Abstract
PARL (presenilin-associated rhomboid-like) is a mitochondrial protein involved in mitochondrial membrane remodelling, and maps to a quantitative trait locus (3q27) associated with metabolic traits. Recently the rs3732581 (Leu262Val) variant was found to be associated with increased levels of plasma insulin, a finding not replicated in a larger cohort. The aim of the current study was to investigate the associations between rs3732581 and levels of plasma insulin, metabolic syndrome (MetS) and its components, and cardiovascular disease. The CUPID population consisted of 556 subjects with angiographically proven CAD and the CUDAS cohort consisted of 1,109 randomly selected individuals from Perth, Western Australia. Samples were genotyped using mutation-specific PCR. No significant associations were observed between rs3732581 and levels of plasma insulin, glucose, BMI or MetS in either population. However, carriers of the minor allele had significantly lower mean intima-media thickness (IMT) [0.69 mm, 95% CI (0.69, 0.70 mm); P = 0.004], compared with major allele homozygotes [mean IMT = 0.71 mm, 95% CI (0.70, 0.72 mm)] in the CUDAS population. Further analysis using a recessive model showed homozygous carriers of the minor allele were predisposed to CAD [OR 1.55, 95% CI (1.11, 2.16); P = 0.01]. Despite the functional evidence for a role of PARL in regulating insulin levels, no association with rs3732581 was found in the current study. Additionally, there were no associations with glucose levels, BMI or MetS. There were significant effects of the variant on mean IMT and risk of CAD. A role for PARL in metabolic conditions cannot be excluded and more comprehensive genetic studies are warranted.
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References
Anonymous (2001) Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). J Am Med Assoc 285:2486–2497
Chapman CM, Palmer LJ, McQuillan BM, Hung J, Burley J, Hunt C, Thompson PL, Beilby JP (2001) Polymorphisms in the angiotensinogen gene are associated with carotid intimal-medial thickening in females from a community-based population. Atherosclerosis 159:209–217
Cipolat S, Rudka T, Hartmann D, Costa V, Serneels L, Craessaerts K, Metzger K, Frezza C, Annaert W, D’Adamio L, Derks C, Dejaegere T, Pellegrini L, D’Hooge R, Scorrano L, De Strooper B (2006) Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 126:163–175
Civitarese AE, Ravussin E (2008) Minireview: mitochondrial energetics and insulin resistance. Endocrinology 149:950–954
Dupont WD, Plummer WD (1997) PS power and sample size program available for free on the Internet. Control Clin Trials 18:274
Fawcett KA, Wareham NJ, Luan J, Syddall H, Cooper C, O’Rahilly S, Day IN, Sandhu MS, Barroso I (2006) PARL Leu262Val is not associated with fasting insulin levels in UK populations. Diabetologia 49:2649–2652
Gensini GG (1983) A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 51:606
Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC Jr, Spertus JA, Costa F (2005) Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Executive summary. Cardiol Rev 13:322–327
Jeyaraju DV, Xu L, Letellier MC, Bandaru S, Zunino R, Berg EA, McBride HM, Pellegrini L (2006) Phosphorylation and cleavage of presenilin-associated rhomboid-like protein (PARL) promotes changes in mitochondrial morphology. Proc Natl Acad Sci USA 103:18562–18567
Kim JY, Hickner RC, Cortright RL, Dohm GL, Houmard JA (2000) Lipid oxidation is reduced in obese human skeletal muscle. Am J Physiol Endocrinol Metab 279:E1039–E1044
Kissebah AH, Sonnenberg GE, Myklebust J, Goldstein M, Broman K, James RG, Marks JA, Krakower GR, Jacob HJ, Weber J, Martin L, Blangero J, Comuzzie AG (2000) Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci USA 97:14478–14483
Lupi R, Del Prato S (2008) Beta-cell apoptosis in type 2 diabetes: quantitative and functional consequences. Diabetes Metab 34:S56–S64
Mallat Z, Tedgui A (2000) Apoptosis in the vasculature: mechanisms and functional importance. Br J Pharmacol 130:947–962
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419
McCaskie PA, Cadby G, Hung J, McQuillan BM, Chapman CM, Carter KW, Thompson PL, Palmer LJ, Beilby JP (2006a) The C-480T hepatic lipase polymorphism is associated with HDL-C but not with risk of coronary heart disease. Clin Genet 70:114–121
McCaskie PA, Carter KW, Palmer LJ (2006) SimHap: a comprehensive modelling framework and a simulation-based approach to haplotypic analysis of population-based data. http://www.genepi.org.au/simhap. Accessed 31 May 2007
McCullagh P, Nelder J (1989) Generalised linear models. Chapman and Hall, London
McQuibban GA, Saurya S, Freeman M (2003) Mitochondrial membrane remodelling regulated by a conserved rhomboid protease. Nature 423:537–541
McQuillan BM, Beilby JP, Nidorf M, Thompson PL, Hung J (1999) Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening. The perth carotid ultrasound disease assessment study (CUDAS). Circulation 99:2383–2388
Pellegrini L, Passer BJ, Canelles M, Lefterov I, Ganjei JK, Fowlkes BJ, Koonin EV, D’Adamio L (2001) PAMP and PARL, two novel putative metalloproteases interacting with the COOH-terminus of Presenilin-1 and -2. J Alzheimers Dis 3:181–190
Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI (2003) Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300:1140–1142
Purcell S, Cherny SS, Sham PC (2003) Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19:149–150
Reaven GM (1995) Pathophysiology of insulin resistance in human disease. Physiol Rev 75:473–486
Rolo AP, Palmeira CM (2006) Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol 212:167–178
Semenkovich CF (2006) Insulin resistance and atherosclerosis. J Clin Invest 116:1813–1822
Walder K, Kerr-Bayles L, Civitarese A, Jowett J, Curran J, Elliott K, Trevaskis J, Bishara N, Zimmet P, Mandarino L, Ravussin E, Blangero J, Kissebah A, Collier GR (2005) The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes. Diabetologia 48:459–468
Zimmet P, Magliano D, Matsuzawa Y, Alberti G, Shaw J (2005) The metabolic syndrome: a global public health problem and a new definition. J Atheroscler Thromb 12:295–300
Acknowledgments
This study was funded by the National Heart Foundation grant-in-aid G97P 5002. BLP was supported by a National Health and Medical Research Council Howard Florey Centenary Fellowship (Grant ID: 404129). KWC was supported by the Australian Research Council. The authors thank the participants of the CUPID and CUDAS cross-sectional studies.
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Powell, B.L., Wiltshire, S., Arscott, G. et al. Association of PARL rs3732581 genetic variant with insulin levels, metabolic syndrome and coronary artery disease. Hum Genet 124, 263–270 (2008). https://doi.org/10.1007/s00439-008-0552-2
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DOI: https://doi.org/10.1007/s00439-008-0552-2