Association of Inflammatory Gene Polymorphisms With Ischemic Stroke in a Chinese Han Population

Nan Zhao; Xin Liu; Yongqin Wang; Xiaoqiu Liu; Jiana Li; Litian Yu; Liyuan Ma; Shuyu Wang; Hongye Zhang; Lisheng Liu; Jingbo Zhao; Xingyu Wang

Disclosures

J Neuroinflammation. 2012;9(162)

Conclusions

The current study made a survey of inflammatory gene polymorphisms in examining the risk for ischemic stroke. The results were largely concordant with previous knowledge of inflammation and vascular diseases. Our study demonstrated CCL11 rs4795895 is associated with ischemic stroke after adjusting for multiple testing. We also found five SNPs were associated with ischemic stroke in the non-hypertensive group and two SNPs were associated with ischemic stroke in the hypertensive group. These results collectively showed that inflammatory genetic variants were significantly associated with increased risk of ischemic stroke, particularly in non-hypertensive individuals. Additional studies in larger populations will be needed to confirm the relationship of inflammatory polymorphisms to stroke and its subtypes.

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Authors' contributions
NZ, XL, YW carried out the molecular genetic studies and drafted the manuscript. MT participated in the sequence alignment. LY, LM, SW, HZ, LL participated in the design of the study. XL, JL participated in the statistical analysis. XW and JZ designed the study, participated in its design and coordination, and drafted the manuscript. All authors read and approved the final manuscript.

Acknowledgements
This study was supported by the Beijing Hypertension League Institute, in part through the National Infrastructure Program of Chinese Genetic Resource (2005DKA21300) and an unrestricted educational grant from F. Hoffmann-La Roche. We thank Ms Wei Zhang, Jian Li, and Jinli Xing for their excellent technical assistance.

Table 1. Characteristics of study participants
	Ischemic stroke patients	Controls	P value
Number of subjects	1,124	1,163
Age, mean (SD), years	59.20 (10.71)	62.32 (10.68)	<0.0001
Male, %	59.82	61.25	0.483
BMI, mean (SD), kg/m²	24.42 (3.00)	25.04 (3.28)	<0.0001
Hypertension, %	64.74	70.19	0.005

Data presented as percentage of participants unless otherwise stated. P values for χ² test for categorical variables, and Student's t test for continuous variables. Hypertension: systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, or current treatment with antihypertensive medication.
BMI = body mass index.

Table 2. Association between single nucleotide polymorphisms (SNPs) and ischemic stroke
Gene	rsID	Minor allele	Risk allele	MAF, control:case	Additive model			FDR
Gene	rsID	Minor allele	Risk allele	MAF, control:case	OR	95% CI	P value	FDR
CCL11	rs4795895	A	G	0.05:0.07	1.47	1.13 - 1.92	0.004	0.152
CCL11	rs3744508	A	A	0.14:0.12	1.2	1.01 -1.43	0.042	0.547
CCR5	rs1799987	A	A	0.46:0.43	1.13	1.00 - 1.27	0.051	0.547
TGFB1	rs1800469	C	C	0.48:0.49	0.9	0.80 - 1.11	0.071	0.547
NOS3	rs1799983	T	G	0.10:0.11	1.19	0.99 - 1.45	0.072	0.547
CCR2	rs1799864	A	A	0.27:0.25	1.11	0.97 - 1.27	0.143	0.614
IL6	rs1800796	G	G	0.33:0.31	1.1	0.97 - 1.25	0.144	0.614
IL4R	rs1801275	G	G	0.17:0.16	1.12	0.96 - 1.32	0.162	0.614
ADRB2	rs1042713	G	G	0.44:0.42	1.09	0.96 - 1.23	0.172	0.614
CD14	rs2569190	T	T	0.37:0.38	1.09	0.96 - 1.23	0.187	0.614
TNF	rs361525	A	A	0.05:0.05	1.2	0.90 - 1.61	0.208	0.614
FCERB1	rs569108	G	G	0.17:0.16	1.11	0.94 - 1.30	0.217	0.614
LTA	rs909253	G	G	0.42:0.41	1.08	0.95 - 1.22	0.227	0.614
IL1A	rs1800587	T	C	0.09:0.10	1.12	0.92 - 1.37	0.258	0.614
LTC4S	rs730012	C	C	0.15:0.14	1.1	0.93 - 1.30	0.263	0.614
ADRB2	rs1042714	G	G	0.07:0.11	1.11	0.92 - 1.34	0.267	0.614
VDR	rs2228570	T	T	0.45:0.43	1.15	0.89 - 1.49	0.282	0.614
IL10	rs1800872	C	A	0.35:0.36	1.07	0.95 - 1.21	0.291	0.614
GC	rs7041	G	G	0.27:0.26	1.07	0.94 - 1.23	0.321	0.642
VDR	rs1544410	A	A	0.06:0.05	1.05	0.94 - 1.19	0.387	0.735
IL5RA	rs2290608	A	A	0.24:0.23	1.06	0.92 - 1.22	0.435	0.787
IL1B	rs16944	T	T	0.49:0.47	1.05	0.93 - 1.18	0.456	0.788
TNF	rs1800629	A	A	0.06:0.06	1.09	0.86 - 1.39	0.478	0.79
CTLA4	rs5742909	T	C	0.13:0.14	1.06	0.89 - 1.26	0.528	0.81
CSF2	rs25882	T	C	0.38:0.39	1.04	0.92 - 1.17	0.533	0.81
TCF7	rs244656	T	A	0.12:0.13	1.04	0.87 - 1.25	0.649	0.856
IL4R	rs1805015	C	C	0.08:0.08	1.05	0.84 - 1.30	0.669	0.856
SELP	rs6131	A	A	0.19:0.20	1.03	0.89 - 1.20	0.674	0.856
IL13	rs1295686	T	C	0.28:0.29	1.03	0.90 - 1.17	0.679	0.856
VCAM1	rs1041163	C	T	0.15:0.16	1.03	0.88 - 1.21	0.687	0.856
CXCL12	rs1801157	A	G	0.21:0.22	1.03	0.89 - 1.19	0.698	0.856
CTLA4	rs231775	A	G	0.31:0.31	1.02	0.90 - 1.16	0.738	0.876
C5	rs17611	G	G	0.42:0.42	1.02	0.90 - 1.15	0.768	0.884
IL4R	rs1805010	G	G	0.48:0.48	1.01	0.90 - 1.14	0.827	0.899
ICAM1	rs5491	T	T	0.07:0.06	1.03	0.80 - 1.31	0.828	0.899
UGB	rs3741240	A	A	0.43:0.43	1.03	0.89 - 1.13	0.965	0.977
NOS2A	rs1137933	T	T	0.13:0.13	1.00	0.84 - 1.19	0.97	0.977
GC	rs4588	A	A	0.32:0.32	1.00	0.88 - 1.14	0.977	0.977

OR was calculated using a reference allele that resulted in an OR > 1. P value and FDR adjusted for age, sex, body mass index and hypertension status in additive model of inheritance.
FDR = false discovery rate; MAF = minor allele frequency.

Table 3. Single nucleotide polymorphisms (SNPs) achieving P <0.05 for association with ischemic stroke based on hypertension-stratified population
Gene	rsID	Minor allele	Risk allele	MAF, control:case	OR	95% CI	P value	FDR
Non-hypertension
CCL11	rs4795895	A	G	0.07:0.05	1.57	1.05 - 2.66	0.032	0.202
CCL11	rs3744508	A	A	0.10:0.16	1.64	1.20 - 2.25	0.002	0.076
LTA	rs909253	G	G	0.39:0.45	1.29	1.03 - 1.60	0.024	0.182
LTC4S	rs730012	C	C	0.11:0.16	1.55	1.13 - 2.12	0.007	0.086
TGFB1	rs1800469	C	C	0.46:0.46	1.30	1.07 - 1.59	0.009	0.086
FCERB1	rs569108	G	G	0.12:0.17	1.49	1.11 - 2.00	0.009	0.086
Hypertension
CCL11	rs4795895	A	G	0.07:0.05	1.45	1.05 - 1.99	0.023	0.291
CCR2	rs1799864	A	A	0.23:0.28	1.26	1.06 - 1.49	0.008	0.152
CCR5	rs1799987	A	A	0.43:0.48	1.23	1.06 - 1.42	0.007	0.152

Non-hypertension: cases = 397 controls = 347; hypertension: cases = 727 controls = 816. OR was calculated using a reference allele that resulted in an OR >1.
P value and FDR adjusted for age, sex and body mass index in additive model of inheritance.
FDR = false discovery rate; MAF = minor allele frequency.