Background Ischaemic stroke in persons of European descent has a genetic basis, but whether the stroke-susceptibility alleles, the strength of any association, and the extent of their attributable risks are the same in persons of non-European descent remains unanswered. Whether ethnicity itself has a relevant or substantial contribution on those effect estimates is controversial. Comparative analyses between the ethnic groups may allow general conclusions to be drawn about polygenic disorders. Methods and Findings We performed a literature-based systematic review of genetic association studies in stroke in persons of non-European descent. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined for each gene–disease association using fixed and random effect models. We further performed a comparative genetic analysis across the different ethnic groups (including persons of European descent derived from our previous meta-analysis) to determine if genetic risks varied by ethnicity. Following a review of 500 manuscripts, eight candidate gene variants were analysed among 32,431 individuals (12,883 cases and 19,548 controls), comprising mainly Chinese, Japanese, and Korean individuals. Of the eight candidate genes studied, three were associated with ischaemic stroke: the angiotensin I converting enzyme (ACE) insertion/deletion (I/D) polymorphism with a mean OR of 1.90 (95% CI 1.23–2.93) in the Chinese and 1.74 (95% CI 0.88–3.42) in the Japanese; the summary OR for the C677T variant of 5,10-methylenetetrahydrofolate reductase (MTHFR) was 1.18 (95% CI 0.90–1.56) in Chinese and 1.34 (95% CI 0.87–2.06) in Koreans; and the pooled OR for the apolipoprotein E (APOE) gene was 2.18 (95% CI 1.52–3.13) in Chinese and 1.51 (95% CI 0.93–2.45) in Japanese. Comparing the commonly investigated stroke genes among the Asian groups against studies in persons of European descent, we found an absence of any substantial qualitative or quantitative interaction for ORs by ethnicity. However, the number of individuals recruited per study in the studies of persons of non-European descent was significantly smaller compared to studies of persons of European descent, despite a similar number of studies conducted per gene. Conclusions These data suggest that genetic associations studied to date for ischaemic stroke among persons of non-European descent are similar to those for persons of European descent. Claims of differences in genetic effects among different ethnic populations for complex disorders such as stroke may be overstated. However, due to the limited number of gene
References
[1]
Sharma P, Korn S (2005) Management strategies for cerebrovascular disease in South Asians. In: Patel KCR, Shah AM, editors. Prevention, treatment and rehabilitation of cardiovascular disease in South Asians. London: The Stationery Office (TSO). pp. 37–50.
[2]
Kiely DK, Wolf PA, Cupples LA, Beiser AS, Myers RH (1993) Familial aggregation of stroke. The Framingham Study. Stroke 24: 1366–1371.
[3]
Rubattu S, Volpe M, Kreutz R, Ganten U, Ganten D, et al. (1996) Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease. Nat Genet 13: 429–434.
[4]
Sharma P (1996) Genes for ischaemic stroke: Strategies for their detection. J Hypertens 14: 277–285.
[5]
Gretarsdottir S, Thorleifsson G, Reynisdottir ST, Manolescu A, Jonsdottir S, et al. (2003) The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet 35: 131–138.
[6]
Liao D, Myers R, Hunt S, Shahar E, Paton C, et al. (1997) Familial history of stroke and stroke risk. The Family Heart Study. Stroke 28: 1908–1912.
[7]
Hrubec Z, Robinette CD (1984) The study of human twins in medical research. N Engl J Med 310: 435–441.
[8]
Brass LM, Isaacsohn JL, Merikangas KR, Robinette CD (1992) A study of twins and stroke. Stroke 23: 221–223.
[9]
Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S, Jonsdottir H, et al. (2004) The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet 36: 233–239.
[10]
Casas JP, Hingorani AD, Bautista LE, Sharma P (2004) Meta-analysis of genetic studies in ischemic stroke: Thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol 61: 1652–1661.
[11]
Ioannidis JP, Ntzani EE, Trikalinos TA (2004) “Racial” differences in genetic effects for complex diseases. Nat Genet 36: 1312–1318.
[12]
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7: 177–188.
[13]
Deek JJ, Altman DG, Bradburn MJ (2001) Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Davey SG, Altman DG, editors. Systemic reviews in health care: Meta-analysis in context. Annapolis Junction (Maryland): BMJ Publishing Group.
[14]
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634.
[15]
Zhang X, Xia J, Jin D (2001) The relationship between angiotensin converting enzyme gene polymorphism and risk factors for cerebral infarct. Zhonghua Liu Xing Bing Xue Za Zhi 22: 435–438.
[16]
Zhang X, Wang D, Xu L, Ma Y, Zhang S (2001) Association between renin-angiotensin system gene polymorphism and type 2 diabetics with stroke in China. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 18: 462–466.
[17]
Yuan XD, Hou QX, Wu SL, Pei HZ, Li HF (2003) A cross-sectional study on angiotensin-converting enzyme and angiotensin II type I receptor gene polymorphism and cerebral infarction. Zhonghua Liu Xing Bing Xue Za Zhi 24: 822–826.
[18]
Wei X, Wang G, Jiang C, Li D, Zhao G (2000) Association between hypertensive cerebrovascular stroke and renin-angiotensin system gene polymorphism from Chinese cohort in Shanghai. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 17: 256–258.
[19]
Wang YM, Liu XD, Dong WW, Yang ZC (2004) The relationship between angiotensin-converting enzyme gene polymorphism and heart rate variability in cerebral stroke. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 21: 156–160.
[20]
Thomas GN, Lin JW, Lam WW, Tomlinson B, Yeung V, et al. (2003) Middle cerebral artery stenosis in type II diabetic Chinese patients is associated with conventional risk factors but not with polymorphisms of the renin-angiotensin system genes. Cerebrovasc Dis 16: 217–223.
[21]
Shen D, Ha D (1998) The relationship between angiotensin-converting enzyme gene polymorphism and brain infarction in Chinese hypertensives. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 15: 136–138.
[22]
Li C, Zhang C, Qiu S, Lu X, Zheng Y, et al. (2002) Polymorphisms of ACE-1 and MTHFR genes and genetic susceptibility of ischemic stroke. Zhonghua Yi Xue Za Zhi 82: 1046–1049.
[23]
Xu Y, Wang X, Zhu J (1998) Angiotensin converting enzyme gene polymorphism and cerebrovascular disease. Zhonghua Shen Jing Ge Za Zhi 31: 152–155.
[24]
Ohkubo R, Nakagawa M, Ikeda K, Kodama T, Arimura K, et al. (2002) Cerebrovascular disorders and genetic polymorphisms: Mitochondrial DNA5178C is predominant in cerebrovascular disorders. J Neurol Sci 198: 31–35.
[25]
Notsu Y, Nabika T, Park HY, Masuda J, Kobayashi S (1999) Evaluation of genetic risk factors for silent brain infarction. Stroke 30: 1881–1886.
[26]
Nakata Y, Katsuya T, Takami S, et al. (1998) Methylenetetrahydrofolate reductase gene polymorphism: Relation to blood pressure and cerebrovascular disease. Am J Hypertens 11: 1019–1023.
[27]
Kario K, Kanai N, Saito K, Nago N, Matsuo T, et al. (1996) Ischemic stroke and the gene for angiotensin-converting enzyme in Japanese hypertensives. Circulation 93: 1630–1633.
[28]
Doi Y, Yoshinari M, Yoshizumi H, Ibayashi S, Wakisaka M, et al. (1997) Polymorphism of the angiotensin-converting enzyme (ACE) gene in patients with thrombotic brain infarction. Atherosclerosis 132: 145–150.
[29]
Seino Y, Ikeda U, Maeda Y, Haga Y, Yashima H, et al. (1998) Angiotensin-converting enzyme gene polymorphism and plasminogen activator inhibitor 1 levels in subjects with cerebral infarction. J Thromb Thrombolysis 5: 263–267.
[30]
Um JY, Joo JC, Kim KY, An NH, Lee KM, et al. (2003) Angiotensin converting enzyme gene polymorphism and traditional Sasang classification in Koreans with cerebral infarction. Hereditas 138: 166–171.
[31]
Um JY, Moon KS, Lee KM, Cho KH, Heo Y, et al. (2003) Polymorphism of angiotensin-converting enzyme, angiotensinogen, and apolipoprotein E genes in Korean patients with cerebral infarction. J Mol Neurosci 21: 23–28.
[32]
Um JY, An NH, Kim SH, Lee KM, Kim YS, et al. (2003) Genetic susceptibility to ischemic cerebrovascular disease in Koreans. J Mol Neurosci 20: 31–38.
[33]
Um JY, Kim HJ, Choi TJ, Jin CS, Park ST, et al. (2001) Polymorphism of the angiotensin-converting enzyme gene in patients with cerebral infarction in Koreans. J Mol Neurosci 17: 279–283.
[34]
Zhang G, Dai C (2001) Gene polymorphisms of homocysteine metabolism-related enzymes in Chinese patients with occlusive coronary artery or cerebral vascular diseases. Thromb Res 104: 187–195.
[35]
Li Z, Sun L, Zhang H, Liao Y, Wang D, et al. (2003) Elevated plasma homocysteine was associated with hemorrhagic and ischemic stroke, but methylenetetrahydrofolate reductase gene C677T polymorphism was a risk factor for thrombotic stroke: A Multicenter Case-Control Study in China. Stroke 34: 2085–2090.
[36]
Huang Y, Zhao YY, Li S (2002) Hyperhomocysteine, methylenetetrahydrofolate reductase gene, and other risk factors in ischemic stroke. Zhonghua Yi Xue Za Zhi 82: 119–122.
[37]
Yingdong Z, Zhigang Z, Yang L, Yingdong Z, Zhigang Z, et al. (2002) Association of plasma homocysteine level and N5,N10-methylenetetrahydrofolate reductase gene polymorphism with cerebral infarction. Chin Med Sci J 17: 231–235.
[38]
Zhang C, Shao Y, Hu X (2003) Relationships between the plasma homocysteine levels and the polymorphisms of its metabolic enzymes and the cerebral infarction. Zhonghua Shen Jing Ge Za Zhi 36: 359–362.
[39]
Zheng YZ, Tong J, Do XP, Pu XQ, Zhou BT (2000) Prevalence of methylenetetrahydrofolate reductase C677T and its association with arterial and venous thrombosis in the Chinese population. Br J Haematol 109: 870–874.
[40]
Yoo JH, Choi GD, Kang SS (2000) Pathogenicity of thermolabile methylenetetrahydrofolate reductase for vascular dementia. Arterioscler Thromb Vasc Biol 20: 1921–1925.
[41]
Kim NK, Choi BO, Jung WS, Choi YJ, Choi KG (2003) Hyperhomocysteinemia as an independent risk factor for silent brain infarction. Neurology 61: 1595–1599.
[42]
Choi BO, Kim NK, Kim SH, Kang MS, Lee S, et al. (2003) Homozygous C677T mutation in the MTHFR gene as an independent risk factor for multiple small-artery occlusions. Thromb Res 111: 39–44.
[43]
Peng DQ, Zhao SP, Wang JL, Peng DQ, Zhao SP, et al. (1999) Lipoprotein (a) and apolipoprotein E epsilon 4 as independent risk factors for ischemic stroke. J Cardiovasc Risk 6: 1–6.
[44]
Jin ZQ, Fan YS, Ding J, Chen M, Fan W, et al. (2004) Association of apolipoprotein E 4 polymorphism with cerebral infarction in Chinese Han population. Acta Pharmacol Sin 25: 352–356.
[45]
Cao W, Chen F, Teng L, Wang S, Fu S, et al. (1999) The relationship between apolipoprotein E gene polymorphism and coronary heart disease and arteriosclerotic cerebral infarction. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 16: 249–251.
[46]
Yang G, Jinjin G, Jianfei N (1997) The relationship between polymorphisms of Apolipoprotein E gene and atherosclerotic cerebral infarction. Zhonghua Shen Jing Ge Za Zhi 30: 236–239.
[47]
Kokubo Y, Chowdhury AH, Date C, Yokoyama T, Sobue H, et al. (2000) Age-dependent association of apolipoprotein E genotypes with stroke subtypes in a Japanese rural population. Stroke 31: 1299–1306.
[48]
Ji Y, Urakami K, Adachi Y, Maeda M, Isoe K, et al. (1998) Apolipoprotein E polymorphism in patients with Alzheimer's disease, vascular dementia and ischemic cerebrovascular disease. Dement Geriatr Cogn Disord 9: 243–245.
[49]
Nakata Y, Katsuya T, Rakugi H, Takami S, Sato N, et al. (1997) Polymorphism of angiotensin converting enzyme, angiotensinogen, and apolipoprotein E genes in a Japanese population with cerebrovascular disease. Am J Hypertens 10: 1391–1395.
[50]
Hu B, Zhou X, Shao H (2000) Relationship between pentanucleotide repeat polymorphism of apolipoprotein(a) gene and atherosclerosis cerebral infarction in Han nationality. Zhonghua Shen Jing Ge Za Zhi 33: 172–175.
[51]
Liu X, Sun L, Li Z, Gao Y, Hui R (2002) Relation of pentanucleotide repeat polymorphism of apolipoprotein (a) gene to plasma lipoprotein (a) level among Chinese patients with myocardial infarction and cerebral infarction. Zhonghua Yi Xue Za Zhi 82: 1396–1400.
[52]
Sun L, Li Z, Zhang H, Ma A, Liao Y, et al. (2003) Pentanucleotide TTTTA repeat polymorphism of apolipoprotein(a) gene and plasma lipoprotein(a) are associated with ischemic and hemorrhagic stroke in Chinese: A multicenter case-control study in China. Stroke 34: 1617–1622.
[53]
Zhang C, Li J, Li L, et al. (2001) The study of PAI-1 promotor region gene polymorphism in cerebrovascular disease. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 18: 383–387.
[54]
Zhan M, Zhou Y, Han Z, Zhan M, Zhou Y, et al. (2003) Plasminogen activator inhibitor-1 4G/5G gene polymorphism in patients with myocardial or cerebrovascular infarction in Tianjin, China. Chin Med J 116: 1707–1710.
[55]
Liu S, Yang L, Wang X (1998) The study of the plasma PAI-1 activity and it's promotor region gene polymorphism in acute cerebral infarction. Zhonghua Shen Jing Ge Za Zhi 31: 264–266.
[56]
Um JY, An NH, Kim HM, Um JY, An NH, et al. (2003) TNF-alpha and TNF-beta gene polymorphisms in cerebral infarction. J Mol Neurosci 21: 167–171.
[57]
Um JY, Kim HM, Um JY, Kim HM (2004) Tumor necrosis factor alpha gene polymorphism is associated with cerebral infarction. Brain Res Mol Brain Res 122: 99–102.
[58]
Lee BC, Ahn SY, Doo HK, Yim SV, Lee HJ, et al. (2004) Susceptibility for ischemic stroke in Korean population is associated with polymorphisms of the interleukin-1 receptor antagonist and tumor necrosis factor-alpha genes, but not the interleukin-1beta gene. Neuroscience Letters 357: 33–36.
[59]
Zhong Y, Ha D, Zhong Y, Ha D (2002) Influence of angiotensin II type 1 receptor gene polymorphism on patients with essential hypertension complicated by brain infarction. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 19: 201–204.
[60]
Zhang X, Wang D, Xu L, Ma Y, Zhang S (2001) Association between renin-angiotensin system gene polymorphism and type 2 diabetics with stroke in China. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 18: 462–466.
[61]
Thomas GN, Lin JW, Lam WW, et al. (2003) Middle cerebral artery stenosis in type II diabetic Chinese patients is associated with conventional risk factors but not with polymorphisms of the renin-angiotensin system genes. Cerebrovasc Dis 16: 217–223.
[62]
Guan L, Zhang A, Song B, Xiao S, Gao Y, et al. (2000) The relationship between angiotensinogen gene CD235 met–>Thr substitution polymorphism and brain infarction in Chinese. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 17: 336–339.
[63]
Yamada Y, Metoki N, Yoshida H, et al. (2006) Genetic risk for ischemic and hemorrhagic stroke. Arterioscler Thromb Vasc Biol 26: 1920–1925.
[64]
Pan Z, Trikalinos TA, Kavvoura FK, Lau J, Ioannidis JP (2005) Local literature bias in genetic epidemiology: An empirical evaluation of the Chinese literature. PLoS Medicine 2: e334.. doi:10.1371/journal.pmed.0020334.
[65]
Mackay J, Mensah GA (2004) The atlas of heart disease and stroke. WHO.. Available: http://www.who.int/cardiovascular_diseas？es/resources/atlas/en/. Accessed:.
[66]
Ioannidis JP, Gwinn M, Little J, Higgins JP, Bernstein JL, et al. (2006) A road map for efficient and reliable human genome epidemiology. Nat Genet 38: 3–5.
[67]
Saxena S, Eliahoo J, Majeed A (2002) Socioeconomic and ethnic group differences in self reported health status and use of health services by children and young people in England: Cross sectional study. BMJ 325: 520.
