Abstract
Recent studies have shown that variants in the COL4A2 genes are associated with sporadic cerebral small vessel disease. The aim of the study was to investigate the relationship between COL4A2 gene polymorphisms and lacunar stroke in Xinjiang Han populations. The improved multiple ligase detection reaction (iMLDR) method was used to analyze the genotypes of seven single-nucleotide polymorphisms (SNPs) in the COL4A2 gene (rs3803230, rs391859, rs4103, rs445348, rs76425569, rs7990383, rs9515185) in a case-control study of 406 lacunar stroke patients and 425 controls. The GG genotype of rs3803230 (adjusted OR = 1.303, 95% CI = 1.146–1.480, P < 0.001) and the GA/AA genotype of rs76425569 (adjusted OR = 1.744, 95% CI = 1.306–2.329, P < 0.001) showed significant increases in the risk of lacunar stroke. The G-A haplotype of rs3803230-rs76425569 carried a significant increase in the risk of lacunar stroke (OR = 1.616, 95% CI = 1.292–2.022, P < 0.001). Hypertension stratification analyses demonstrated that the GA/AA genotype of rs76425569 was significantly associated with lacunar stroke in the hypertensive group (adjusted OR = 1.316, 95% CI = 1.083–1.598, P = 0.006). In the non-hypertensive group, the GG genotype of rs3803230 (adjusted OR = 1.584, 95% CI = 1.257–1.997, P < 0.001) and GA/AA genotype of rs76425569 were significantly associated with lacunar stroke (adjusted OR = 1.312, 95% CI = 1.054–1.635, P = 0.015). The TT genotype of rs4103 was significantly associated with lacunar stroke in the non-hypertensive group (adjusted OR = 1.355, 95% CI = 1.152–1.594, P < 0.001). This study demonstrates that the COL4A2 gene could play a role in the pathogenesis of lacunar stroke in the Han population of China.
Similar content being viewed by others
References
American Diabetes Association: clinical practice recommendations 1997. Diabetes Care 20:S1–S70
Arboix A, Roig H, Rossich R, Martinez E, Garc-Eroles L (2004) Differences between hypertensive and non-hypertensive ischemic stroke. Eur J Neurol 11:687–692
ARDIoGRAMplusC4D Consortium, Deloukas P, Kanoni S et al (2013) Large-scale association analysis identifies new risk loci for coronary artery disease [J]. Nat Genet 45:25–33
Gunda B, Mine M, Kovács T, Hornyák C, Bereczki D, Várallyay G, Rudas G, Audrezet MP, Tournier-Lasserve E (2014) COL4A2 mutation causing adult onset recurrent intracerebral hemorrhage and leukoencephalopathy. J Neurol 261:500–503
Hara K, Shiga A, Fukutake T et al (2009) Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med 360:1729–1739
Khoshnoodi J, Pedchenko V, Hudson BG (2008) Mammalian collagen IV. Microsc Res Tech 71:357–370
O’Donnell CJ, Kavousi M, Smith AV et al (2011) Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction [J]. Circulation 124:2855–2864
Pöschl E, Schlötzer-Schrehardt U, Brachvogel B, Saito K, Ninomiya Y, Mayer U (2004) Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 131:1619–1628
Rannikmäe K, Davies G, Thomson PA et al (2015) Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. Neurology 84:918–926
Rannikmäe K, Sivakumaran V, Millar H et al (2017) COL4A2 is associated with lacunar ischemic stroke and deep ICH. Neurology 89:1829–1839
Ross R (1986) The pathogenesis of atherosclerosis—an update. N Engl J Med 314:488–500
Schunkert H, Konig IR, Kathiresan S et al (2011) Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease [J]. Nat Genet 43:333–338
Sudlow CL, Warlow CP (1997) Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. Stroke 28:491–499
Tarasov KV, Sanna S, Scuteri A et al (2009) COL4A1 is associated with arterial stiffness by genome-wide association scan. Circ Cardiovasc Genet 2:151–158
Tome VA, Bruckner-Tuderman L (2010) Basement membranes and human disease. Cell Tissue Res 339:167–188
Traylor M, Bevan S, Baron JC, Hassan A, Lewis CM, Markus HS (2015) Genetic architecture of lacunar stroke. Stroke 46:2407–2412
Turner AW, Nikpay M, Silva A, Lau P, Martinuk A, Linseman TA, Soubeyrand S, McPherson R (2015) Functional interaction between COL4A1/COL4A2 and SMAD3 risk loci for coronary artery disease. Atherosclerosis 242:543–552
Verbeek E, Meuwissen ME, Verheijen FW et al (2012) COL4A2 mutation associated with familial prorencephaly and small-vessel disease. Eur J Hum Genet 20:844–851
Yamada Y, Kato K, Oguri M et al (2008) Genetic risk for myocardial infarction determined by polymorphisms of candidate genes in a Japanese population. J Med Genet 45:216–221
Yang W, Ng FL, Chan K, Pu X, Poston RN, Ren M, An W, Zhang R, Wu J, Yan S, Situ H, He X, Chen Y, Tan X, Xiao Q, Tucker AT, Caulfield MJ, Ye S (2016) Coronary-heart-disease-associated genetic variant at the COL4A1/COL4A2 locus affects COL4A1/COL4A2 expression, vascular cell survival, atherosclerotic plaque stability and risk of myocardial infarctionn. PLoS Genet 12:1006127
Yi P, Chen Z, Zhao Y, Guo J, Fu H, Zhou Y, Yu L, Li L (2009) PCR/LDR/capillary electrophoresis for detection of single-nucleotide differences between fetal and maternal DNA in maternal plasma. Prenat Diagn 29:217–222
Zhang AJ, Yu XJ, Wang M (2010) The clinical manifestations and pathophysiology of cerebral small vessel disease. Neurosci Bull 26:257–264
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (81160145) and the Seventh Division Science Foundation of China.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of Interest
The authors declare that they have no conflict of interest.
Ethical Standards
The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University, Urumqi, China (no. 20160512).
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Liang, C., Zhang, J., Liu, H. et al. Association of COL4A2 Gene Polymorphisms with Lacunar Stroke in Xinjiang Han Populations. J Mol Neurosci 69, 133–139 (2019). https://doi.org/10.1007/s12031-019-01342-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-019-01342-8