tjb-2018-0546
Vancouver	DEMİRCAN A,ÇOŞKUNPINAR E,KANCA D,Ozkara G,Yanar F,KURNAZ GÖMLEKSİZ Ö,Buğra Z,ÖZTÜRK O,YILMAZ AYDOĞAN H Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study. Türk Biyokimya Dergisi. 2019; 44(6): 822 - 830. 10.1515/tjb-2018-0546
IEEE	DEMİRCAN A,ÇOŞKUNPINAR E,KANCA D,Ozkara G,Yanar F,KURNAZ GÖMLEKSİZ Ö,Buğra Z,ÖZTÜRK O,YILMAZ AYDOĞAN H "Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study." Türk Biyokimya Dergisi, 44, ss.822 - 830, 2019. 10.1515/tjb-2018-0546
ISNAD	DEMİRCAN, Aslıhan vd. "Role of SNPs of CPTIA and CROT genes in the carnitine-shuttle in coronary artery disease: a case-control study". Türk Biyokimya Dergisi 44/6 (2019), 822-830. https://doi.org/10.1515/tjb-2018-0546