Background The SNP (rs2230500) in PRKCH (the gene encoding protein kinase C η) is associated with ischemic stroke and cerebral hemorrhage in the Chinese population, but the molecular mechanisms are not clear. The aim of the present study is to investigate the association between the SNP and atherosclerosis that is common pathological basis of ischemic stroke and cerebral hemorrhage. Methodology/Principal Findings We examined the associations of the SNP with carotid intima-media thickness (CIMT), atherosclerosis diagnosed by CIMT, and factors related with inflammation in the Beijing Child Blood Pressure Study. A total of 1190 subjects participated in the follow-up study. The SNP was genotyped by allele-specific real-time PCR assay. The SNP (rs2230500) in PRKCH was significantly associated with CIMT (in far wall of left common carotid arteries, P = 0.016; in far wall of right common carotid arteries, P = 0.012) under a recessive model after adjustment for age, gender, smoking, and hypertension. The SNP was also significantly associated with complement C3 (P = 0.012) under a dominant model after adjustment for age, gender, and high sensitivity C-reactive protein. Conclusions/Significance Our data provide evidence that the SNP (rs2230500) in PRKCH decreases the risk of CIMT that is a worthwhile predictor of stroke and complement system possibly mediates this process.
References
[1]
World Health Organization (2008) World Health Statistics 2008. Geneva, Switzerland: World Health Organization.
[2]
Bonow RO, Smaha LA, Smith SC Jr, Mensah GA, Lenfant C (2002) World Heart Day 2002: the international burden of cardiovascular disease: responding to the emerging global epidemic. Circulation 106: 1602–1605.
[3]
Reddy KS (2004) Cardiovascular disease in non-Western countries. N Engl J Med 350: 2438–2440.
[4]
Scott J (2004) Pathophysiology and biochemistry of cardiovascular disease. Curr Opin Genet Dev 14: 271–279.
[5]
Hixson JE (1991) Apolipoprotein E polymorphisms affect atherosclerosis in young males. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Arterioscler Thromb Vasc Biol 11: 1237–1244.
[6]
Urbina EM, Williams RV, Alpert BS, Collins RT, Daniels SR, et al. (2009) American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young. Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research: a scientific statement from the American Heart Association. Hypertension 54: 919–950.
[7]
McGill HC Jr, McMahan CA (1998) Determinants of atherosclerosis in the young: Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Am J Cardiol 82: 30T–36T.
[8]
de Groot E, Hovingh GK, Wiegman A, Duriez P, Smit AJ, et al. (2004) Measurement of arterial wall thickness as a surrogate marker for atherosclerosis. Circulation 109: III33–III38.
[9]
Lorenz MW, von Kegler S, Steinmetz H, Markus HS, Sitzer M (2006) Carotid intima-media thickening indicates a higher vascular risk across a wide age range: prospective data from the Carotid Atherosclerosis Progression Study (CAPS). Stroke 37: 87–92.
[10]
Simon A, Megnien JL, Chironi G (2010) The value of carotid intima-media thickness for predicting cardiovascular risk. Arterioscler Thromb Vasc Biol 30: 182–185.
[11]
Kastelein JJ, de Groot E (2008) Ultrasound imaging techniques for the evaluation of cardiovascular therapies. Eur Heart J 29: 849–858.
[12]
Polak JF, Pencina MJ, O’Leary DH, D’Agostino RB (2011) Common carotid artery intima-media thickness progression as a predictor of stroke in multi-ethnic study of atherosclerosis. Stroke 42: 3017–3021.
[13]
Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE (1997) Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 96: 1432–1437.
[14]
O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, et al. (1999) Cardiovascular Health Study Collaborative Research Group. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 340: 14–22.
[15]
Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352: 1685–1695.
[16]
Ross R (1999) Atherosclerosis - an inflammatory disease. N Engl J Med 340: 115–126.
[17]
Millonig G, Malcom GT, Wick G (2002) Early inflammatory-immunological lesions in juvenile atherosclerosis from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY)-study. Atherosclerosis 160: 441–448.
[18]
Oksjoki R, Kovanen PT, Pentik?inen MO (2003) Role of complement activation in atherosclerosis. Curr Opin Lipidol 14: 477–482.
[19]
Szeplaki G, Prohaszka Z, Duba J, Rugonfalvi-Kiss S, Karadi I, et al. (2004) Association of high serum concentration of the third component of complement (C3) with pre-existing severe coronary artery disease and new vascular events in women. Atherosclerosis 177: 383–389.
[20]
Kubo M, Hata J, Ninomiya T, Matsuda K, Yonemoto K, et al. (2007) A nonsynonymous SNP in PRKCH (protein kinase C eta) increases the risk of cerebral infarction. Nat Genet 39: 212–217.
[21]
Serizawa M, Nabika T, Ochiai Y, Takahashi K, Yamaguchi S, et al. (2008) Association between PRKCH gene polymorphisms and subcortical silent brain infarction. Atherosclerosis 199: 340–345.
[22]
Wu L, Shen Y, Liu X, Ma X, Xi B, et al. (2009) The 1425G/A SNP in PRKCH is associated with ischemic stroke and cerebral hemorrhage in a Chinese population. Stroke 40: 2973–2976.
[23]
World Health Organization (1995) Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. Technical Report Series No. 854. Geneva, Switzerland: World Health Organization.
[24]
Zureik M, Bureau JM, Temmar M, Adamopoulos C, Courbon D, et al. (2003) Echogenic carotid plaques are associated with aortic arterial stiffness in subjects with subclinical carotid atherosclerosis. Hypertension 41: 519–527.
[25]
Hu DY, Guo YF (2008) Non-invasive detection of arterial function evaluation of the clinical significance of China expert consensus. Cardiovascular disease prevention guidelines and consensus 2008. People’s Health Publishing House. pp. 37–43.
[26]
Germer S, Holland MJ, Higuchi R (2000) High-throughput SNP allele-frequency determination in pooled DNA samples by kinetic PCR. Genome Res 10: 258–266.
[27]
Onat A, Can G, Rezvani R, Cianflone K (2011) Complement C3 and cleavage products in cardiometabolic risk. Clin Chim Acta 412: 1171–1179.
[28]
Muscari A, Bozzoli C, Puddu GM, Sangiorgi Z, Dormi A, et al. (1995) Association of serum C3 levels with the risk of myocardial infarction. Am J Med 98: 357–364.
[29]
Dernellis J, Panaretou M (2006) Effects of C-reactive protein and the third and fourth components of complement (C3 and C4) on incidence of atrial fibrillation. Am J Cardiol 97: 245–248.
[30]
Nishizuka Y (1995) Protein kinase C and lipid signaling for sustained cellular responses. FASEB J 9: 484–496.
[31]
Pham TN, Brown BL, Dobson PR, Richardson VJ (2003) Protein kinase C-eta (PKC-eta) is required for the development of inducible nitric oxide synthase (iNOS) positive phenotype in human monocytic cells. Nitric Oxide 9: 123–134.