Polymorphisms of genes in nitric oxide-forming pathway associated with ischemic stroke in chinese han population

ABSTRACT AIM: To investigate the association of polymorphisms in four critical genes implicated in the NO-forming pathway with ischemic stroke (IS) in a Chinese Han population. METHODS: DNA

samples of 558 IS patients and 557 healthy controls from Chinese Han population were genotyped using the TaqmanTM 7900HT Sequence Detection System. Six SNPs (rs841, rs1049255, rs2297518,

rs1799983, rs2020744, rs4673) of the 4 related genes (eNOS, iNOS, GCH1, and CYBA) in the NO forming pathway were analyzed using the SPSS 13.0 software package for Windows. RESULTS: One SNP

located in the intron of GCH1 (rs841) was associated with IS independent of the traditional cardiovascular risk factors in co-dominant and dominant models (_P_=0.003, _q_=0.027; _P_=0.00006,

_q_=0.0108; respectively). Moreover, the combination of rs1049255 CC+CT and rs841 GA+AA genotypes was associated with significantly higher risk for IS after adjustments (OR=1.73, 95% CI:

1.27–2.35, _P_<0.0001, _q_<0.0001). CONCLUSION: The data suggest that genetic variants within the NO-forming pathway alter susceptibility to IS in Chinese Han population. Replication

of the present results in other independent cohorts is warranted. SIMILAR CONTENT BEING VIEWED BY OTHERS ASSOCIATION STUDY BETWEEN GENETIC POLYMORPHISMS IN MTHFR AND STROKE SUSCEPTIBILITY IN

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26 April 2025 INTRODUCTION Ischemic stroke (IS), known to be a multifactorial disorder, is the leading cause of disability and the second leading cause of death in China1. IS usually

results from hypertension, atherosclerosis, diabetes, smoking, vasculitis or other etiologies. Beyond the conventional risk factors, evidence is accumulating that genetic factors may also

contribute to the risk of stroke development2. Nitric oxide (NO) is synthesized by the enzyme nitric oxide synthase (NOS) from _L_-arginine and oxygen in endothelial cells, neurons, glia and

macrophages3. NO plays an important role in the control of cerebral blood flow, thrombogenesis, and the modulation of neuronal activity4. High concentrations of NO originating from cerebral

ischemia mediate inflammatory and cytotoxic pathways leading to neuronal death5. NO is also important to protect vessels against atherosclerosis6. NO bioavailability is tightly regulated by

a balance between its production and detoxification or degradation, and therefore, cerebral ischemia could be related to abnormalities in the expression and activity of NOS. Several

potential functional polymorphisms in the nitric oxide-forming pathway have recently been discovered, including (1) Leu608Ser (rs2297518) in inducible [_iNOS_]7, (2, 3) Glu298Asp (rs1799983)

and T-786C (rs2070744) in the promoter region of endothelial [_eNOS_]8, 9, 10, 11, 12, (4, 5) Tyr72His (rs4673) and C+640T (rs1049255) in the 3′-untranslated region (UTR) of the cytochrome

b-245, alpha polypeptide gene (_CYBA_)13, 14, 15, 16, which encodes the p22_phox_ subunit of the NADPH oxidase, and (6) G+243A (rs841) in the 3′-UTR of the GTP cyclohydrolase 1 gene

(_GCH1_)17. With special attention to the biological process of cerebral ischemia regulation, we investigated whether polymorphisms in these genes implicated in the pathway of NO formation

are associated with IS in a large cohort in the Chinese Han population. MATERIALS AND METHODS STUDY POPULATION AND DATA COLLECTION This was a multicenter, collaborative study for assessment

of risk factors for stroke sponsored by the Ministry of Science and Technology of China. The study protocol was approved by the review board of Tongji Medical College at Huazhong University

of Science and Technology and the ethics committees at all participating hospitals. An informed consent form was obtained from all participants. A total of 558 IS patients were recruited

between November 2004 and June 2006 from five hospitals in Wuhan, China. Only 2 subtypes of stroke — cerebral thrombosis (atherothrombosis) and lacunar infarction (lacunar) —were included.

Subjects with subarachnoid hemorrhage, embolic brain infarction, brain tumors and cerebrovascular malformation were excluded from the study, as were those with severe systemic diseases such

as pulmonary fibrosis, endocrine and metabolic disease (except diabetes mellitus), severe inflammatory diseases, autoimmune disease, tumors and serious chronic diseases (_eg_, hepatic

cirrhosis and renal failure). Subjects with cardioembolic stroke and documented atrial fibrillation were also excluded from our study. Stroke diagnosis was based on the results of

neurological examination and CT or MRI according to the International Classification of Diseases, ninth edition. Five hundred fifty-seven ethnically and geographically matched controls were

randomly selected either from normal individuals of nearby community-based residents (89.6%) or inpatients (10.4%) with minor illnesses. All control subjects were free of neurological

diseases following the same exclusion criteria as cases. They were also asked for a detailed medical history and received a physical examination of neurological systems, including an

evaluation of body mass index. DNA ISOLATION AND GENOTYPING DNA was extracted from leukocytes as previously described18. All samples were genotyped using the TaqmanTM 7900HT Sequence

Detection System according to the manufacturer's instructions. Each assay was conducted using 10 ng DNA in a 5 μL reaction consisting of TaqManTM universal PCR master mix (Applied

Biosystems, Foster City, CA, USA), forward and reverse primers and FAM and VIC labeled probes designed by Applied Biosystems [ABI Assays-on-Demand (rs841, C_9866639_10; rs1049255,

C_7516913_10; rs2297518, C_11889257_10; rs1799983, C_3219460_20; rs4673, C_2038_20) and Assays-on-Design (rs2070744)]. Allelic discrimination was measured automatically using the Sequence

Detection Systems 2.1 software (autocaller confidence level 95%). A total of 10% of all genotypes were repeated in independent PCRs to check for consistency and to ensure intraplate and

interplate genotype quality control. No genotyping discrepancies were detected between the repeated samples. In addition, all the DNA samples for cases and controls were run in the same

batches. STATISTICAL ANALYSIS Statistical analysis were performed with the SPSS 13.0 software package for Windows (SPSS Inc, Chicago, IL, USA). The normality of quantitative variable

distribution was assessed using the 1-sample Kolmogorov-Smirnov test, and a transformation was applied to non-normal variables when necessary. Summary statistics were expressed as the

mean±standard error or as percentages. The χ2 test was used to assess the deviation from Hardy-Weinberg equilibrium for genotype frequencies in both cases and controls. Continuous variables

were compared between cases of stroke and controls using Student's _t_-test. Frequencies of categorical variables were compared by χ2 test or Fisher's exact test. The potential

independent role of each single-nucleotide polymorphism (SNP) on stroke was investigated with multiple unconditional logistic regression analysis adjusted for age, sex, body mass index,

hypertension, hyperlipidemia, diabetes mellitus and smoking status. To minimize the false positive results generated from the multiple statistical tests used in our analysis, we adopted a

method proposed by Story and Tibshirani to estimate the FDR (false discovery rate)-based _q_ value using QVALUE software (setting [lambda]=0, false discovery rate level<0.05)19. All

association analyses were conducted in three genetic models: co-dominant, dominant and recessive. Power calculations were performed using the QUANTO software program20 (Version 1.2.3).

RESULTS BASELINE CHARACTERISTICS OF THE SUBJECTS Table 1 summarizes the clinical characteristics of individuals enrolled in the study. The mean age, gender ratio and total cholesterol level

were similar in cases and controls. Expectedly, there were significantly higher percentages of hypertension, diabetes mellitus, hyperlipidemia, and smoking in overall IS and subtype groups

versus the controls (_P_<0.05). Body mass index, systolic blood pressure, and diastolic blood pressure were also higher in cases than controls. Compared to the control group, patients in

both the overall IS and subtype groups had significantly lower HDL cholesterol (_P_<0.05). GENOTYPES IN RELATION TO ISCHEMIC STROKE AND ITS SUBTYPES Next, we assessed associations between

six SNPs from four related genes (three at two isoforms of NOS, one at GCH1, and two at CYBA) and IS in the Chinese Han population. All genotype distributions were consistent with

Hardy-Weinberg equilibrium (_P_>0.05). Table 2 lists single SNP allelic frequencies of the four genes among IS subjects (_n_=558) and control subjects (_n_=557). Mutiplicative-type

corrections such as Bonferroni corrections for correlated genetic factors and tests are highly conservative. Therefore, we present the _q_ value, a measure of false discovery rate expected

for a given _P_ value in the follow-up analysis. Notably, rs841 in the intron region of _GCH1_ demonstrated allelic frequency differences between overall IS and lacunar stroke subjects

compared with controls (_P_=0.001 and 0.002, respectively), which maintained statistical significance after multiple comparison correction (_q_=0.018 for both) (Table 2). To further

investigate how each of the SNP alleles interact in conferring genetic risk for IS, we conducted a genotypic association analysis assuming 3 common genetic models (co-dominant, dominant and

recessive). Interestingly, SNP rs841 showed consistent effects using both a co-dominant (without adjustment for covariates, _P_=0.001, _q_=0.009; after adjustment for traditional risk

factors, _P_=0.003, _q_=0.027) and a dominant model (without adjustment for covariates, _P_=0.0003, _q_=0.0054; after adjustment for traditional risk factors, _P_=0.0006, _q_=0.0108) (Table

3). To test the possible effect of the IS subtypes in detecting an association, we then re-assessed the association between rs841 and the cerebral thrombosis and lacunar infarction groups

(Supplementary Tables 1 and 2). It is of interest to note that rs841 was significantly associated with both subtypes (nominal _P_<0.05). However, none of these results pass the

significance threshold after multiple corrections. These negative results could be due to reduced sample size and statistical power for subtype analysis. ASSOCIATION OF GENOTYPE COMBINATIONS

WITH ISCHEMIC STROKE We applied the logistic regression analyses to test potential interactions among polymorphisms within genes involved in the NO-forming pathway that may confer IS risk

and identified significant interactions between rs1049255 and rs841 (_P_<0.001). In comparison with the reference combination of rs1049255 CC+CT and rs841 GG wild type genotypes, the

combination of the rs1049255 CC+CT genotype together with the rs841 GA+AA genotype was found to be significantly associated with IS (_P_=0.002, _q_=0.008; Table 4). The distribution

combinations of other genotypes did not differ from the wild-type reference in overall IS. The combination of rs1049255 CC+CT and rs841 GA+AA genotypes was associated with significantly

higher risk of IS even after adjustment for sex, age, and multiple cardiovascular risk factors (OR=1.73, 95% CI: 1.27–2.35; _P_<0.0001, _q_<0.0001) (Table 5). Given that the reduced

sample size for IS subtypes resulted in largely insufficient power to test potential interactions, subtype analyses were not performed. Taken together, our data suggest an interaction of

NO-forming pathway genes in the risk of IS. DISCUSSION This study is to investigate the association between genetic polymorphisms in the genes implicated in NO production and risk for IS

development in the Chinese Han population. The present results indicate that polymorphisms in _GCH1_ (rs841) are independently associated with an increased risk for IS. In contrast, we

failed to detect significant independent association with the rest of SNPs even though they have been suggested to be associated with cardiovascular diseases such as hypertension, coronary

heart disease or stroke21, 22, 23. Nitric oxide, produced by nitric oxide synthase, is an important bioregulatory molecule and displays diverse biological activities. Tetrahydrobiopterin

(BH4) is an essential cofactor for all three NOS isoforms, and basal enzyme activity correlates with the amount of BH4 bound tightly to NOS24. BH4 deficiency is proposed to lead to NOS

uncoupling associated with decreased NO bioavailability and increased production of superoxide radicals from the uncoupled enzymatic form25. GTP cyclohydrolase 1 (GCH1) is the first-step and

rate-limiting enzyme for BH4 biosynthesis in its _de novo_ pathway26. Experimental mouse models with alterations in systemic or vascular-specific _GCH1_ expression have shown that GCH1 is a

key regulator of vascular BH4 levels _in vivo_27, 28. Low brain levels of BH4 have been shown in the mouse model for dominantly inherited GCH1 deficiency29. Recent evidence suggests that

one SNP (rs841), located in the 3′-UTR of the _GCH1_ gene, is also associated with reduced biopterin-dependent effects17. The _CYBA_ gene, located on the long arm of chromosome 16 at

position 24, encodes human p22_phox_, which is an essential subunit for the functionality of the NADPH oxidase30. NADPH oxidase is an important enzymatic source of oxidative stress as well

as uncoupled NOS caused by BH4 deficiency and plays a key role in the pathophysiology of several major cardiovascular diseases, including stroke31. Previous studies have shown the

association between CYBA polymorphisms and vascular diseases30. Our combined analysis identified _GCH1_ (rs841) and _CYBA_ (rs1049255) interactions, indicating that these two functional

polymorphisms may confer risk for IS through biological interactions with each other. Further studies might be required to ascertain whether _CYBA_ (rs1049255) affects _GCH1_ expression and

how such an effect might be mediated. To control for potential false-positive results, we took several factors into consideration and carefully designed our study. First, all selected

candidate SNPs have substantial functional effects that are likely involved in the development of IS. Second, assuming disease prevalence between 0.5% and 1%, our combined sample size can

reach >98% power to detect a susceptibility locus with a genotypic relative risk >1.65 at the nominal type I error rate of <0.05 for SNPs with minor allele frequencies >0.31

under the dominant model. Third, we recruited only ethnically and geographically matched subjects from Chinese Han cohorts. Given the homogenous study population, we expect population

substructure to be minimal. However, additional replication of the association signals in other independent cohorts is warranted. In summary, genetic variants in the genes implicated in NO

formation could have potentially important effects on the pathogenesis of vascular diseases, and genotyping of these variants may provide an additional tool to predict the risk for ischemic

stroke in the Chinese Han population. AUTHOR CONTRIBUTION Jiang-tao YAN, Lan ZHANG and Yu-jun XU performed the research; Xiao-jing WANG and Cong-yi WANG contributed new analytical tools and

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274–8. Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS This study was supported by China 973 program (No 2007CB512004), and 863 program (No 2006AA02A406). AUTHOR

INFORMATION Author notes * Jiang-tao Yan and Lan Zhang: These authors contributed to this work equally. AUTHORS AND AFFILIATIONS * Institute of Hypertension and Department of Internal

Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China Jiang-tao Yan, Lan Zhang, Yu-jun Xu & Dao-wen Wang * Department of

Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, 15219, PA, USA Xiao-jing Wang * Center for Biotechnology and Genomic Medicine, Medical College of Georgia,

Augusta, 30912, GA, USA Cong-yi Wang Authors * Jiang-tao Yan View author publications You can also search for this author inPubMed Google Scholar * Lan Zhang View author publications You can

also search for this author inPubMed Google Scholar * Yu-jun Xu View author publications You can also search for this author inPubMed Google Scholar * Xiao-jing Wang View author

publications You can also search for this author inPubMed Google Scholar * Cong-yi Wang View author publications You can also search for this author inPubMed Google Scholar * Dao-wen Wang

View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Dao-wen Wang. ADDITIONAL INFORMATION Supplementary tables are

available at Acta Pharmacologica Sinica website of NPG. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TABLE 1 Distribution of Genotypes in three models in Atherothrombosis of Ischemic Stroke

SUPPLEMENTARY TABLE 2 Distribution of Genotypes in three models in Lacunar Infarction of Ischemic Stroke RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE

Yan, Jt., Zhang, L., Xu, Yj. _et al._ Polymorphisms of genes in nitric oxide-forming pathway associated with ischemic stroke in Chinese Han population. _Acta Pharmacol Sin_ 32, 1357–1363

(2011). https://doi.org/10.1038/aps.2011.114 Download citation * Received: 11 November 2010 * Accepted: 17 July 2011 * Published: 03 October 2011 * Issue Date: November 2011 * DOI:

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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * ischemic stroke * nitric oxide * polymorphism *

genetics * Chinese Han population