Skip to main content
SpringerLink
Log in

Functional Variants of Lipid Level Modifier MLXIPL, GCKR, GALNT2, CILP2, ANGPTL3 and TRIB1 Genes in Healthy Roma and Hungarian Populations

  • Research
  • Published:
Pathology & Oncology Research

Abstract

The role of triglyceride metabolism in different diseases, such as cardiovascular or cerebrovascular diseases is still under extensive investigations. In genome-wide studies several polymorphisms have been reported, which are highly associated with plasma lipid level changes. Our goal was to examine eight variants: rs12130333 at the ANGPTL3, rs16996148 at the CILP2, rs17321515 at the TRIB1, rs17145738 and rs3812316 of the MLXIPL, rs4846914 at GALNT2, rs1260326 and rs780094 residing at the GCKR loci. A total of 399 Roma (Gypsy) and 404 Hungarian population samples were genotyped using PCR-RFLP method. Significant differences were found between Roma and Hungarian population samples in both MLXIPL variants (C allele frequency of rs17145738: 94.1% vs. 85.6%, C allele frequency of rs3812316: 94.2% vs. 86.8% in Romas vs. in Hungarians, p < 0.05), in ANGPTL3 (T allele frequency of rs1213033: 12.2% vs. 18.5% in Romas vs. Hungarians, p < 0.05) and GALNT2 (G allele frequency of rs4846914: 46.6% vs. 54.5% Romas vs. in Hungarians, p < 0.05), while no differences over SNPs could be verified and the known minor alleles showed no correlation with triglyceride levels in any population samples. The current study revealed fundamental differences of known triglyceride modifying SNPs in Roma population. Failure of finding evidence for affected triglyceride metabolism shows that these susceptibility genes are much less effective compared for example to the apolipoprotein A5 gene.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Szalai C, Keszei M, Duba J, Prohaszka Z, Kozma GT, Csaszar A, Balogh S, Almassy Z, Fust G, Czinner A (2004) Polymorphism in the promoter region of the apolipoprotein A5 gene is associated with an increased susceptibility for coronary artery disease. Atherosclerosis 173(1):109–114

    Article  CAS  PubMed  Google Scholar 

  2. Vaessen SF, Schaap FG, Kuivenhoven JA, Groen AK, Hutten BA, Boekholdt SM, Hattori H, Sandhu MS, Bingham SA, Luben R, Palmen JA, Wareham NJ, Humphries SE, Kastelein JJ, Talmud PJ, Khaw KT (2006) Apolipoprotein A-V, triglycerides and risk of coronary artery disease: the prospective Epic-Norfolk Population Study. J Lipid Res 47(9):2064–2070

    Article  CAS  PubMed  Google Scholar 

  3. Martinelli N, Girelli D, Ferraresi P, Olivieri O, Lunghi B, Manzato F, Corrocher R, Bernardi F (2007) Increased factor VIII coagulant activity levels in male carriers of the factor V R2 polymorphism. Blood Coagul Fibrinolysis 18(2):125–129

    Article  CAS  PubMed  Google Scholar 

  4. Maasz A, Kisfali P, Jaromi L, Horvatovich K, Szolnoki Z, Csongei V, Safrany E, Sipeky C, Hadarits F, Melegh B (2008) Apolipoprotein A5 gene IVS3 + G476A allelic variant confers susceptibility for development of ischemic stroke. Circ J 72(7):1065–1070

    Article  CAS  PubMed  Google Scholar 

  5. Maasz A, Kisfali P, Szolnoki Z, Hadarits F, Melegh B (2008) Apolipoprotein A5 gene C56G variant confers risk for the development of large-vessel associated ischemic stroke. J Neurol 255(5):649–654

    Article  CAS  PubMed  Google Scholar 

  6. Feitosa MF, An P, Ordovas JM, Ketkar S, Hopkins PN, Straka RJ, Arnett DK, Borecki IB (2011) Association of gene variants with lipid levels in response to fenofibrate is influenced by metabolic syndrome status. Atherosclerosis 215(2):435–439

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Garelnabi M, Lor K, Jin J, Chai F, Santanam N (2012) The paradox of ApoA5 modulation of triglycerides: Evidence from clinical and basic research. Clin Biochem

  8. Mohas M, Kisfali P, Jaromi L, Maasz A, Feher E, Csongei V, Polgar N, Safrany E, Cseh J, Sumegi K, Hetyesy K, Wittmann I, Melegh B (2010) GCKR gene functional variants in type 2 diabetes and metabolic syndrome: do the rare variants associate with increased carotid intima-media thickness? Cardiovasc Diabetol 9:79

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Jaromi L, Csongei V, Polgar N, Szolnoki Z, Maasz A, Horvatovich K, Farago B, Sipeky C, Safrany E, Magyari L, Kisfali P, Mohas M, Janicsek I, Lakner L, Melegh B (2010) Functional variants of glucokinase regulatory protein and apolipoprotein A5 genes in ischemic stroke. J Mol Neurosci 41(1):121–128

    Article  CAS  PubMed  Google Scholar 

  10. Jaromi L, Csongei V, Polgar N, Rappai G, Szolnoki Z, Maasz A, Horvatovich K, Safrany E, Sipeky C, Magyari L, Melegh B (2011) Triglyceride level-influencing functional variants of the ANGPTL3, CILP2, and TRIB1 loci in ischemic stroke. Neuromolecular Med 13(3):179–186

    Article  CAS  PubMed  Google Scholar 

  11. Johansen CT, Hegele RA (2012) Allelic and phenotypic spectrum of plasma triglycerides. Biochim Biophys Acta 1821(5):833–842

    Article  CAS  PubMed  Google Scholar 

  12. Souverein OW, Jukema JW, Boekholdt SM, Zwinderman AH, Tanck MW (2005) Polymorphisms in APOA1 and LPL genes are statistically independently associated with fasting TG in men with CAD. Eur J Hum Genet 13(4):445–451

    Article  CAS  PubMed  Google Scholar 

  13. Havasi V, Szolnoki Z, Talian G, Bene J, Komlosi K, Maasz A, Somogyvari F, Kondacs A, Szabo M, Fodor L, Bodor A, Melegh B (2006) Apolipoprotein A5 gene promoter region T-1131C polymorphism associates with elevated circulating triglyceride levels and confers susceptibility for development of ischemic stroke. J Mol Neurosci 29(2):177–183

    Article  CAS  PubMed  Google Scholar 

  14. Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, Nordestgaard BG (2008) Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA 300(18):2142–2152

    Article  CAS  PubMed  Google Scholar 

  15. Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, Heath SC, Timpson NJ, Najjar SS, Stringham HM, Strait J, Duren WL, Maschio A, Busonero F, Mulas A, Albai G, Swift AJ, Morken MA, Narisu N, Bennett D, Parish S, Shen H, Galan P, Meneton P, Hercberg S, Zelenika D, Chen WM, Li Y, Scott LJ, Scheet PA, Sundvall J, Watanabe RM, Nagaraja R, Ebrahim S, Lawlor DA, Ben-Shlomo Y, Davey-Smith G, Shuldiner AR, Collins R, Bergman RN, Uda M, Tuomilehto J, Cao A, Collins FS, Lakatta E, Lathrop GM, Boehnke M, Schlessinger D, Mohlke KL, Abecasis GR (2008) Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 40(2):161–169

    Article  CAS  PubMed  Google Scholar 

  16. Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, Kaplan L, Bennett D, Li Y, Tanaka T, Voight BF, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt NP, Parish S, Clarke R, Zelenika D, Kubalanza KA, Morken MA, Scott LJ, Stringham HM, Galan P, Swift AJ, Kuusisto J, Bergman RN, Sundvall J, Laakso M, Ferrucci L, Scheet P, Sanna S, Uda M, Yang Q, Lunetta KL, Dupuis J, de Bakker PI, O’Donnell CJ, Chambers JC, Kooner JS, Hercberg S, Meneton P, Lakatta EG, Scuteri A, Schlessinger D, Tuomilehto J, Collins FS, Groop L, Altshuler D, Collins R, Lathrop GM, Melander O, Salomaa V, Peltonen L, Orho-Melander M, Ordovas JM, Boehnke M, Abecasis GR, Mohlke KL, Cupples LA (2009) Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 41(1):56–65

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Labreuche J, Touboul PJ, Amarenco P (2009) Plasma triglyceride levels and risk of stroke and carotid atherosclerosis: a systematic review of the epidemiological studies. Atherosclerosis 203(2):331–345

    Article  CAS  PubMed  Google Scholar 

  18. Perez-Martinez P, Garcia-Rios A, Delgado-Lista J, Perez-Jimenez F, Lopez-Miranda J (2011) Nutrigenetics of the postprandial lipoprotein metabolism: evidences from human intervention studies. Curr Vasc Pharmacol 9(3):287–291

    Article  CAS  PubMed  Google Scholar 

  19. Aslibekyan S, Goodarzi MO, Frazier-Wood AC, Yan X, Irvin MR, Kim E, Tiwari HK, Guo X, Straka RJ, Taylor KD, Tsai MY, Hopkins PN, Korenman SG, Borecki IB, Chen YD, Ordovas JM, Rotter JI, Arnett DK (2012) Variants identified in a GWAS meta-analysis for blood lipids are associated with the lipid response to fenofibrate. PLoS One 7(10):e48663

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Grundy SM (2002) Approach to lipoprotein management in 2001 National Cholesterol Guidelines. Am J Cardiol 90(8A):11i–21i

    Article  CAS  PubMed  Google Scholar 

  21. Brautbar A, Covarrubias D, Belmont J, Lara-Garduno F, Virani SS, Jones PH, Leal SM, Ballantyne CM (2011) Variants in the APOA5 gene region and the response to combination therapy with statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia. Atherosclerosis 219(2):737–742

    Article  CAS  PubMed  Google Scholar 

  22. Kisfali P, Mohas M, Maasz A, Hadarits F, Marko L, Horvatovich K, Oroszlan T, Bagosi Z, Bujtor Z, Gasztonyi B, Wittmann I, Melegh B (2008) Apolipoprotein A5 IVS3 + 476A allelic variant associates with increased trigliceride levels and confers risk for development of metabolic syndrome in Hungarians. Circ J 72(1):40–43

    Article  CAS  PubMed  Google Scholar 

  23. Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS, Wahlstrand B, Hedner T, Corella D, Tai ES, Ordovas JM, Berglund G, Vartiainen E, Jousilahti P, Hedblad B, Taskinen MR, Newton-Cheh C, Salomaa V, Peltonen L, Groop L, Altshuler DM, Orho-Melander M (2008) Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 40(2):189–197

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Shimizugawa T, Ono M, Shimamura M, Yoshida K, Ando Y, Koishi R, Ueda K, Inaba T, Minekura H, Kohama T, Furukawa H (2002) ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J Biol Chem 277(37):33742–33748

    Article  CAS  PubMed  Google Scholar 

  25. Seidelmann SB, Li L, Shen GQ, Topol EJ, Wang QK (2008) Identification of a novel locus for triglyceride on chromosome 1p31-32 in families with premature CAD and MI. J Lipid Res 49(5):1034–1038

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Izar MC, Fonseca FA, Ihara SS, Kasinski N, Sang WH, Lopes IE, Pinto Ldo E, Relvas WG, Lourenco D, Tufik S, de Paola AA, Carvalho AC (2003) Risk factors, biochemical markers, and genetic polymorphisms in early coronary artery disease. Arq Bras Cardiol 80(4):379–395

    Article  PubMed  Google Scholar 

  27. Thomsen SB, Rathcke CN, Skaaby T, Linneberg A, Vestergaard H (2012) The association between genetic variations of CHI3L1, levels of the encoded glycoprotein YKL-40 and the lipid profile in a Danish population. PLoS One 7(10):e47094

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Baroni MG, Berni A, Romeo S, Arca M, Tesorio T, Sorropago G, Di Mario U, Galton DJ (2003) Genetic study of common variants at the Apo E, Apo AI, Apo CIII, Apo B, lipoprotein lipase (LPL) and hepatic lipase (LIPC) genes and coronary artery disease (CAD): variation in LIPC gene associates with clinical outcomes in patients with established CAD. BMC Med Genet 4:8

    Article  PubMed Central  PubMed  Google Scholar 

  29. Meigs JB, Nathan DM, D’Agostino RB Sr, Wilson PW (2002) Fasting and postchallenge glycemia and cardiovascular disease risk: the Framingham offspring study. Diabetes Care 25(10):1845–1850

    Article  PubMed  Google Scholar 

  30. Pennacchio LA, Rubin EM (2003) Apolipoprotein A5, a newly identified gene that affects plasma triglyceride levels in humans and mice. Arterioscler Thromb Vasc Biol 23(4):529–534

    Article  CAS  PubMed  Google Scholar 

  31. Ma X, Bacci S, Mlynarski W, Gottardo L, Soccio T, Menzaghi C, Iori E, Lager RA, Shroff AR, Gervino EV, Nesto RW, Johnstone MT, Abumrad NA, Avogaro A, Trischitta V, Doria A (2004) A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians. Hum Mol Genet 13(19):2197–2205

    Article  CAS  PubMed  Google Scholar 

  32. Saidi S, Slamia LB, Ammou SB, Mahjoub T, Almawi WY (2007) Association of apolipoprotein E gene polymorphism with ischemic stroke involving large-vessel disease and its relation to serum lipid levels. J Stroke Cerebrovasc Dis 16(4):160–166

    Article  PubMed  Google Scholar 

  33. Moorjani P, Patterson N, Loh P, Lipson M, Kisfali P, Melegh B, Bonin M, Kádaši L, Rieß O, Berger B, Reich D, Melegh B (2013) Reconstructing Roma history from genome-wide data. . American Journal of Human Genetics

  34. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16(3):1215

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Martinelli N, Trabetti E, Bassi A, Girelli D, Friso S, Pizzolo F, Sandri M, Malerba G, Pignatti PF, Corrocher R, Olivieri O (2007) The −1131 T > C and S19W APOA5 gene polymorphisms are associated with high levels of triglycerides and apolipoprotein C-III, but not with coronary artery disease: an angiographic study. Atherosclerosis 191(2):409–417

    Article  CAS  PubMed  Google Scholar 

  36. Vaxillaire M, Cavalcanti-Proenca C, Dechaume A, Tichet J, Marre M, Balkau B, Froguel P (2008) The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population. Diabetes 57(8):2253–2257

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Hishida A, Morita E, Naito M, Okada R, Wakai K, Matsuo K, Nakamura K, Takashima N, Suzuki S, Takezaki T, Mikami H, Ohnaka K, Watanabe Y, Uemura H, Kubo M, Tanaka H, Hamajima N (2012) Associations of apolipoprotein A5 (APOA5), glucokinase (GCK) and glucokinase regulatory protein (GCKR) polymorphisms and lifestyle factors with the risk of dyslipidemia and dysglycemia in Japanese—a cross-sectional data from the J-MICC Study. Endocr J 59(7):589–599

    Article  CAS  PubMed  Google Scholar 

  38. Dussaillant C, Serrano V, Maiz A, Eyheramendy S, Cataldo LR, Chavez M, Smalley SV, Fuentes M, Rigotti A, Rubio L, Lagos CF, Martinez JA, Santos JL (2012) APOA5 Q97X mutation identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family. BMC Med Genet 13:106

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Warner JP, Leek JP, Intody S, Markham AF, Bonthron DT (1995) Human glucokinase regulatory protein (GCKR): cDNA and genomic cloning, complete primary structure, and chromosomal localization. Mamm Genome 6(8):532–536

    Article  CAS  PubMed  Google Scholar 

  40. Hayward BE, Dunlop N, Intody S, Leek JP, Markham AF, Warner JP, Bonthron DT (1998) Organization of the human glucokinase regulator gene GCKR. Genomics 49(1):137–142

    Article  CAS  PubMed  Google Scholar 

  41. Orho-Melander M, Melander O, Guiducci C, Perez-Martinez P, Corella D, Roos C, Tewhey R, Rieder MJ, Hall J, Abecasis G, Tai ES, Welch C, Arnett DK, Lyssenko V, Lindholm E, Saxena R, de Bakker PI, Burtt N, Voight BF, Hirschhorn JN, Tucker KL, Hedner T, Tuomi T, Isomaa B, Eriksson KF, Taskinen MR, Wahlstrand B, Hughes TE, Parnell LD, Lai CQ, Berglund G, Peltonen L, Vartiainen E, Jousilahti P, Havulinna AS, Salomaa V, Nilsson P, Groop L, Altshuler D, Ordovas JM, Kathiresan S (2008) Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations. Diabetes 57(11):3112–3121

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Rafiq S, Venkata KK, Gupta V, Guru VD, Spurgeon CJ, Parameshwaran S, Madana SN, Kinra S, Bowen L, Timpson NJ, Smith GD, Dudbridge F, Prabhakaran D, Ben-Shlomo Y, Reddy KS, Ebrahim S, Chandak GR (2012) Evaluation of seven common lipid associated loci in a large Indian sib pair study. Lipids Health Dis 11(1):155

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Veiga-da-Cunha M, Delplanque J, Gillain A, Bonthron DT, Boutin P, Van Schaftingen E, Froguel P (2003) Mutations in the glucokinase regulatory protein gene in 2p23 in obese French caucasians. Diabetologia 46(5):704–711

    CAS  PubMed  Google Scholar 

  44. Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R, Dykas DJ, Bale AE, Giannini C, Pierpont B, Shaw MM, Groop L, Caprio S (2012) Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 55(3):781–789

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Pisciotta L, Favari E, Magnolo L, Simonelli S, Adorni MP, Sallo R, Fancello T, Zavaroni I, Ardigo D, Bernini F, Calabresi L, Franceschini G, Tarugi P, Calandra S, Bertolini S (2012) Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3. Circ Cardiovasc Genet 5(1):42–50

    Article  CAS  PubMed  Google Scholar 

  46. Liu Y, Zhou D, Zhang Z, Song Y, Zhang D, Zhao T, Chen Z, Sun Y, Yang Y, Xing Q, Zhao X, Xu H, He L (2010) Effects of genetic variants on lipid parameters and dyslipidemia in a Chinese population. J Lipid Res 52(2):354–360

    Article  PubMed  Google Scholar 

  47. Vrablik M, Hubacek JA, Dlouha D, Lanska V, Rynekrova J, Zlatohlavek L, Prusikova M, Ceska R, Adamkova V (2012) Impact of variants within seven candidate genes on statin treatment efficacy. Physiol Res

  48. Tai ES, Sim XL, Ong TH, Wong TY, Saw SM, Aung T, Kathiresan S, Orho-Melander M, Ordovas JM, Tan JT, Seielstad M (2009) Polymorphisms at newly identified lipid-associated loci are associated with blood lipids and cardiovascular disease in an Asian Malay population. J Lipid Res 50(3):514–520

    Article  CAS  PubMed  Google Scholar 

  49. Maasz A, Kisfali P, Horvatovich K, Mohas M, Marko L, Csongei V, Farago B, Jaromi L, Magyari L, Safrany E, Sipeky C, Wittmann I, Melegh B (2007) Apolipoprotein A5 T-1131C variant confers risk for metabolic syndrome. Pathol Oncol Res 13(3):243–247

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Study was supported by the grant of Hungarian Science Foundation OTKA K103983 and T73430.

Conflict of Interests

The authors declare that they have no conflict of interests related to this manuscript.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, Clinical Centre, University of Pecs, Szigeti u. 12, Pecs, H-7624, Hungary

    Katalin Sumegi, Luca Jaromi, Lili Magyari, Erzsebet Kovesdi, Balazs Duga, Renata Szalai, Anita Maasz, Petra Matyas, Ingrid Janicsek & Bela Melegh

  2. Szentágothai Research Centre, University of Pecs, Ifjusag u. 20, Pecs, H-7624, Hungary

    Katalin Sumegi, Luca Jaromi, Lili Magyari, Erzsebet Kovesdi, Balazs Duga & Bela Melegh

Authors
  1. Katalin Sumegi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luca Jaromi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lili Magyari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Erzsebet Kovesdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Balazs Duga
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Renata Szalai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anita Maasz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Petra Matyas
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ingrid Janicsek
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bela Melegh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bela Melegh.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sumegi, K., Jaromi, L., Magyari, L. et al. Functional Variants of Lipid Level Modifier MLXIPL, GCKR, GALNT2, CILP2, ANGPTL3 and TRIB1 Genes in Healthy Roma and Hungarian Populations. Pathol. Oncol. Res. 21, 743–749 (2015). https://doi.org/10.1007/s12253-014-9884-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-014-9884-5

Keywords

Search

Navigation