Abstract
Objective To test the hypothesis that the identification of mutation in the carboxypeptidase E (CPE) gene which leads to marked hyperproinsulinaemia is consistent with a possible role for mutations in CPE in the development of coronary heart disease. Methods The study subjects consisted of 51 consecutive patients (34 males and 17 females) who will undergo coronary angiography for suspected or known coronary atherosclerosis. Coronary heart disease (CHD) was defined as having a luminal diameter stenosis ≥50% in at least one of three major coronary arteries by coronary angiography or based on the Rose Questionnaire. The insulin and proinsulin level were measured using highly sensitive two-site sandwich ELISA methods. Screening for mutations of the eight exons of the CPE gene was performed by polymerase chain reaction followed by bidirectional sequencing. Results We scanned eight exons and exon–intron junctional region. Overall, we found 12 distinct variants in the intron region and three variants in the exon region. Among the 15 variants, 10 mutations were rare. The further explored study reveal that the above five non-rare variants would not affect the level of glucose, insulin, and proinsulin. However, the results suggest that the prevalence of the coronary heart disease was significant difference between the wild type group and mutant type group according to the A4545G (P = 0.020). The results from the logistic regression reveal that the subjects with the CPE mutation of A4545G, the odds ratio for the coronary heart disease was 0.196 (95% CI: 0.046 to 0.830, P = 0.027). Conclusions In the present study, the mutation of CPE gene would not affect the level of glucose, insulin, and proinsulin. The hypothesis of a possible role for mutations in CPE in the development of coronary heart disease needs further study.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Chen H, Jawahar S, Qian Y et al (2001) Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity. Hum Mutat 18(2):120–131
Davies MJ, Rayman G, Gray IP et al (1993) Insulin deficiency and increased plasma concentration of intact and 32/33 split proinsulin in subjects with impaired glucose tolerance. Diabet Med 10(4):313–320
Ward WK, LaCava EC, Paquette TL et al (1987) Disproportionate elevation of immunoreactive proinsulin in type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance. Diabetologia 30(9):698–702
Naggert JK, Fricker LD, Varlamov O et al (1995) Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nature Genet 10:135–142
Yudkin JS, May M, Elwood P et al (2002) Concentrations of proinsulin like molecules predict coronary heart disease risk independently of insulin: prospective data from the Caerphilly Study. Diabetologia 45(3):327–336
Zethelius B, Byberg L, Hales CN et al (2002) Proinsulin is an independent predictor of coronary heart disease: report from a 27-year follow-up study. Circulation 105(18):2153–2158
Zethelius B, Lithell H, Hales CN et al (2005) Insulin sensitivity, proinsulin and insulin as predictors of coronary heart disease. A population-based 10-year, follow-up study in 70-year old men using the euglycaemic insulin clamp. Diabetologia 48(5):862–867
Lindahl B, Dinesen B, Eliasson M et al (1999) High proinsulin concentration precedes acute myocardial infarction in a nondiabetic population. Metabolism 48(9):1197–1202
Lindahl B, Dinesen B, Eliasson M et al (2000) High proinsulin levels precede first-ever stroke in a nondiabetic population. Stroke 31(12):2936–2941
Judkins MP (1967) A percutaneous transfemoral technique. Radiology 89:815–821
Gensini GG (1983) A more meaningful scoring system for determinating the severity of coronary heart disease. Am J Cardiol 51:606
Andersen L, Dinesen B, Jørgensen PN et al (1993) Enzyme immunoassay for intact human insulin in serum or plasma. Clin Chem 39:578–582
Wolk R, Berger P, Lennon RJ et al (2003) Body mass index: a risk factor for unstable angina and myocardial infarction in patients with angiographically confirmed coronary artery disease. Circulation 108:2206–2211
Rose GA (1962) The diagnosis of ischemic heart pain and claudication in field survey. Bull WHO 27:645–658
Fricker LD (1991) Peptide processing exopeptidases: amino and cardoxypeptidases involved with peptide biosynthesis. In: Fricker LD (ed) Peptide biosynthesis and processing. CRC Press, Boca Raton, 199–228
Williams SV, Jones TA, Cottrell S et al (1991) Fine mapping of probes in the adenomatous polyposis coli region of chromosome 5 by in situ hybridization. Genes Chromosomes Cancer 3(5):382–389
Cool DR, Normant E, Shen F et al (1997) Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice. Cell 88(1):73–83
Utsunomiya N, Ohagi S, Sanke T et al (1998) Organization of the human carboxypeptidase E gene and molecular scanning for mutations in Japanese subjects with NIDDM or obesity. Diabetologia 41(6):701–705
Chen H, Jawahar S, Qian Y et al (2001) Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity. Hum Mutat 18(2):120–131
Acknowledgments
Special thanks to Dr. Lennart Andersen, Dr. Jens Christian Wortmann, and Dr. Thomas Peter Dyrberg, at Novo Nordisk, Bagsvaerd, Denmark, for providing the free monoclonal antibodies including OXI-005, HUI-018, PEP-001 and HUI-001. This study was supported by the National Natural Science Foundation of China, No. 30400173 to Dr. Enzhi Jia.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Jia, EZ., Wang, J., Yang, ZJ. et al. Molecular scanning of the human carboxypeptidase E gene for mutations in Chinese subjects with coronary atherosclerosis. Mol Cell Biochem 307, 31–39 (2008). https://doi.org/10.1007/s11010-007-9581-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-007-9581-8