The association of interleukin-21 polymorphisms with interleukin-21 serum levels and risk of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is one of the common autoimmune diseases, with complex genetic components. Interleukin-21 (IL-21) is the most recently discovered member of the type-I cytokine family, which has a variety of effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production. Previous studies have identified that IL-21 was associated with different autoimmune and inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis and SLE. Variations in the DNA sequence in the IL-21 gene may lead to altered IL-21 production and/or activity, and thus this can modulate an individual's susceptibility to SLE. To test this hypothesis, we investigated the association of the IL-21 polymorphisms and its serum levels with the risk of SLE in a Chinese population. We analyzed three single nucleotide polymorphisms of IL-21 gene rs907715 C/T, rs2221903 T/C and rs2055979 C/A in 175 patients with SLE and 190 age- and sex-matched controls, using Snapshot SNP genotyping assays and DNA sequencing method. Soluble IL-21 (sIL-21) levels were measured by ELISA. There were significant differences in the genotype and allele frequencies of IL-21 gene rs2055979 C/A polymorphism between the group of patients with SLE and the control group (P < 0.05). sIL-21 levels were increased in patients with SLE compared with controls (P < 0.01). Moreover, genotypes carrying the IL-21 rs2055979 A variant allele were associated with increased IL-21 levels compared to the homozygous wild-type genotype in patients with SLE. The rs2055979 C/A polymorphism of IL-21 and its sIL-21 levels were associated with SLE in the Chinese population. Our data suggests that IL-21 gene may play a role in the development of SLE.     

Replication study of PLCE1 and C20orf54 polymorphism and risk of esophageal cancer in a Chinese population

Esophageal cancer is one of the most aggressive cancers in the world. Recent large-scale genome-wide association studies (GWAS) reported that functional genetic variations in the phospholipase C epsilon gene (PLCE1) were strongly associated with risk of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) in Chinese population. For C20orf54 rs13042395 genotype and risk of esophageal cancer, the results were inconsistent. We conducted a replication case-control study to evaluate the genetic effects of these two functional single nucleotide polymorphisms (SNPs) on the development of esophageal cancer. A total of 380 cases and 380 controls were recruited for this study. The genotypes were determined by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF MS). The variant alleles of the functional polymorphism, PLCE1 rs2274223 SNP was associated with the increased risk of esophageal cancer [adjusted odds ratio (OR) = 1.95, 95 % confidence interval (CI) = 1.05-3.59 for PLCE1 rs2274223 GG vs. AA]. However, there was no significant association between the C20orf54 rs13042395 genotype and esophageal cancer risk (adjusted OR = 0.99, 95 % CI = 0.63-1.57 for C20orf54 rs13042395 TT vs. CC). Stratified analyses indicated a significantly increased risk of esophageal cancer associated with the PLCE1 rs2274223 AG genotype was more evident among females, younger patients and never drinkers, compared with the PLCE1 rs2274223 AA genotypes. Stratified analyses also indicated a significantly increased risk of esophageal cancer associated with the PLCE1 rs2274223 GG genotype was more evident among never smokers and never drinkers compared with the PLCE1 rs2274223 AA genotypes. These findings indicated that functional polymorphisms PLCE1 rs2274223 might contribute to esophageal cancer susceptibility.     

MCPH1 protein expression and polymorphisms are associated with risk of breast cancer

Microcephalin 1 (MCPH1) has a crucial role in the DNA damage response by promoting the expression of checkpoint kinase 1 (CHK1) and breast cancer susceptibility gene 1 (BRCA1). MCPH1 containing BRCT domain has been suggested as a tumor suppressor in breast and ovarian cancers. We analyzed the effect of both protein expression and MCPH1 polymorphisms in breast cancer patients. Low nuclear expression of microcephalin was present in 52.4% of breast cancers and was associated with allele T in rs2912010 (p = 0.046). However, cytoplasmic microcephalin expression increased with increasing grade (p = 0.010). An association between low nucleus microcephalin expression and allele T was identified in rs2912010 (p = 0.046). After data analysis, allele distribution of the MCPH1 polymorphisms was not different between breast cancer patients and healthy controls. But the polymorphism was associated with negative status for ER (rs2912010/C2302T; p = 0.032, rs1057090/C2358T; p = 0.027, rs2912016/C2494A; p = 0.024), and allele T in both rs2912010 and rs1057090 was associated with increasing tumor grade (rs2912010; p = 0.040, rs1057090; p = 0.043) in breast cancer. We are first to report that association of MCPH1 protein expression and its polymorphisms in breast cancer. The MCPH1 polymorphisms and protein expression were associated with tumorigenesis in breast cancer and may be a useful biomarker for identification of the aggressive types of breast cancer.     

Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia

A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10(-12)); however, this association did not achieve genome-wide significance (p ≤ 10(-7)) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10(-8); allelic risk = 0.80, 95% confidence interval (CI) = 0.74-0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67-0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.     

Polymorphisms of CHRNA5-CHRNA3-CHRNB4 Gene Cluster and NSCLC Risk in Chinese Population

AIM: To explore the potential association between single-nucleotide polymorphisms (SNPs) and haplotypes of the CHRNA5-CHRNA3-CHRNB4 gene cluster and the non-small cell lung cancer (NSCLC) susceptibility in never-smoking Chinese. METHODS: A case-control study was conducted with 200 NSCLC patients and 200 healthy controls, matched on age and sex. Five SNPs distributed in CHRNA5-CHRNA3-CHRNB4 gene cluster were selected for genotyping. The association between genotype and lung cancer risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) from multivariate unconditional logistic regression analyses with adjustment for gender and age. RESULTS: For CHRNA3 rs578776 status, data were available in 199 NSCLC patients and 199 controls. The G/G homozygote in CHRNB4 rs7178270 had a reduced risk of developing NSCLC (OR = 0.553; 95% CI = 0.309–0.989; P = .0437), especially squamous cell carcinoma (SQC) (OR = 0.344; 95% CI = 0.161–0.732; P = .0043), compared with those who carry at least one C allele (C/C and C/G). The polymorphisms of rs578776, rs938682, rs17486278, and rs11637635 were not significantly different between controls and cases or between controls and histologic subgroups, adenocarcinoma and SQC, respectively. CONCLUSIONS: In our study, we found that the SNP of CHRNB4 rs7178270 is significantly associated with reduced risk of NSCLC, especially with reduced risk of SQC in never-smoking Chinese population.     

RAGE Genetic Polymorphisms Are Associated with Risk,Chemotherapy Response and Prognosis in Patients with Advanced NSCLC

Aim

To explore the association between genetic polymorphisms of the receptor for advanced glycation end-products (RAGE) and susceptibility, chemotherapy response rate and prognosis of non-small cell lung cancer (NSCLC).

Method

This is a prospective study in which 562 patients with NSCLC and 764 healthy controls were enrolled. Three RAGE genetic polymorphisms, namely, −429T/C, −374T/A and 82G/S were genotyped. Platinum-based chemotherapy was given to 432 subjects with advanced inoperable NSCLC and their responses to chemotherapy were evaluated.

Results

All the polymorphic genotypes of RAGE polymorphisms were associated with susceptibility for NSCLC. Only the 82G/S polymorphisms denoted a significant difference between responders and non-responders to chemotherapy. The 82SS genotype and 82S allele distribution not only increased the NSCLC risk, but also was associated with a lower chemotherapy response rate and poor prognosis, indicated by overall survival and progression free survival.

Conclusion

The 82G/S genetic polymorphism of RAGE gene might be used as a genetic marker to screen for patients sensitive to thermotherapy and to predict the prognosis of NSCLC.     

Association analysis of ERBB2 amplicon genetic polymorphisms and STARD3 expression with risk of gastric cancer in the Chinese population

The purpose of this study was to investigate whether risk of gastric cancer (GC) was associated with single nucleotide polymorphisms (SNPs) in a gene cluster on the chromosome 17q12-q21 (ERBB2 amplicon) in the Chinese Han population. We detected twenty-six SNPs in this gene cluster containing steroidogenic acute regulatory-related lipid transfer domain containing 3 (STARD3), protein phosphatase 1 regulatory subunit 1B (PPP1R1B/DARPP32), titin-cap (TCAP), per1-like domain containing 1(PERLD1/CAB2), human epidermal growth factor receptor-2 (ERBB2/HER2), zinc-finger protein subfamily 1A 3 (ZNFN1A3/IKZF3) and DNA topoisomerase 2-alpha (TOP2A) genes in 311 patients with GC and in 425 controls by Sequenom. We found no associations between genetic variations and GC risk. However, haplotype analysis implied that the haplotype CCCT of STARD3 (rs9972882, rs881844, rs11869286 and rs1877031) conferred a protective effect on the susceptibility to GC (P = 0.043, odds ratio [OR] = 0.805, 95% confidence intervals [95% CI] = 0.643–0.992). The STARD3 rs1877031 TC genotype endued histogenesis of gastric mucinous adenocarcinoma and signet-ring cell carcinoma (P = 0.021, OR = 2.882, 95% CI = 1.173–7.084). We examined the expression of STARD3 in 243 tumor tissues out of the 311 GC patients and 20 adjacent normal gastric tissues using immumohistochemical (IHC) analysis and tissue microarrays (TMA). The expression of STARD3 was observed in the gastric parietal cells and in gastric tumor tissues and significantly correlated with gender (P = 0.004), alcohol drinking (P < 0.001), tumor location (P = 0.007), histological type (P = 0.005) and differentiation (P = 0.023) in GC. We concluded that the combined effect of haplotype CCCT of STARD3 might affect GC susceptibility. STARD3 expression might be related to the tumorigenesis of GC in the Chinese population.     

Association study of polymorphisms in the receptor for advanced glycation end-products (RAGE) gene with susceptibility and prognosis of heart failure

Background

Functional polymorphisms in the receptor for advanced glycation end-products (RAGE) gene have been implicated in several vascular diseases. However, to date, no study investigated the association of RAGE polymorphisms with heart failure (HF).

Objective

In this study we tested the hypothesis that the 63-bp insertion/deletion, the − 374T > A (rs1800624) and the − 429T > C (rs1800625) polymorphisms in the RAGE gene might be associated with susceptibility to HF and could predict all-cause mortality in Brazilian outpatients with left ventricular systolic dysfunction.

Methods

A total of 273 consecutive HF patients (196 Caucasian- and 77 African-Brazilians) and 334 healthy blood donors (260 Caucasian- and 74 African-Brazilians) were enrolled in a tertiary care university hospital. Genotyping of RAGE polymorphisms was done by polymerase chain reaction (PCR) or PCR followed by enzyme restriction analysis.

Results

The allele, genotype and haplotype frequencies of − 374T > A and − 429T > C polymorphisms were not significantly different between HF patients and healthy blood donors in both ethnic groups. However, among African-Brazilians, the frequency of carriership of the del allele was lower in HF patients than in blood donors (2.6% vs 12.2%, respectively, p = 0.008). Patients were followed-up for a median of 38 months and the survival analysis did not reveal a consistent association between RAGE polymorphisms and all-cause death in both ethnic groups.

Conclusion

The − 374T > A and − 429T > C polymorphisms in the RAGE gene were not associated with the susceptibility and prognosis of HF. Notwithstanding, the 63-bp ins/del polymorphism might be involved in the susceptibility to HF in African-Brazilians.     

Association of thymidylate synthase gene 3'-untranslated region polymorphism with sensitivity of non-small cell lung cancer to pemetrexed treatment: TS gene polymorphism and pemetrexed sensitivity in NSCLC

Background

Thymidylate synthase (TS) is a key enzyme responsible for DNA synthesis and repair. Altered expression of TS protein or TS gene polymorphisms has been associated with cancer progression and treatment response. This study investigated the expressions of TS and its gene SNPs in non-small cell lung cancer (NSCLC), and then its association with sensitivity to pemetrexed treatment. Immunohistochemistry and qRT-PCR were performed on 160 resected NSCLC specimens and corresponding normal tissues to assess the expressions of TS protein and TS mRNA, and for associations with clinicopathological data. Blood samples of 106 lung adenocarcinoma patients were examined for polymorphisms of the TS gene 3’-UTR 1494del 6 bp, which was then investigated for associations with responses of the patients to pemetrexed treatment and survival.

Results

Expression of both TS protein and its mRNA was elevated in NSCLC tissues compared with matched normal tissues, and significantly higher in lung squamous cell carcinoma than in lung adenocarcinoma. TS expression was associated with poor tumor differentiation. Furthermore, the genotyping data showed that 56% of lung adenocarcinoma patients had the TS gene 3’-UTR 1494 bp (−6 bp/-6 bp) genotype and the rest had TS gene 3’-UTR 1494 bp (−6 bp/+6 bp). There was no TS 3’-UTR 1494 bp (+6 bp/+6 bp) genotype in any patients. Statistical analysis revealed that gender, tumor stage, and TS 3’-UTR 1494del 6 bp polymorphism were significant prognostic factors after short-term pemetrexed treatment. Log-rank analysis revealed that patients with the (−6 bp/-6 bp) genotype had significantly better progression-free and overall survival than patients with (−6 bp/+6 bp).

Conclusions

This study showed that TS protein is highly expressed in NSCLC and that polymorphisms of TS 3’-UTR 1494del 6 bp are associated with sensitivity of lung adenocarcinoma patients to pemetrexed treatment. This suggests that TS gene polymorphisms should be further evaluated as prognostic markers for personalized therapy in lung adenocarcinoma.     

Role of EGFR SNPs in survival of advanced lung adenocarcinoma patients treated with Gefitinib

Aim

As a novel molecularly targeting agent for non-small-cell lung cancer (NSCLC), Gefitinib can block its tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Genetic variations in EGFR may affect its protein function or expression and lead to diverse outcomes in NSCLC patients after Gefitinib therapy. Therefore, this prospective study examined whether EGFR single nucleotide polymorphisms (SNPs) are associated with different survival time in advanced lung adenocarcinoma patients treated with Gefitinib.

Methods

One hundred and twenty-eight patients with stage IIIB or IV lung adenocarcinoma receiving Gefitinib target therapy between 2008 and 2010 were recruited in this study. Six EGFR haplotype-tagging SNPs were genotyped by the Sequenom MassArray system. Survival by different genotypes was compared using Kaplan–Meier methods. Cox proportional hazards models were applied to estimate the effect of prognostic factors on overall survival (OS) and progression-free survival (PFS).

Results

After the median 16.6 months of follow-up, the unfavorable EGFR rs2293347AA or GA genotype was significantly correlated with shorter OS (AA vs. GG: 2.0 vs. 21.0 months; hazard ratio (HR) = 2.44, 95% confidence interval (CI) = 1.06–5.56; P = 0.036; GA vs. GG: 15.0 vs. 21.0 months; HR = 1.75, 95%CI = 1.08–2.86, P = 0.025) compared with the favorable rs2293347GG genotype. The prognostic significance of EGFR rs4947492 polymorphism on OS also existed (GG carriers vs. AA carriers: median OS = 24.6 vs. 14.9 months, HR = 0.29, 95%CI = 0.10–0.83, P = 0.021). No significant associations were found among other EGFR SNPs and survival.

Conclusion

EGFR rs2293347 and rs4947492 SNPs might be potential predictive markers of OS in advanced lung adenocarcinoma patients treated with Gefitinib.     

Gene polymorphisms and serum levels of TL1A in patients with rheumatoid arthritis

Recent findings showed elevated expression of tumor necrosis factor (TNF)-like ligand 1A (TL1A) in rheumatoid arthritis (RA) patients and arthritis mice. However, whether TL1A gene polymorphisms may correlate with RA susceptibility needs to be discussed. This case-control study was performed on 350 RA patients and 556 healthy subjects to identify TL1A genetic variants (rs3810936, rs6478109, and rs7848647) and their possible association with TL1A levels, susceptibility to and severity of RA. Odds ratio and 95% confidence interval were calculated to represent the correlation between TL1A polymorphisms and RA. The TL1A serum levels were evaluated. Results showed that frequencies of TC, TT + TC genotypes of rs3810936, rs7848647 in RA patients were significantly lower in RA patients compared with controls. Patients with C allele showed more severe disease course (disease activity index: erythrocyte sedimentation rate, rheumatoid factor) than in carriers of T allele. However, the allele or genotype frequencies of rs6478109 were not associated with RA. In addition, TL1A genetic variants conferred higher TL1A levels in RA patients compared with controls. In conclusion, these findings indicated an association between TL1A rs3810936, rs7848647 variation and the susceptibility of RA in a sample of Chinese individuals, and TL1A may correlate with severity of RA.     

FoxP3 genetic variants and risk of non-small cell lung cancer in the Chinese Han population

CD4⁺CD25⁺ regulatory T cell-mediated immunosuppression is one of the crucial mechanisms that tumor cells use to evade the immune system. The forkhead box P3 (FoxP3) gene regulates regulatory T-cell development and function and may modulate the susceptibility to non-small cell lung cancer (NSCLC). Because a single nucleotide polymorphism (SNP) within the FoxP3 gene (rs3761548 in the promoter region) is associated with susceptibility to Graves' disease, this study detected rs3761548 in a hospital-based case–control study. A total of 192 NSCLC patients and 259 healthy subjects were recruited for the polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) analysis of FoxP3 SNP. The data showed that the A allele of rs3761548 significantly increased NSCLC risk (P = 0.000, OR = 2.32, 95%CI = 1.736–3.102). The AC genotype, AA genotype, and the combined A variant genotype (AA + AC) were also associated with a higher risk of NSCLC (OR [95%CI] = 2.147[1.419–3.247], 4.413[2.359–8.255], and 2.563[1.746–3.761], respectively). Moreover, a significantly higher frequency of AA + AC genotype was observed in patients with stage II NSCLC (OR, 2.053; 95%CI, 1.033–4.078). In conclusion, the data from the current study demonstrated for the first time the association of the FoxP3 SNP with a risk of developing NSCLC in the Chinese Han population.     

The prevalence of CD33 and MS4A6A variant in Chinese Han population with Alzheimer's disease

CD33 and MS4A6A genes play potential key roles in the pathogenesis of Alzheimer's disease (AD). One recent genome-wide association study has revealed that the rs3865444 polymorphism in the CD33 gene and rs610932 polymorphism in the MS4A6A gene are associated with susceptibility to AD in Caucasians. To evaluate the relationship between the polymorphism of the CD33, MS4A6A gene and AD in the ethnic Chinese Han, we conducted a case-control study (n = 383, age > 54) to determine the prevalence of single-nucleotide polymorphism of two genes in patients with AD in Chinese population of Mainland, and clarified whether these polymorphisms are risk factors for AD. The prevalence of the allele (T) in the rs3865444 polymorphism of the CD33 gene and allele (C) in rs610932 polymorphism of the MS4A6A gene was significantly different in AD patients and control subjects (P < 0.001, respectively), and the results were not influenced by age, gender, or APOE status. Our data revealed the allele (T) of the rs3865444 polymorphism of the CD33 gene and the allele (C) of the rs610932 polymorphism of the MS4A6A gene may contribute to AD risk in the Chinese Han population.     

The role of adiponectin (ADIPOQ) gene polymorphisms in the susceptibility and prognosis of non-small cell lung cancer

To study the role of the adiponectin (ADIPOQ) gene single-nucleotide polymorphism (SNP) in the susceptibility and prognosis for non-small cell lung cancer (NSCLC), we recruited 344 patients with NSCLC, of which 141 had undergone surgical resection and post-surgery follow up.?For controls, there were 264 healthy volunteers for the control group, matched in age and sex with the NSCLC patients. Genotyping of SNPs in the ADIPOQ gene, namely, rs266729 (11365C>G); rs822395 (4034A>C); rs822396 (3964A>G); rs2241766 (+45T>G) were performed. Of all SNPs in the ADIPOQ gene, only the TT genotype and T allele frequency of the rs2241766 were more prevalent in NSCLC subjects than in controls. The TT genotype of rs2241766 was significantly associated with susceptibility to NSCLC before and after adjustment for age, sex, body mass index, and smoking status. In the survival analyses of subjects receiving surgical resection, only the SNPs of rs2241766 were significantly related to overall survival of NSCLC. Our results suggest that the SNP rs2241766 of the ADIPOQ gene may determine both susceptibility to NSCLC, and the prognosis for those who underwent surgical treatment.     

Association between two genetic variants of CD226 gene and Cervical Squamous Cell Carcinoma: A case–control study

Cervical carcinoma is a common gynecologic tumor severely influencing the health and life quality of women worldwide. CD226, a costimulatory molecule, is mainly participated in the activation and differentiation of T cells. Recent studies have investigated the association between two genetic variants (rs763361 and rs727088) of CD226 gene and many diseases. In order to evaluate whether these two variants are associated with Cervical Squamous Cell Carcinoma (CSCC), a case–control study including 349 CSCC patients and 380 unrelated healthy controls was carried out to determine the genotypes of these two variants by using the methods of polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and DNA sequencing methods. Significantly increased CSCC risk was observed to be associated with G allele of rs727088 locus (OR = 1.422, 95% CI = 1.129–1.792). We have also observed that increased CSCC risk was statistically associated with rs727088 polymorphism in a dominant model (OR = 1.41, 95% CI = 1.05–1.89). Results of stratified analysis revealed that both rs763361 and rs727088 polymorphisms were not associated with clinical characters. Collectively, this study supports that rs727088 polymorphism may contribute to increased CSCC susceptibility.