Association of genetic polymorphisms of claudin‐1 with small vessel vascular dementia

The most recent hypothesis of the development of small vessel vascular dementia (VaD) emphasises the role of blood‐brain barrier (BBB) dysfunction. It is hypothesised that certain genetic polymorphisms of the BBB tight junction claudin‐1 protein, in combination with adverse environmental risk factors, increase the risk of BBB dysfunction and small vessel VaD. In this case‐control study, 97 control participants, with a mean Mini Mental State Exam (MMSE) score of 29.1, and 38 VaD participants were recruited and completed a questionnaire on their medical history and lifestyle factors. Blood was also collected and two single nucleotide polymorphisms (SNPs), rs17501010 and rs893051 of claudin‐1 genotyping, were analysed by real‐time polymerase chain reaction (PCR) assay. A significantly higher frequency of all rs893051 SNP genotypes (GC and CC) was found in the VaD population (OR=4.8, P=0.006 and OR=6, P<0.001 respectively). Patients with TT genotype of rs17501010 were also more likely to have VaD (OR=3.25, P=0.022). Stratification analysis revealed that having combined haplotype GC+CC of rs893051 and lipid disorders was associated with higher risk of VaD (OR=9.9, P<0.001). For patients with type 2 diabetes the odds ratio of VaD increased significantly in GC+CC genotypes of rs893051 (OR=12.57, P<0.0001) and GT+TT of rs17501010 (OR=5.33, P=0.01).     

The prevalence of unique SNPs in the renin‐angiotensin system highlights the need for pharmacogenetics in Indigenous Australians

Genetic differences between ethnic populations affect susceptibility to disease and efficacy of drugs. This study examined and compared the prevalence of single nucleotide polymorphisms (SNPs) in genes of the renin–angiotensin system (RAS) in a desert community of Indigenous Australians and in non‐Indigenous Australians. The polymorphisms were angiotensinogen, AGT G‐217A (rs5049); AGT G+174A (rs4762); Angiotensin II type 1 receptor, AGTR1 A+1166C (rs5186); angiotensin converting enzyme, ACE A‐240T (rs4291), ACE T‐93C (rs4292); renin, REN T+1142C (rs5706). They were measured using allelic discrimination assays. The prevalence of REN T+1142C SNP was similar in the two populations; 99% were homozygous for the T allele. All other SNPs were differently distributed between the two populations (P < 0.0001). In non‐Indigenous Australians, the A allele at position 204 of ACE rs4291 was prevalent (61.8%) whereas in the Indigenous Australians the A allele was less prevalent (28%). For rs4292, the C allele had a prevalence of 37.9% in non‐Indigenous Australians but in Indigenous Australians the prevalence was only 1%. No Indigenous individuals were homozygous for the C allele of AGTR1 (rs5186). Thus the prevalence of RAS SNPs in this Indigenous Australian desert community was different from non‐Indigenous Australians as was the prevalence of cytokine SNPs (as shown in a previous study). These differences may affect susceptibility to chronic renal and cardiovascular disease and may alter the efficacy of drugs used to inhibit the RAS. These studies highlight the need to study the pharmacogenetics of drug absorption, distribution, metabolism and excretion in Indigenous Australians for safe prescribing guidelines.     

Assessment of the link between endothelin K198n Snp,endothelin concentration and acute myocardial infarction in Egyptians

The aim of the current study was to assess the link between EDN K198N SNP, ET‐1 serum concentration and acute myocardial infarction (AMI) in Egyptians. The study cohort consisted of 84 patients at AMI onset and 84 age‐matched healthy controls. Endothelin genotypes and concentrations were determined by sequencing and ELISA, respectively. Genotype distribution was not significantly different between AMI patients and controls (P=.8341). The mean serum ET‐1 concentration of patients (13.83±0.7 pg/mL) was significantly higher than controls (7.26±0.2 pg/mL) (P<.0001). ET‐1 serum concentrations did not vary significantly among various EDN genotypes in patients (P=.378) and controls (P=.6164). Hence, we conclude that EDN K198N genotypes were not related to either ET‐1 concentration or incidence of early‐onset AMI in Egyptians. But, AMI patients had higher ET‐1 concentrations than controls.     

Genetic Variations,Exposure to Persistent Organic Pollutants and Breast Cancer Risk – A Greenlandic Case–Control Study

This study investigated the effects of single nucleotide polymorphisms (SNPs) in xenobiotic and steroid hormone‐metabolizing genes in relation to breast cancer risk and explored possible effect modifications on persistent organic pollutants (POPs) and breast cancer associations. The study also assessed effects of Greenlandic BRCA1 founder mutations. Greenlandic Inuit women (77 cases and 84 controls) were included. We determined two founder mutations in BRCA1: Cys39Gly (rs80357164) and 4684delCC, and five SNPs in xenobiotic and oestrogen‐metabolizing genes: CYP17A1 ‐34T>C (rs743572), CYP19A1 *19C>T (rs10046), CYP1A1 Ile462Val (rs1048943), CYP1B Leu432Val (rs1056836) and COMT Val158Met (rs4680). We used chi‐square test for comparison of categorical variables between groups. Odds ratio (OR) estimates with 95% confidence interval (95%CI) were obtained using logistic regression models. The variant allele of BRCA1 Cys39Gly increased breast cancer risk (Gly/Cys versus Cys/Cys, OR: 12.2, 95%CI: 1.53; 98.1), and carriers of the variant allele of CYP17A1 ‐34T>C had reduced risk (CT+CC versus TT, OR: 0.44, 95%CI: 0.21; 0.93). CYP17A1 ‐34T>C was an effect modifier on the association between perfluoroalkyl acids (PFAAs) and breast cancer risk (∑PFAA, ratio of OR: 0.18, 95%CI: 0.03; 0.97). Non‐significant modifying tendencies were seen for the other SNPs on the effect of polychlorinated biphenyls, organochlorine pesticides and PFAAs. In summary, the BRCA1 Cys39Gly and CYP17A1 ‐34T>C genetic variations were associated with breast cancer risk. Our results indicate that the evaluated genetic variants modify the effects of POP exposure on breast cancer risk; however, further studies are needed to document the data from the relatively small sample size.     

Case‐control pharmacogenetic study of HCN1/HCN2 variants and genetic generalized epilepsies

Epilepsy is a common complex neurological disorder, and some forms are resistant to drug treatment. The HCN1/HCN2 genes encode hyperpolarization‐activated cyclic nucleotide‐gated channels, which play important roles in the electrophysiology of neurons. We investigated the association between HCN1/HCN2 variants and drug resistance or the risk of genetic generalized epilepsies (GGEs). We used matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry to assess nine variants of HCN1/HCN2 in 284 healthy participants and 483 GGEs (279 drug‐responsive, 204 drug‐resistant). Frequencies of HCN2 rs7255568 and rs3752158 G alleles differed in GGEs and in controls (P = .039, P = .027, respectively). The frequency of HCN2 haplotype (CAC) was higher in patients than controls (P = .046). The frequency of the HCN1 rs10462087 CC+CT genotype was lower in patients with childhood absence epilepsy (CAE) than controls (P = .047). Rs7255568 was associated with the risk of CAE (P = .028) and juvenile myoclonic epilepsy (JME) (P = .02). Rs3752158 was associated with the risk of generalized tonic‐clonic seizures, JME, and febrile seizures (all P < .05). The frequency of the HCN2 haplotype (CAC) was higher in patients with JME (P = .015) and in those with febrile seizures (P = .024) than in controls. No significant association was found between HCN1/HCN2 alleles, genotypes or haplotypes, and drug resistance in patients. After Bonferroni's multiple comparisons correction, only the HCN2 rs3752158 C allele and GC+CC genotype frequencies in patients with JME were higher than those in controls (19.2% vs 11.6%, odds ratio (OR) = 1.71, 95% CI = 1.18‐2.32), P = .004 < 0.05/9; 36% vs 22.2%, OR = 1.62(1.18‐2.23), P = .003 < 0.05/9). Our study suggests that HCN2 rs3752158 is involved in the susceptibility to JME.     

Susceptibility loci reported in genome‐wide association studies are associated with Crohn’s disease in Canadian children

Aliment Pharmacol Ther 31 , 1186–1191

Summary

Background Recent genome‐wide association studies based on adult and paediatric populations have implicated >30 genes/loci as susceptibility loci for Crohn’s disease (CD). Aims To investigate whether reported genes/loci were also associated with CD in Canadian children. Design and Methods A case‐control design was implemented at three paediatric gastroenterology clinics in Canada. Children ≤18 years of age with a confirmed diagnosis of CD were recruited along with controls. Single nucleotide polymorphisms (SNPs) in five genome‐wide association studies reported genes/loci were genotyped. Associations between individual SNPs and CD were examined. Results A total of 406 cases and 415 controls were studied. The mean (±s.d.) age of the cases was 12.3 (±3.2) years. Most cases were male (56.6%), had ileo‐colonic disease (L3 ± L4, 52.0%) and inflammatory behaviour (B1 ± p, 86.9%) at diagnosis. Allelic association analysis (two‐tailed) showed that three of the five targeted SNPs were significantly associated with overall susceptibility for CD (ZNF365, r10995271, P = 0.001; PTPN2, rs1893217, P = 0.005; STAT3, rs744166, P = 0.01). Associations with SNP rs4613763 in the PTGER4 locus were marginally nonsignificant (P = 0.07). The ZNF365 and STAT3 SNPs were predominantly associated with ileal disease with or without colonic involvement. Conclusion The identified susceptibility genes/loci for adult‐onset CD also confer risk for paediatric‐onset CD.     

小样本探讨黄嘌呤脱氢酶和鸟苷酸合成酶基因多态性对硫唑嘌呤所致骨髓抑制和脱发的影响

摘要：目的 研究黄嘌呤脱氢酶(Xanthine dehydrogenase,XDH)和鸟苷酸合成酶(Guanosine monophosphate synthetase,GMPS)基因多态性对硫唑嘌呤(Azathioprine,AZA)所致骨髓抑制和脱发的影响,探讨上述位点联合NUDT15 rs116855232检测对预测AZA所致骨髓抑制的价值。方法 回顾性分析曾经服用或正在服用AZA治疗自身免疫性疾病患者,收集静脉血采用直接测序法测定GMPS rs61750368、rs61750369,XDH rs2295475、rs1884725、rs17011368、rs566362和NUDT15 rs116855232基因型。依据不良反应进行分组,分析上述基因型与AZA所致骨髓抑制和脱发的相关性,NUDT15 rs116855232作为对照位点。结果 共纳入80例患者,2组在年龄、日剂量、疗程、BMI以及6-硫鸟嘌呤核苷酸浓度均无显著性差异(P＞0.05)。Logistic回归分析表明,AZA所致骨髓抑制与XDH rs229547突变相关(P=0.003, OR=3.10, 95% CI: 1.45~6.25),该基因预测骨髓抑制敏感度为69.6%,特异度为63.2%,ROC曲线AUC为0.66;NUDT15 rs116855232突变也和AZA所致骨髓抑制相关(P=0.008, OR=3.46, 95% CI: 1.21~9.93);其余位点基因型暂未发现与骨髓抑制和脱发相关。rs116855232野生型且rs2295475突变型的患者对比两位点野生型的患者,其骨髓抑制的危险值升高(OR=6.53, P=0.004),而两位点同时突变者骨髓抑制的危险值更高(OR=51.67, P＜0.001)。结论 在中国自身免疫性疾病患者中XDH rs2295475突变可能为AZA诱导骨髓抑制的独立危险因素,尽管预测准确度较低但仍有预测价值。尤其XDH联合NUDT15 rs116855232监测,可能会弥补NUDT15 野生型者对骨髓抑制预测不足的风险,提高NUDT15突变型对骨髓抑制预测的准确性,但以上结果还更多临床研究验证。     

Association of UGT2B7, UGT1A9, ABCG2, and IL23R polymorphisms with rejection risk in kidney transplant patients

ABSTRACT

Despite advances in testing compatibility between donor and recipient, graft rejection remains a current concern. Single-nucleotide polymorphisms (SNPs) that codify altered enzymes of metabolism, drug transport, and the immune system may contribute to graft rejection in transplant patients. This study examined the association between SNPs present in genes of these processes and occurrence of graft rejection episodes in 246 kidney transplant patients, 35% of which were diagnosed with rejection. Genotype–gene expression associations were also assessed. Peripheral blood samples were used for genotyping of 24 SNPs on the following genes: CYP3A4, CYP3A5, CYP2E1, POR, UGT2B7, UGT1A9, ABCB1, ABCC2, ABCG2, SLCO1B1, TNF, IL2, IRF5, TGFB1, NFKBIA, IL10, IL23R, NFAT, and CCR5 by real-time PCR. The analysis of gene expression was performed by RT-qPCR. The association between graft rejection episodes and polymorphic variants was assessed using odds ratios. Polymorphisms rs7662029 (UGT2B7) and rs6714486 (UGT1A9) were associated with occurrence of graft rejection episodes, rs7662029 (UGT2B7) exhibited a protective effect (1.85-fold), and rs6714486 (UGT1A9) an increased 1.6-fold increased risk of graft rejection. Among drug transporter genes, only rs2231142 (ABCG2) demonstrated an association with a 1.92-fold decrease in the risk of graft rejection. The immunological SNP rs10889677 (IL23R) was associated with a 1.9-fold enhanced risk of graft rejection. Association between genotypes and gene expression was not detected. Therefore, SNPs of UGT2B7, UGT1A9, ABCG2, and IL23R genes may be useful as candidate markers for screening of risk graft rejection in renal transplant patients. These markers may improve medical decisions, avoiding adverse effects.     

Pharmacogenetics of Risperidone‐Induced Insulin Resistance in Children and Adolescents with Autism Spectrum Disorder

The purpose of this study was to explore the association of genetic polymorphism of genes related to pharmacokinetics or pharmacodynamics with insulin resistance in children and adolescents with autism spectrum disorder (ASD) and treated with risperidone. All 89 subjects underwent measurement of fasting blood glucose and insulin levels, body‐weight and height. Genotyping was performed by TaqMan real‐time polymerase chain reaction (PCR) (pharmacokinetics genes: cytochrome P450 2D6 (CYP2D6) *4 (rs3892097), *5 (gene deletion), *10 (rs1065852) and *41 (rs28371725), ATP‐binding cassette transporter B1 (ABCB1) 2677 G>T/A (rs2032582) and 3435C>T (rs1045642) and pharmacodynamics genes: dopamine receptor D2 (DRD2) Tag‐SNP (C>T) (rs4436578), DRD2 Tag1A (C>T) (rs1800497), leptin gene (LEP) ‐2548G>A (rs7799039), ghrelin gene (GHRL) ‐604G>A (rs27647) and brain‐derived neurotrophic factor (BDNF) 196G>A (rs6265)). Drug levels were analysed by liquid chromatography–tandem mass spectrometry (LC‐MS/MS). The results revealed that 5 (5.62%) patients presented with hyperglycaemia. Insulin resistance was detected in 15 (16.85%) patients. Insulin resistance was associated with LEP 2548 G>A and BDNF 196 G>A polymorphism (p = 0.051 and p = 0.03). There was no association of pharmacokinetic gene polymorphisms (CYP2D6 and ABCB1) and risperidone levels with insulin resistance. Multiple regression analysis indicated that BDNF 196 G>A polymorphism was significantly associated with insulin resistance (p = 0.025). This finding suggested that BDNF 196 G>A polymorphism may be a genetic marker for predicting insulin resistance before initiating treatment in patients treated with risperidone. Because of the small sample size, further studies are needed to confirm these results.     

GSTA1*‐69C/T and GSTO2*N142D as asthma‐ and allergy‐related risk factors in Italian adult patients

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Lack of association between genetic polymorphisms of CYP3A4, CYP2C9 and CYP2C19 and antituberculosis drug‐induced liver injury in a community‐based Chinese population

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Correlation of IMPDH1 Gene Polymorphisms with Subclinical Acute Rejection and Mycophenolic Acid Exposure Parameters on Day 28 after Renal Transplantation

Abstract: The risk of acute rejection in patients with higher exposure to mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), might be due to inosine 5′‐monophosphate dehydrogenase (IMPDH) polymorphisms. The correlations with subclinical acute rejection, IMPDH1 polymorphisms and MPA exposure on day 28 post‐transplantation were investigated in 82 Japanese recipients. Renal transplant recipients were given combination immunosuppressive therapy consisting of tacrolimus and 1.0, 1.5 or 2.0 g/day of MMF in equally divided doses every 12 hr at designated times. There were no significant differences in the incidence of subclinical acute rejection between IMPDH1 rs2278293 or rs2278294 polymorphisms (p = 0.243 and 0.735, respectively). However, in the high MPA night‐time exposure range (AUC >60 μg·h/ml and C₀ ≥ 1.9 μg/ml), there was a significant difference in the incidence of subclinical acute rejection between IMPDH1 rs2278293 A/A, A/G and G/G genotypes (each p = 0.019), but not the IMPDH1 rs2278294 genotype. In the higher daytime MPA exposure range, patients with the IMPDH1 rs2278293 G/G genotype also tended to develop subclinical acute rejection. In patients with the IMPDH rs2278293 A/A genotype, the risk of subclinical acute rejection episode tends to be low and the administration of MMF was effective. The risk of subclinical acute rejection for recipients who cannot adapt in therapeutic drug monitoring (TDM) of MPA seems to be influenced by IMPDH1 rs2278293 polymorphism. The prospective analysis of IMPDH1 rs2278293 polymorphism as well as monitoring of MPA plasma concentration after transplantation might help to improve MMF therapy.     

The role of ITPA and ribavirin transporter genes polymorphisms in prediction of ribavirin‐induced anaemia in chronic hepatitis C Egyptian patients

Few data are available concerning the roles of polymorphisms of inosine triphosphatase (ITPA) gene and ribavirin (RBV) transporter genes in the prediction of RBV‐induced anaemia among Egyptians with chronic hepatitis C (CHC). Genotyping of three ITPA gene variants and two variants of RBV transporter genes has been performed in 123 patients under pegylated interferon‐α/ribavirin treatment. The baseline haemoglobin and ITPA rs1127354 CA/AA have been found as predictors of anaemia at 4, 8 and 12 weeks of RBV therapy. In addition, ITPA rs7270101 AC/CC and age predicted anaemia after 12 weeks of therapy. In conclusion, the ITPA variant rs1127354C>A significantly predict RBV‐induced anaemia during the first 3 months of treatment and it is recommended to be assessed before RBV administration.     

Polymorphisms of genes in nitric oxide-forming pathway associated with ischemic stroke in Chinese Han population

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 Taqman^TM 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.     

Association of genetic polymorphisms in GADD45A, MDM2, and p14 with the risk of chronic benzene poisoning in a Chinese occupational population

Benzene reactive metabolites can lead to DNA damage and trigger the p53-dependent defense responses to maintain genomic stability. We hypothesized that the p53-dependent genes may play a role in the development of chronic benzene poisoning (CBP). In a case-control study of 303 patients with benzene poisoning and 295 workers occupationally exposed to benzene in south China, we investigated associations between the risk of CBP and polymorphisms in three p53-dependent genes. Potential interactions of these polymorphisms with lifestyle factors were also explored. We found p14^ARF rs3731245 polymorphism was associated with risk of CBP (P = 0.014). Compared with those carrying the GG genotype, individuals carrying p14^ARF rs3731245 GA+AA genotypes had a reduced risk of CBP ([adjusted odds ratio (OR_adj) = 0.57, 95%CI = 0.36–0.89]. Further analysis showed p14^ARF TGA/TAG diplotype was associated with an increased risk of CBP (P = 0.0006), whereas p14^ARF TGG/TAA diplotype was associated with a decreased risk of CBP (P = 0.0000001). In addition, we found individuals carrying both MDM2 Del1518 WW genotype and p14^ARF rs3731245 GA+AA genotypes had a lower risk of CBP (OR_adj = 0.25; 95%CI = 0.10–0.62; P = 0.003). Although these results require confirmation and extension, our findings suggest that genetic polymorphisms in p14^ARF may have an impact on the risk of CBP in the study population.     

Association of the genetic polymorphism of EPHX1 and EPHX2 with the susceptibility to chronic benzene poisoning

The aim of this study was to explore the association of the genetic polymorphism of EPHX1 and EPHX2 with the susceptibility to chronic benzene poisoning (CBP). A case-control study of 268 patients with CBP and 268 healthy workers matched by age and sex, all of whom were occupationally exposed to benzene, was conducted. The single nucleotide polymorphisms (SNPs, rs2854451, rs3738047, rs2234922 and rs1051741) of EPHX1 gene and the SNP (rs751141) of EPHX2 gene were tested by the TaqMan PCR method. In the subjects carrying the genotype of EPHX1 rs3738047 GG, the risk of CBP was decreased in the individuals simultaneously carrying EPHX1 rs2234922 G (P = 0.02). Alternatively, in the subjects carrying the genotype of EPHX1 rs2234922 AA, the risk of CBP was increased in the individuals simultaneously carrying the allele of EPHX2 rs751141A (P = 0.03). It was also found that there were potential interactions between alcohol consumption and the polymorphism of EPHX1 rs1051741 (χ_H ² = 5.28, P = 0.02) or rs2234922 (χ_H ² = 6.71, P = 0.01). Compared to individuals with EPHX1 rs1051741 CC or rs2234922 AA genotype in the drinkers, the risk of CBP in those carrying genotypes of EPHX1 rs1051741 CT+TT or rs2234922 AG+GG was decreased, respectively (P = 0.04, P < 0.01). Haplotype analysis of polymorphisms in EPHX1 showed that the risk of CBP was increased in the subjects with haplotype 2 (rs2854451-A, rs3738047-G, rs2234922-A, rs1051741-C) or haplotype 4 (rs2854451-G, rs3738047-A, rs2234922-G, rs1051741-T), but decreased in those with haplotype 6 (rs2854451-G, rs3738047-G, rs2234922-G, rs1051741-T) or haplotype 10 (rs2854451-A, rs3738047-A, rs2234922-G, rs1051741-T), respectively. Logistic regression analysis revealed that smoking might play a role in modifying the risk of CBP (OR = 0.313, 95% CI: 0.123–0.794, P = 0.015). The genetic polymorphism in EPHX1 may be associated with the risk of CBP in the Chinese occupational population and further research is needed for the association between the genetic polymorphism in EPHX2 and the susceptibility to CBP. Translated from Fudan University Journal of Medical Sciences, 2006, 33(4): 427–432 [译自: 复旦大学学报 (医学版)]     

Association of HMGB1 and HMGB2 genetic polymorphisms with lung cancer chemotherapy response

The aim of the present study was to investigate the association of genetic polymorphisms in high mobility group box 1 and 2 (HMGB1 and HMGB2, respectively) with platinum‐based chemotherapy responses in Chinese lung cancer patients. In total, 338 Chinese lung cancer patients (154 responders and 184 non‐responders) were recruited to the study. All patients received at least two cycles of first‐line platinum‐based chemotherapy. Three tagging single nucleotide polymorphisms (SNPs) of HMGB1 and two tagging SNPs of HMGB2 were detected in patients. We found that rs1412125 and rs2249825 of HMGB1 were significantly associated with the platinum‐based chemotherapy response in both recessive and genotypic models. In addition, rs1412125 showed significant association with platinum‐based chemotherapy response for the subgroup of patients aged >55 years in additive, recessive and genotypic models. No significant associations were detected between other SNPs and the platinum‐based chemotherapy response. The HMGB1 SNPs (rs1412125 and rs2249825) were associated with platinum‐based chemotherapy responses in Chinese lung cancer patients. In conclusion, HMGB1 SNPs may serve as potential biomarkers for predicting the efficacy of platinum‐based chemotherapy.