Association between PPARG genetic polymorphisms and ischemic stroke risk in a northern Chinese Han population: a case-control study
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摘要
Two common polymorphisms of the peroxisome proliferator-activated receptor gamma(PPARG) gene, rs1801282 and rs3856806, may be important candidate gene loci affecting the susceptibility to ischemic stroke. This case-control study sought to identify the relationship between these two single-nucleotide polymorphisms and ischemic stroke risk in a northern Chinese Han population. A total of 910 ischemic stroke participants were recruited from the First Hospital of China Medical University, Shenyang, China as a case group, of whom 895 completed the study. The 883 healthy controls were recruited from the Health Check Center of the First Hospital of China Medical University, Shenyang, China. All participants or family members provided informed consent. The study protocol was approved by the Ethics Committee of the First Hospital of China Medical University, China on February 20, 2012(approval No. 2012-38-1). The protocol was registered with the Chinese Clinical Trial Registry(registration number: ChiCTR-COC-17013559). Plasma genomic DNA was extracted from all participants and analyzed for rs1801282 and rs3856806 single nucleotide polymorphisms using a SNaPshot Multiplex sequencing assay. Odds ratios(ORs) and 95% confidence intervals(CIs) were calculated using unconditional logistic regression to estimate the association between ischemic stroke and a particular genotype. Results demonstrated that the G allele frequency of the PPARG gene rs1801282 locus was significantly higher in the case group than in the control group(P < 0.001). Individuals carrying the G allele had a 1.844 fold increased risk of ischemic stroke(OR = 1.844, 95% CI: 1.286–2.645, P < 0.001). Individuals carrying the rs3856806 T allele had a 1.366 fold increased risk of ischemic stroke(OR = 1.366, 95% CI: 1.077–1.733, P = 0.010). The distribution frequencies of the PPARG gene haplotypes rs1801282-rs3856806 in the control and case groups were determined. The frequency of distribution in the G-T haplotype case group was significantly higher than that in the control group. The risk of ischemic stroke increased to 2.953 times in individuals carrying the G-T haplotype(OR = 2.953, 95% CI: 2.082–4.190, P < 0.001). The rs1801282 G allele and rs3856806 T allele had a multiplicative interaction(OR = 3.404, 95% CI: 1.631–7.102, P < 0.001) and additive interaction(RERI = 41.705, 95% CI: 14.586–68.824, AP = 0.860; 95% CI: 0.779–0.940; S = 8.170, 95% CI: 3.772–17.697) on ischemic stroke risk, showing a synergistic effect. Of all ischemic stroke cases, 86% were attributed to the interaction of the G allele of rs1801282 and the T allele of rs3856806. The effect of the PPARG rs1801282 G allele on ischemic stroke risk was enhanced in the presence of the rs3856806 T allele(OR = 8.001 vs. 1.844). The effect of the rs3856806 T allele on ischemic stroke risk was also enhanced in the presence of the rs1801282 G allele(OR = 2.546 vs. 1.366). Our results confirmed that the G allele of the PPARG gene rs1801282 locus and the T allele of the rs3856806 locus may be independent risk factors for ischemic stroke in the Han population of northern China, with a synergistic effect between the two alleles.
Two common polymorphisms of the peroxisome proliferator-activated receptor gamma(PPARG) gene, rs1801282 and rs3856806, may be important candidate gene loci affecting the susceptibility to ischemic stroke. This case-control study sought to identify the relationship between these two single-nucleotide polymorphisms and ischemic stroke risk in a northern Chinese Han population. A total of 910 ischemic stroke participants were recruited from the First Hospital of China Medical University, Shenyang, China as a case group, of whom 895 completed the study. The 883 healthy controls were recruited from the Health Check Center of the First Hospital of China Medical University, Shenyang, China. All participants or family members provided informed consent. The study protocol was approved by the Ethics Committee of the First Hospital of China Medical University, China on February 20, 2012(approval No. 2012-38-1). The protocol was registered with the Chinese Clinical Trial Registry(registration number: ChiCTR-COC-17013559). Plasma genomic DNA was extracted from all participants and analyzed for rs1801282 and rs3856806 single nucleotide polymorphisms using a SNaPshot Multiplex sequencing assay. Odds ratios(ORs) and 95% confidence intervals(CIs) were calculated using unconditional logistic regression to estimate the association between ischemic stroke and a particular genotype. Results demonstrated that the G allele frequency of the PPARG gene rs1801282 locus was significantly higher in the case group than in the control group(P < 0.001). Individuals carrying the G allele had a 1.844 fold increased risk of ischemic stroke(OR = 1.844, 95% CI: 1.286–2.645, P < 0.001). Individuals carrying the rs3856806 T allele had a 1.366 fold increased risk of ischemic stroke(OR = 1.366, 95% CI: 1.077–1.733, P = 0.010). The distribution frequencies of the PPARG gene haplotypes rs1801282-rs3856806 in the control and case groups were determined. The frequency of distribution in the G-T haplotype case group was significantly higher than that in the control group. The risk of ischemic stroke increased to 2.953 times in individuals carrying the G-T haplotype(OR = 2.953, 95% CI: 2.082–4.190, P < 0.001). The rs1801282 G allele and rs3856806 T allele had a multiplicative interaction(OR = 3.404, 95% CI: 1.631–7.102, P < 0.001) and additive interaction(RERI = 41.705, 95% CI: 14.586–68.824, AP = 0.860; 95% CI: 0.779–0.940; S = 8.170, 95% CI: 3.772–17.697) on ischemic stroke risk, showing a synergistic effect. Of all ischemic stroke cases, 86% were attributed to the interaction of the G allele of rs1801282 and the T allele of rs3856806. The effect of the PPARG rs1801282 G allele on ischemic stroke risk was enhanced in the presence of the rs3856806 T allele(OR = 8.001 vs. 1.844). The effect of the rs3856806 T allele on ischemic stroke risk was also enhanced in the presence of the rs1801282 G allele(OR = 2.546 vs. 1.366). Our results confirmed that the G allele of the PPARG gene rs1801282 locus and the T allele of the rs3856806 locus may be independent risk factors for ischemic stroke in the Han population of northern China, with a synergistic effect between the two alleles.
Two common polymorphisms of the peroxisome proliferator-activated receptor gamma(PPARG) gene, rs1801282 and rs3856806, may be important candidate gene loci affecting the susceptibility to ischemic stroke. This case-control study sought to identify the relationship between these two single-nucleotide polymorphisms and ischemic stroke risk in a northern Chinese Han population. A total of 910 ischemic stroke participants were recruited from the First Hospital of China Medical University, Shenyang, China as a case group, of whom 895 completed the study. The 883 healthy controls were recruited from the Health Check Center of the First Hospital of China Medical University, Shenyang, China. All participants or family members provided informed consent. The study protocol was approved by the Ethics Committee of the First Hospital of China Medical University, China on February 20, 2012(approval No. 2012-38-1). The protocol was registered with the Chinese Clinical Trial Registry(registration number: ChiCTR-COC-17013559). Plasma genomic DNA was extracted from all participants and analyzed for rs1801282 and rs3856806 single nucleotide polymorphisms using a SNaPshot Multiplex sequencing assay. Odds ratios(ORs) and 95% confidence intervals(CIs) were calculated using unconditional logistic regression to estimate the association between ischemic stroke and a particular genotype. Results demonstrated that the G allele frequency of the PPARG gene rs1801282 locus was significantly higher in the case group than in the control group(P < 0.001). Individuals carrying the G allele had a 1.844 fold increased risk of ischemic stroke(OR = 1.844, 95% CI: 1.286–2.645, P < 0.001). Individuals carrying the rs3856806 T allele had a 1.366 fold increased risk of ischemic stroke(OR = 1.366, 95% CI: 1.077–1.733, P = 0.010). The distribution frequencies of the PPARG gene haplotypes rs1801282-rs3856806 in the control and case groups were determined. The frequency of distribution in the G-T haplotype case group was significantly higher than that in the control group. The risk of ischemic stroke increased to 2.953 times in individuals carrying the G-T haplotype(OR = 2.953, 95% CI: 2.082–4.190, P < 0.001). The rs1801282 G allele and rs3856806 T allele had a multiplicative interaction(OR = 3.404, 95% CI: 1.631–7.102, P < 0.001) and additive interaction(RERI = 41.705, 95% CI: 14.586–68.824, AP = 0.860; 95% CI: 0.779–0.940; S = 8.170, 95% CI: 3.772–17.697) on ischemic stroke risk, showing a synergistic effect. Of all ischemic stroke cases, 86% were attributed to the interaction of the G allele of rs1801282 and the T allele of rs3856806. The effect of the PPARG rs1801282 G allele on ischemic stroke risk was enhanced in the presence of the rs3856806 T allele(OR = 8.001 vs. 1.844). The effect of the rs3856806 T allele on ischemic stroke risk was also enhanced in the presence of the rs1801282 G allele(OR = 2.546 vs. 1.366). Our results confirmed that the G allele of the PPARG gene rs1801282 locus and the T allele of the rs3856806 locus may be independent risk factors for ischemic stroke in the Han population of northern China, with a synergistic effect between the two alleles.
引文
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Lee Y,Cha YS,Park Y,Lee M(2017)PPARgamma2 C1431T polymorphism interacts with the antiobesogenic effects of kochujang,a korean fermented,soybean-based red pepper paste,in overweight/obese subjects:a 12-week,double-blind randomized clinical trial.J Med Food 20:610-617.
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Certo M,Endo Y,Ohta K,Sakurada S,Bagetta G,Amantea D(2015)Activation of RXR/PPARgamma underlies neuroprotection by bexarotene in ischemic stroke.Pharmacol Res 102:298-307.
Cheng YC,Anderson CD,Bione S,Keene K,Maguire JM,Nalls M,Rasheed A,Zeginigg M,Attia J,Baker R,Barlera S,Biffi A,Bookman E,Brott TG,Brown RD Jr,Chen F,Chen WM,Ciusani E,Cole JW,Cortellini L,et al.(2012)Are myocardial infarction-associated single-nucleotide polymorphisms associated with ischemic stroke?Stroke 43:980-986.
Culman J,Zhao Y,Gohlke P,Herdegen T(2007)PPAR-gamma:therapeutic target for ischemic stroke.Trends Pharmacol Sci 28:244-249.
Deng S,Zhu G,Liu F,Zhang H,Qin X,Li L,Zhiyi H(2010)CYP4F2gene V433M polymorphism is associated with ischemic stroke in the male Northern Chinese Han population.Prog Neuropsychopharmacol Biol Psychiatry 34:664-668.
Evans DM,Marchini J,Morris AP,Cardon LR(2006)Two-stage two-locus models in genome-wide association.PLoS Genet 2:e157.
Gao Y,Jiang B,Sun H,Ru X,Sun D,Wang L,Wang L,Jiang Y,Feigin VL,Wang Y,Wang W(2018)The burden of stroke in China:Results from a nationwide population-based epidemiological survey.PLoSOne 13:e0208398.
Fisher RA(1918)On the correlation between relatives on the supposition of Mendelian inheritance.Trans Med Chir Soc Edinb 52:399-433.
Ivanova EA,Parolari A,Myasoedova V,Melnichenko AA,Bobryshev YV,Orekhov AN(2015)Peroxisome proliferator-activated receptor(PPAR)gamma in cardiovascular disorders and cardiovascular surgery.J Cardiol 66:271-278.
Janani C,Ranjitha Kumari BD(2015)PPAR gamma gene--a review.Diabetes Metab Syndr 9:46-50.
Jih J,Mukherjea A,Vittinghoff E,Nguyen TT,Tsoh JY,Fukuoka Y,Bender MS,Tseng W,Kanaya AM(2014)Using appropriate body mass index cut points for overweight and obesity among Asian Americans.Prev Med 65:1-6.
Kasim NB,Huri HZ,Vethakkan SR,Ibrahim L,Abdullah BM(2016)Genetic polymorphisms associated with overweight and obesity in uncontrolled Type 2 diabetes mellitus.Biomark Med 10:403-415.
Kim M,Kim M,Yoo HJ,Shon J,Lee JH(2018)Associations between hypertension and the peroxisome proliferator-activated receptor-delta(PPARD)gene rs7770619 C>T polymorphism in a Korean population.Hum Genomics 12:28.
Lee BC,Lee HJ,Chung JH(2006)Peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism is associated with reduced risk for ischemic stroke with type 2 diabetes.Neurosci Lett 410:141-145.
Lee JH,Zhang J,Yu SP(2017)Neuroprotective mechanisms and translational potential of therapeutic hypothermia in the treatment of ischemic stroke.Neural Regen Res 12:341-350.
Lee Y,Cha YS,Park Y,Lee M(2017)PPARgamma2 C1431T polymorphism interacts with the antiobesogenic effects of kochujang,a korean fermented,soybean-based red pepper paste,in overweight/obese subjects:a 12-week,double-blind randomized clinical trial.J Med Food 20:610-617.
Leng RX,Pan HF,Liu J,Yang XK,Zhang C,Tao SS,Wang DG,Li XM,Li XP,Yang W,Ye DQ(2016)Evidence for genetic association of TBX21 and IFNG with systemic lupus erythematosus in a Chinese Han population.Sci Rep 6:22081.
Li Q,Tian Z,Wang M,Kou J,Wang C,Rong X,Li J,Xie X,Pang X(2019)Luteoloside attenuates neuroinflammation in focal cerebral ischemia in rats via regulation of the PPARgamma/Nrf2/NF-kappaB signaling pathway.Int Immunopharmacol 66:309-316.
Li Z,Zhang Z,He Z,Tang W,Li T,Zeng Z,He L,Shi Y(2009)A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers:update of the SHEsis(http://analysis.bio-x.cn).Cell Res 19:519-523.
Liska MG,Crowley MG,Tuazon JP,Borlongan CV(2018)Neuroprotective and neuroregenerative potential of pharmacologically-induced hypothermia with D-alanine D-leucine enkephalin in brain injury.Neural Regen Res 13:2029-2037.
Liu F,He Z,Deng S,Zhang H,Li N,Xu J(2011)Association of adiponectin gene polymorphisms with the risk of ischemic stroke in a Chinese Han population.Mol Biol Rep 38:1983-1988.
Liu J,Wang LN(2015)Peroxisome proliferator-activated receptor gamma agonists for preventing recurrent stroke and other vascular events in patients with stroke or transient ischaemic attack.Cochrane Database Syst Rev:Cd010693.
Liu M,Bachstetter AD,Cass WA,Lifshitz J,Bing G(2017)Pioglitazone attenuates neuroinflammation and promotes dopaminergic neuronal survival in the nigrostriatal system of rats after diffuse brain injury.JNeurotrauma 34:414-422.
Liu Y,Wan W,Fang F,Guo L,Zhao Y,Zhang X,Huang F(2018)Clinical relevance of peroxisome proliferator-activated receptor-gamma gene polymorphisms with sepsis.J Clin Lab Anal 32:e22340.
Liu ZM,Hu M,Chan P,Tomlinson B(2015)Early investigational drugs targeting PPAR-alpha for the treatment of metabolic disease.Expert Opin Investig Drugs 24:611-621.
Lv X,Zhang L,Sun J,Cai Z,Gu Q,Zhang R,Shan A(2017)Interaction between peroxisome proliferator-activated receptor gamma polymorphism and obesity on type 2 diabetes in a Chinese Han population.Diabetol Metab Syndr 9:7.
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