The Mitochondrial DNA Variant 16189T>C Is Associated with Coronary Artery Disease and Myocardial Infarction in Saudi Arabs

Abstract

By virtue of the functional role of the mitochondrion in energy and reactive oxygen species production, mutations in mitochondrial DNA (mtDNA) are potential candidates for cardiovascular-related disorders. Further, the mtDNA is extremely polymorphic and several diagnostic single-nucleotide polymorphisms have been used to assort sequences into haplogroups with defined continental and regional ranges. However, the relevance of these haplogroups and mutations with respect to coronary artery disease (CAD) susceptibility remains unclear. In this study, we evaluated the role of the 16189T>C variants and mtDNA haplogroups as predisposing factors for CAD in 669 Saudi patients with angiographically established disease compared with 258 disease-free controls. The 16189T>C was associated with CAD (1.524 [1.076-2.159]; p = 0.017). However, this association was influenced by age as well as the presence of myocardial infarction and hypertension. Among the haplogroups, only the N1c showed a borderline protective relationship (p = 0.074) with CAD as an independent risk factor. This association turned significant in the total sample (0.176 [0.042-0.736]; p = 0.017) and in the <50-year age group (0.075 [0.008-0.743]; p = 0.027), when included as a possible confounding factor. Our results suggested that the impact of mtDNA polymorphism on CAD manifestation is influenced by important confounders, particularly the presence of myocardial infarction, hypertension, and age.

Get full access to this article

View all access options for this article.

References

Abu-Amero

, Larruga

, Cabrera

, Gonzalez

. 2008a. Mitochondrial DNA structure in the Arabian Peninsula. BMC Evol Biol, 8:45-54.

Abu-Amero

, Gonzalez

, Larruga

et al. 2007. Eurasian and African mitochondrial DNA influences in the Saudi Arabian population. BMC Evol Biol, 7:32-46.

Abu-Amero

, Hellani

, Bohlega

. 2008b. Absence of mtDNA mutations in leukocytes of CADASIL patients. BMC Res Notes, 1:16-19.

Abu-Amero

, Larruga

, Gonzalez

, Bosley

. 2008c. The role of mitochondrial haplogroups in non-arteritic anterior ischemic optic neuropathy. Ophthalmic Genet, 29:111-116.

Abu-Amero

, Morales

, Bosley

et al. 2008d. The role of mitochondrial haplogroups in glaucoma: a study in an Arab population. Mol Vis, 14:518-522.

Alpert

, Thygesen

, Antman

, Bassand

. 2000. Myocardial infarction redefined—a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol, 36:959-969.

Bai

, Leal

, Covarrubias

et al. 2007. Mitochondrial genetic background modifies breast cancer risk. Cancer Res, 67:4687-4694.

Botto

, Berti

, Manfredi

et al. 2005. Detection of mtDNA with 4977 bp deletion in blood cells and atherosclerotic lesions of patients with coronary artery disease. Mutat Res, 570:81-88.

Corral-Debrinski

, Shoffner

, Lott

, Wallace

. 1992. Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. Mutat Res, 275:169-180.

10.

Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. 2003. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 26,Suppl 1:S5-S20.

11.

Fuku

, Park

, Yamada

et al. 2007. Mitochondrial haplogroup N9a confers resistance against type 2 diabetes in Asians. Am J Hum Genet, 80:407-415.

12.

Gerbitz

, van den Ouweland

, Maassen

, Jaksch

. 1995. Mitochondrial diabetes mellitus: a review. Biochim Biophys Acta, 1271:253-260.

13.

Gutierrez

, Ballinger

, Darley-Usmar

, Landar

. 2006. Free radicals, mitochondria, and oxidized lipids: the emerging role in signal transduction in vascular cells. Circ Res, 99:924-932.

14.

Herrnstadt

, Howell

. 2004. An evolutionary perspective on pathogenic mtDNA mutations: haplogroup associations of clinical disorders. Mitochondrion, 4:791-798.

15.

Katagiri

, Asano

, Ishihara

et al. 1994. Mitochondrial diabetes mellitus: prevalence and clinical characterization of diabetes due to mitochondrial tRNA(Leu(UUR)) gene mutation in Japanese patients. Diabetologia, 37:504-510.

16.

Kofler

, Mueller

, Eder

et al. 2009. Mitochondrial DNA haplogroup T is associated with coronary artery disease and diabetic retinopathy: a case control study. BMC Med Genet, 10:35-41.

17.

Lee

, Park

, Pak

, Lee

. 2005. The role of mitochondrial DNA in the development of type 2 diabetes caused by fetal malnutrition. J Nutr Biochem, 16:195-204.

18.

, Su

, Huang

et al. 2007. mtDNA evidence: genetic background associated with related populations at high risk for esophageal cancer between Chaoshan and Taihang Mountain areas in China. Genomics, 90:474-481.

19.

Livesey

, Wimhurst

, Carter

et al. 2004. The 16189 variant of mitochondrial DNA occurs more frequently in C282Y homozygotes with haemochromatosis than those without iron loading. J Med Genet, 41:6-10.

20.

Lusis

, Fogelman

, Fonarow

. 2004a. Genetic basis of atherosclerosis: part I: new genes and pathways. Circulation, 110:1868-1873.

21.

Lusis

, Fogelman

, Fonarow

. 2004b. Genetic basis of atherosclerosis: part II: clinical implications. Circulation, 110:2066-2071.

22.

Maca-Meyer

, Gonzalez

, Larruga

et al. 2001. Major genomic mitochondrial lineages delineate early human expansions. BMC Genet, 2:13-20.

23.

Park

, Chan

, Chuang

et al. 2008. A mitochondrial DNA variant at position 16189 is associated with type 2 diabetes mellitus in Asians. Diabetologia, 51:602-608.

24.

Poulton

, Bednarz

, Scott-Brown

et al. 2002. The presence of a common mitochondrial DNA variant is associated with fasting insulin levels in Europeans in Auckland. Diabet Med, 19:969-971.

25.

Poulton

, Das

. 2004. Correction: no evidence of an association between the T16189C mtDNA variant and late onset dementia (Gibson et al.) J Med Genet, 41:957author reply 957-958.

26.

Poulton

, Luan

, Macaulay

et al. 2002. Type 2 diabetes is associated with a common mitochondrial variant: evidence from a population-based case-control study. Hum Mol Genet, 11:1581-1583.

27.

Takagi

, Yamada

, Gong

et al. 2004. Association of a 5178C→A (Leu237Met) polymorphism in the mitochondrial DNA with a low prevalence of myocardial infarction in Japanese individuals. Atherosclerosis, 175:281-286.

28.

Tang

, Zhou

, Li

et al. 2006. Variation of mitochondrial gene and the association with type 2 diabetes mellitus in a Chinese population. Diabetes Res Clin Pract, 73:77-82.

29.

Tang

, Zhou

et al. 2005. [Association of mitochondrial DNA variation with type 2 diabetes mellitus] (Chi) Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 22:636-640.

30.

Torroni

, Achilli

, Macaulay

et al. 2006. Harvesting the fruit of the human mtDNA tree. Trends Genet, 22:339-345.

31.

Wallace

, Shoffner

, Trounce

et al. 1995. Mitochondrial DNA mutations in human degenerative diseases and aging. Biochim Biophys Acta, 1271:141-151.

32.

Wang

, Bamlet

, de Andrade

et al. 2007. Mitochondrial genetic polymorphisms and pancreatic cancer risk. Cancer Epidemiol Biomarkers Prev, 16:1455-1459.

33.

, Hu

, Chen

et al. 2006. Mitochondrial polymorphisms as risk factors for endometrial cancer in southwest China. Int J Gynecol Cancer, 16:1661-1667.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.06 MB