Advances in Genetics of Stroke in Young Adults

doi:10.3969/j.issn.1673-5765.2022.09.002

Abstract

Abstract: The incidence of stroke in young adults is on the rise, and the discovery of preclinical biomarkers would be of great clinical value. In addition to rare stroke-related monogenic diseases, many studies on the genetic susceptibility have shown that stroke in young adults is of multifactorial inheritance. In the past two decades, genome wide association study (GWAS), validation studies and meta-analysis have been applied to genetics research of stroke in young adults. This article reviewed the genetics evidence, related single gene and candidate genes mutation of stroke in young adults, to provide references for the clinical diagnosis and treatment.

Key words: Stroke; Young adult; Genetics; Genome wide association study

摘要： 青年卒中的发病率呈上升趋势，发现临床前生物标志物将获益巨大。除了罕见的卒中相关单基因疾病，许多遗传易感性研究表明青年卒中是多基因遗传病。近20年来，全基因组关联分析、验证研究和meta分析研究方法被应用于青年卒中的遗传学研究。本篇综述阐述了青年卒中的遗传学证据以及相关的单基因突变和候选基因变异，为疾病诊治提供参考。

关键词: 卒中; 青年; 遗传学; 全基因组关联分析

CHENG Anqi, XU Weihai. Advances in Genetics of Stroke in Young Adults[J]. Chinese Journal of Stroke, 2022, 17(09): 920-924.

程安琪, 徐蔚海. 青年卒中遗传学研究进展[J]. 中国卒中杂志, 2022, 17(09): 920-924.

References

[1] SMAJLOVIĆ D，SALIHOVIĆ D，IBRAHIMAGIĆ O C，et al. Characteristics of stroke in young adults in Tuzla Canton，Bosnia and Herzegovina[J]. Coll Antropol，2013，37（2）：515-519.
[2] MARINI C，RUSSO T，FELZANI G. Incidence of stroke in young adults：a review[J/OL]. Stroke Res Treat，2010，2011：535672[2022-07-22]. https://doi. org/10.4061/2011/535672.
[3] KRISHNAMURTHI R V，MORAN A E，FEIGIN V L，et al. Stroke prevalence，mortality and disability-adjusted life years in adults aged 20-64 years in 1990-2013：data from the global burden of disease 2013 study[J]. Neuroepidemiology，2015，45（3）：190-202.
[4] CABRAL N L，FREIRE AT，CONFORTO A B，et al. Increase of stroke incidence in young adults in a middle-income country：a 10-year population-based study[J]. Stroke，2017，48（11）：2925-2930.
[5] BI Q，WANG T，ZHANG W W. Frequency and etiological diagnosis of ischemic stroke in Chinese young adults[J]. Neurol Res，2012，34（4）：354-358.
[6] MACCLELLAN L R，MITCHELL B D，COLE J W，et al. Familial aggregation of ischemic stroke in young women：the stroke prevention in young women study[J]. Genet Epidemiol，2006，30（7）：602-608.
[7] SCHULZ U G，FLOSSMANN E，ROTHWELL P M. Heritability of ischemic stroke in relation to age，vascular risk factors，and subtypes of incident stroke in population-based studies[J]. Stroke，2004，35（4）：819-824.
[8] YAO X Y，LIN Y，GENG J L，et al. Age- and gender-specific prevalence of risk factors in patients with first-ever ischemic stroke in China[J/OL]. Stroke Res Treat，2012，2012：136398[2022-07-22]. https://doi.org/10.1155/2012/136398.
[9] BLUHER A，DEVAN W J，HOLLIDAY E G，et al. Heritability of young- and old-onset ischaemic stroke[J]. Eur J Neurol，2015，22（11）：1488-1491.
[10] BEVAN S，TRAYLOR M，ADIB-SAMII P，et al. Genetic heritability of ischemic stroke and the contribution of previously reported candidate gene and genomewide associations[J]. Stroke，2012，43（12）：3161-3167.
[11] HOLLIDAY E G，MAGUIRE J M，EVANS T J，et al. Common variants at 6p21.1 are associated with large artery atherosclerotic stroke[J]. Nat Genet，2012，44（10）：1147-1151.
[12] 李影，周晓梅，刘立斌，等. 青年卒中与中老年卒中危险因素和病因分型对比研究[J]. 当代医学，2020，26（33）：34-36.
[13] XIN X Y，SONG Y Y，MA J F，et al. Gene polymorphisms and risk of adult early-onset ischemic stroke：a meta-analysis[J]. Thromb Res，2009，124（5）：619-624.
[14] JIMÉNEZ-GONZÁLEZ M C，SANTIAGO-GERMÁN D，CASTILLO-HENKEL E F，et al. Identification of genetic risk factors associated with ischaemic stroke in young Mexican patients[J]. Neurologia（Engl Ed），2021，36（5）：337-345.
[15] SALOMI B S B，SOLOMON R，TURAKA V P，et al. Cryptogenic stroke in the young：role of candidate gene polymorphisms in Indian patients with ischemic etiology[J]. Neurol India，2021，69（6）：1655-1662.
[16] ZADRO R，HERAK D C. Inherited prothrombotic risk factors in children with first ischemic stroke[J]. Biochem Med（Zagreb），2012，22（3）：298-310.
[17] WHITLOCK J A，JANCO R L，PHILLIPS J A 3rd. Inherited hypercoagulable states in children[J]. Am J Pediatr Hematol Oncol，1989，11（2）：170-173.
[18] ISRAELS S J，SESHIA S S. Childhood stroke associated with protein C or S deficiency[J]. J Pediatr，1987，111（4）：562-564.
[19] PATEL M L，SACHAN R，SETH G. Combined deficiency of proteins C and S：ischaemic stroke in young individuals[J/OL]. BMJ Case Rep，2013，2013：bcr2012008016[2022-07-20]. http://dx.doi.org/10. 1136/bcr-2012-008016.
[20] BOTTO N，SPADONI I，GIUSTI S，et al. Prothrombotic mutations as risk factors for cryptogenic ischemic cerebrovascular events in young subjects with patent foramen ovale[J]. Stroke，2007，38（7）：2070-2073.
[21] JIANG B，RYAN K A，HAMEDANI A，et al. Prothrombin G20210A mutation is associated with young-onset stroke：the genetics of early-onset stroke study and meta-analysis[J]. Stroke，2014，45（4）：961-967.
[22] HAMEDANI A G，COLE J W，CHENG Y，et al. Factor V leiden and ischemic stroke risk：the genetics of early onset stroke（GEOS）study[J]. J Stroke Cerebrovasc Dis，2013，22（4）：419-423.
[23] HAMEDANI A G，COLE J W，MITCHELL B D，et al. Meta-analysis of factor V leiden and ischemic stroke in young adults：the importance of case ascertainment[J]. Stroke，2010，41（8）：1599-1603.
[24] REINER A P，SISCOVICK D S，ROSENDAAL F R. Platelet glycoprotein gene polymorphisms and risk of thrombosis：facts and fancies[J]. Rev Clin Exp Hematol，2001，5（3）：262-287，311-312.
[25] MAHMUTBEGOVIC N，MEHICEVIC A，ADLER G，et al. Bosnian study on markers of ischaemic stroke in adults 20-50 years old（SMISAO）：preliminary report[J]. Folia Biol（Praha），2020，66（5/6）：169-178.
[26] PEZZINI A，GRASSI M，DEL ZOTTO E，et al. Cumulative effect of predisposing genotypes and their interaction with modifiable factors on the risk of ischemic stroke in young adults[J]. Stroke，2005，36（3）：533-539.
[27] HE X W，ZHAO Y，SHI Y H，et al. DNA methylation analysis identifies differentially methylated sites associated with early-onset intracranial atherosclerotic stenosis[J]. J Atheroscler Thromb，2020，27（1）：71-99.
[28] OU M H，LIU S D，MA X P，et al. IL-6 promoter polymorphism increased risks of recurrent stroke in the young patients with moderate internal carotid artery stenosis[J]. J Cell Biochem，2018，119（3）：2886-2890.
[29] HARRIOTT A M，DUEKER N，CHENG Y C，et al. Polymorphisms in migraine-associated gene，atp1a2，and ischemic stroke risk in a biracial population：the genetics of early onset stroke study[J/OL]. Springerplus，2013，2（1）：46[2022-07-20]. https://doi. org/10.1186/2193-1801-2-46.
[30] CHENG Y C，ANDERSON C D，BIONE S，et al. Are myocardial infarction-associated single-nucleotide polymorphisms associated with ischemic stroke?[J]. Stroke，2012，43（4）：980-986.
[31] GUO D C，PAPKE C L，TRAN-FADULU V，et al. Mutations in smooth muscle alpha-actin（ACTA2）cause coronary artery disease，stroke，and moyamoya disease，along with thoracic aortic disease[J]. Am J Hum Genet，2009，84（5）：617-627.
[32] GRETARSDOTTIR S，THORLEIFSSON G，REYNISDOTTIR S T，et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke[J]. Nat Genet，2003，35（2）：131-138.
[33] MUNSHI A，BABU M S，KAUL S，et al. Phosphodiesterase 4D（PDE4D）gene variants and the risk of ischemic stroke in a South Indian population[J]. J Neurol Sci，2009，285（1/2）：142-145.
[34] YUE X J，LIU L X，YAN H Q，et al. Association between PDE4D polymorphism and ischemic stroke in young population[J]. Saudi J Biol Sci，2019，26（5）：1023-1026.
[35] SONG Q，COLE J W，O'CONNELL J R，et al. Phosphodiesterase 4D polymorphisms and the risk of cerebral infarction in a biracial population：the stroke prevention in young women study[J]. Hum Mol Genet，2006，15（16）：2468-2478.
[36] HE Y，YANG D Z，YU H，et al. Genetic variants of phosphodiesterase 4D gene are associated with an enhanced risk for ischemic stroke in young Chinese population[J]. Neurol India，2013，61（1）：21-25.
[37] HE Y，BAI J Y，SONG B，et al. Sex-dependent association of phosphodiesterase 4D gene polymorphisms with ischemic stroke in Henan Han population[J]. Chin Med J（Engl），2012，125（13）：2255-2259.
[38] LIAO Y C，LIN H F，GUO Y C，et al. Sex-differential genetic effect of phosphodiesterase 4D（PDE4D）on carotid atherosclerosis[J/OL]. BMC Med Genet，2010，11：93[2022-07-20]. https://doi. org/10.1186/1471-2350-11-93.
[39] MALIK R，CHAUHAN G，TRAYLOR M，et al. Multiancestry genome-wide association study of 520，000 subjects identifies 32 loci associated with stroke and stroke subtypes[J]. Nat Genet，2018，50（4）：524-537.
[40] JIN M，ZHANG H，ZHANG Q，et al. Association of single-nucleotide polymorphism on chromosome 9 and ischemic stroke in Heilongjiang province in China[J]. Int J Clin Exp Pathol，2021，14（6）：726-733.
[41] DI CASTELNUOVO A，PEZZINI A，LATELLA M C，et al. Polymorphisms in chromosome 9 and risk of ischemic stroke in two European white populations，and a meta-analysis[J]. J Thromb Haemost，2009，7（2）：365-367.
[42] CHENG Y C，STANNE T M，GIESE A K，et al. Genome-wide association analysis of young-onset stroke identifies a locus on chromosome 10q25 near HABP2[J]. Stroke，2016，47（2）：307-316.
[43] CHENG Y C，O'CONNELL J R，COLE J W，et al. Genome-wide association analysis of ischemic stroke in young adults[J]. G3（Bethesda），2011，1（6）：505-514.
[44] JAWOREK T，RYAN K A，GAYNOR B J，et al. Exome array analysis of early-onset ischemic stroke[J]. Stroke，2020，51（11）：3356-3360.