A polymorphism of matrix Gla protein gene is associated with kidney stone in the Chinese Han population

Purpose

Matrix Gla protein (MGP) is a molecular determinant regulating the extracellular matrix calcification. To further confirm whether the MGP genetic polymorphism was universally associated with the risk of kidney stone, we investigated the association of genetic polymorphisms of MGP with kidney stone in the Chinese Han population.

Materials and methods

728 subjects were recruited for the study. We firstly re-sequenced the human genomic MGP gene including the 1500 bp promoter, 5′-UTR, 4 exons and 3′-untranslated regions, identified single nucleotide polymorphisms (SNPs) in MGP, and performed an association analysis with kidney stones in 54 subjects of the Chinese Han population. A candidate tag SNP was genotyped in total subjects using an allele specific PCR, and further analyzed the association with kidney stone.

Results

We identified 18 polymorphisms including four tag SNPs. A tag SNPrs4236 was associated with kidney stones. The G allele carrier had a 1.373-fold reduced kidney stone risk compared with A allele carriers in SNPrs4236 (odds ratios (OR) = 1.373; 95%CI, 1.051–1.793; p = 0.019). However, we did not find an association between the polymorphism and clinical characteristics of kidney stones.

Conclusions

Our findings showed that SNPrs4236 of the MGP gene is associated with kidney stones in the Chinese Han population, and influences the genetic susceptibility to kidney stones. In the future, functional assays of the polymorphism should permit a better understanding of the role of MGP genetic variants and kidney stones.     

TSLPR gene polymorphism is associated with systemic lupus erythematosus in the Korean population

Human thymic stromal lymphopoietin receptor (TSLPR) was identified from T lymphocytes and dendritic cells, and is believed to play an important role in the development of inflammatory and allergic responses. We previously identified 11 single-nucleotide polymorphisms (SNPs) and 2 variation sites in the TSLPR gene, and showed that SNPs in the TSLPR gene are associated with susceptibility to atopic asthma in the Korean population. The present study aimed to investigate whether polymorphisms in the TSLPR gene are associated with systematic lupus erythematosus (SLE). The genotype and allele frequencies of the g.33G>C SNP of the TSLPR gene in SLE patients were significantly different from those of the control group (P = 0.005). Additional analysis showed that the genotype and allele frequencies of the g.33G>C of the TSLPR gene were suggestively associated with female SLE patients. We also investigated the correlation between SNPs in the TSLPR gene and the total serum levels of anti-nuclear antibodies (ANA) in SLE patients. The g.21884G>A SNP of the TSLPR gene in SLE patients showed a significant association with ANA levels (P = 0.014). Our results suggest that SNPs in the TSLPR gene could be associated with susceptibility to SLE in the Korean population.     

A single-nucleotide polymorphism of the TNFAIP3 gene is associated with systemic lupus erythematosus in Chinese Han population

Systemic lupus erythematosus (SLE) is a complex systemic disease influenced by genetic and environmental factors. The exact pathogenesis of SLE is still unknown. Recently, several genome-wide association studies (GWA) in European population have found many novel susceptibility genes for SLE including TNFAIP3. In order to examine whether TNFAIP3 is associated with SLE in Chinese Han population, we genotyped one of its non-synonymous mutation SNP rs2230926, showing significant association evidence with SLE in European population, with 1,420 cases and 4,461 controls of Chinese Han by using Sequenom MassArray system. Highly significant association between SNP rs2230926 and SLE of Chinese Han was detected [OR = 1.65, 95% confidence interval (CI): 1.392–1.986, P = 2.03 × 10⁻⁸]. Interestingly, rs2230926 of TNFAIP3 was also associated with arthritis, ANA and some other subphenotypes of the disease. Our findings suggest that SNP rs2230926 in the TNFAIP3 might be a common genetic factor for SLE within different populations in terms of Chinese Han and European population.     

Interleukin-8 gene polymorphism is associated with acute coronary syndrome in the Chinese Han population

Background

Acute coronary syndrome (ACS) is one of the most common forms of heart disease. Recent studies have shown that interleukin (IL)-8 plays a key role in the development of atherosclerotic plaques, but the relationship between the common genetic variants of IL-8 and ACS has not been extensively studied.

Methods

This case-control study in the Chinese Han population included 675 patients with ACS and 636 age- and sex-matched controls. We investigated IL-8 polymorphisms and their association with susceptibility to ACS. The investigation was replicated in the second study comprising 360 cases and 360 control subjects. The plasma concentration of IL-8 was measured by enzyme-linked immunosorbent assay.

Results

IL-8 −251 A/T polymorphism was associated with increased susceptibility to ACS (P = 0.004; odds ratio = 1.30; 95% confidence interval: 1.12–1.53). The second study yielded similar results. An increased IL-8 level was found in the plasma of acute myocardial infarction patients, suggesting that IL-8 −251 A/T may affect the expression of IL-8.

Conclusion

IL-8 −251 A/T polymorphism is associated with ACS risk in the Chinese Han population and the A allele of IL-8 −251 A/T may be an independent predictive factor for ACS.     

Temporomandibular disorder is associated with a serotonin transporter gene polymorphism in the Japanese population

Background  

Selective serotonin-reuptake inhibitors (SSRIs) are commonly prescribed for the treatment of depression and can be used as nonhormonal alternatives to manage hot flashes for women with a history of breast cancer and unable to take hormone replacement therapy. There are, however, few reports on the efficacy of SSRIs for the treatment of natural postmenopausal climacteric symptoms. In this pilot study, we evaluate the SSRI, fluvoxamine, for controlling climacteric symptoms and vasomotor symptoms, in particular.     

Functional polymorphism located in MMP-9 gene promoter is strongly associated with obesity

The adipose tissue expansion is accompanied by remodeling of extracellular matrix performed by matrix metalloproteinases (MMPs). Higher plasma and tissue MMP-9 levels are found in obese; therefore, we evaluated if the functional C(-1562)T polymorphism (rs3918242) located in promoter region of the MMP-9 gene is associated with obesity in women. We studied 112 lean and 114 obese women. Plasma MMP-9 and tissue inhibitor of MMP-9 (TIMP)-1 were measured using enzyme-linked immunosorbent assay. We found different genotype frequencies between lean and obese women (p=0.008), prevailing T-allele in obese (2.3-fold). However, although obese women present higher levels of plasma MMP-9, lack of modulation by the polymorphism was found (all p>0.05). Our findings suggest that C(-1562)T polymorphism may contribute to pathogenetic mechanisms involved in the development of obesity in women.     

Genetic variation in the NBS1 gene is associated with hepatic cancer risk in a Chinese population

NBS1 plays important roles in maintaining genomic stability as a key DNA repair protein in the homologous recombination repair pathway and as a signal modifier in the intra-S phase checkpoint. We hypothesized that polymorphisms of NBS1 are associated with hepatic cancer (HCC) risk. The NBS1 rs1805794 C/G polymorphism has been frequently studied in some cancers with discordant results, but its association with HCC has not been investigated. Moreover, studies of the 3'UTR variant rs2735383 have not touched upon HCC. This study examined the contribution of these two polymorphisms to the risk of developing HCC in a Chinese population. NBS1 genotypes were determined in 865 HCC patients and 900 controls and the associations with risk of HCC were estimated by logistic regression. Compared with the rs1805794 GG genotype, the GC genotype had a significantly increased risk of HCC (adjusted odds ratios [OR]=1.41; 95% confidence interval [CI]=1.11-1.80), the CC carriers had a further increased risk of HCC (OR=2.27; 95% CI=1.68-3.14), and there was a trend for an allele dose effect on risk of HCC (p<0.001). Also, we found that the risk effect of rs1805794 CC+CG was more pronounced in HCC patients that drank (OR=2.28, 95% CI=1.55-3.29 for drinkers; OR=1.31, 95% CI=1.00-1.77 for nondrinkers). However, there was no significant difference in genotype frequencies of rs2735383 G/C site between cases and controls. These findings suggest that rs1805794 C/G polymorphism in NBS1 may be a genetic modifier for developing HCC.     

A functional polymorphism in miRNA-196a2 is associated with colorectal cancer risk in a Chinese population

Single-nucleotide polymorphisms in microRNAs (miRNAs) may alter miRNA expression levels or processing and, thus, may contribute to cancer development. We hypothesized that miRNA-196a2 polymorphism is associated with risk of colorectal cancer (CRC). In a case-control study of 573 patients with CRC and 588 cancer-free controls frequency matched by age and sex, we genotyped the functional polymorphism rs11614913 (T>C) and assessed its association with the risk of CRC in a Chinese population. We found that the CT/CC genotypes were associated with a significantly increased risk of CRC (odds ratio [OR]=1.44, 95% confidence interval [CI]=1.10-1.88), compared with the TT genotype. Further, the polymorphism was significantly associated with the risk of patients with advanced stage tumor (Dukes C and D) (OR=1.65, 95% CI=1.11-2.46). Our results suggest that the functional polymorphism rs11614913 in miRNA-196a2 is involved in the etiology of CRC and, thus, may be a marker for genetic susceptibility to CRC.     

Increased risk of advanced prostate cancer associated with MnSOD Ala-9-Val gene polymorphism

We aimed to investigate the association between manganese superoxide dismutase (MnSOD) Ala-9-Val gene polymorphism and the initiation and/or progression of prostate cancer (PCa) as well as to evaluate its potential interactions with advanced age and smoking status. MnSOD Ala-9-Val gene polymorphism was carried out in 134 (mean age 64.1 ± 7.48) PCa patients and 159 (mean age 62.5 ± 7.53) healthy controls with serum prostate specific antigen (PSA) levels (<4 ng/ml) and normal digital rectal examination (DRE) findings in this prospectively designed study. PCa patients were classified as low stage disease (T₁ or T₂ and N₀M₀ stages) and high stage disease (T₃ or T₄ and N₀M₀ or N₁ or M₁ stages). Genotypes for MnSOD Ala-9-Val gene polymorphism were identified by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFPL). Despite lack of association between different genotypes of MnSOD Ala-9-Val gene polymorphism and the presence of PCa, patients with Ala/Ala genotype were at an increased risk of high stage disease compared with those with the Val/Val genotype [odds ratio (OR), 3.77; 95% CI, 1.30–10.94; P = 0.012]. However, no significant difference was observed in the distribution of each genotype among PCa patients, with respect to tumor grade. On the other hand, smoking status and aging did not seem to change the association between genotypes and PCa risk. Ala/Ala genotype of MnSOD polymorphism may have an effect on adverse features of PCa such as high stage disease.     

Functional promoter -31G>C variant in survivin gene is associated with risk and progression of renal cell cancer in a Chinese population

Background

Survivin is an inhibitor of apoptosis protein and is involved in the occurrence and progression of human malignancies. Recently, a functional polymorphism (−31G>C, rs9904341) in the promoter of survivin has been shown to influence its expression and confer susceptibility to different types of cancer. The present study was aimed to investigate whether the polymorphism also influences susceptibility and progression of renal cell cancer (RCC) in a Chinese population.

Methods

We genotyped this polymorphism using the TaqMan assay in a case-control study comprised of 710 RCC patients and 760 controls. The logistic regression was used to assess the genetic association with occurrence and progression of RCC.

Results

Compared with the genotypes containing G allele (GG and GC), we found a statistically significant increased occurrence of RCC associated with the CC genotype [P = 0.006, adjusted odds ratio (OR) = 1.38, 95% confidence interval (CI) = 1.08–1.76]. The polymorphism was associated with risk of developing advanced stage (OR = 2.02, 95%CI = 1.34–3.07) and moderately differentiated (OR = 1.75; 95%CI = 1.20–2.54) RCC. Furthermore, the patients carrying the CC genotype had a significantly greater prevalence of high clinical stage disease (P_trend = 0.003). Similar results were also observed when we restricted the analysis to clear cell RCC, a major histological type of RCC.

Conclusions

Our results suggest that the functional −31G>C polymorphism in the promoter of survivin may influence the susceptibility and progression of RCC in the Chinese population. Large population-based prospective studies are required to validate our findings.     

Interleukin-10-1082 gene polymorphism is associated with papillary thyroid cancer

The etiopathogenesis of thyroid cancer has not been clearly elucidated although the role of chronical inflammation and the imbalance between pro- and anti-inflammatory cytokines may play a role in the etiology. The aim of the present study was to investigate whether cytokine gene polymorphisms are associated with papillary thyroid cancer (PTC), and to evaluate the relationship between genotypes and clinical/laboratory manifestation of PTC. Tumor necrosis factorα (TNFα) G-308A (rs 1800629), interleukin-6 (IL-6) G-174C (rs 1800795) and IL-10 A-1082G (rs 1800896) single nucleotide polymorphisms in DNA from peripheral blood leukocytes of 190 patients with thyroid cancer and 216 healthy controls were investigated by real-time PCR combined with melting curve analysis. There was no notable risk for PTC afflicted by TNFα-308 and IL-6-174 alone. However, IL-10-1082 G allele frequency were higher among PTC patients than healthy controls (p = 0.009). The patients with IL-10-1082 GG geotype have twofold increased risk of developing thyroid cancer according to AA genotype (OR 2.07, 95 % CI 1.21–3.55). In addition, the concomitant presence of IL-10-1082 G allele (GG + AG genotypes) together with IL-6 -174 GG genotype has a nearly twofold increased risk for thyroid cancer (OR 1.75 with 95 % CI 1.00–3.05, p = 0.049). We suggest that IL-10-1082 G allele is associated with an increased risk of PTC. The polymorphism of IL-10 gene can improve our knowledge about the pathogenesis of PTC, and could provide to estimate people at the increased risk for PTC.     

The 46359CT polymorphism of DNMT3B is associated with the risk of cervical cancer

Abnormal methylation is related to cancer development. Since DNMT3B is an enzyme that modulates genomic methylation, we hypothesized that genetic variants of the promoter DNMT3B may be associated with an increased risk of developing cervical cancer. Our aim was to investigate the association between ?579GT and 46359CT polymorphisms of DNMT3B and cervical cancer, high-grade squamous intraepithelial lesions (HSIL), and low-grade squamous intraepithelial lesions (LSIL). Samples from 200 healthy women and 130 women with squamous intraepithelial lesions (70 with cervical cancer, 30 with HSIL, and 30 with LSIL) were analyzed. Polymorphism genotyping was performed using PCR and restriction fragment length polymorphism. The ?579GT polymorphism was not associated with cervical cancer, HSIL, or LSIL. The CT genotype of 46359CT polymorphism was significantly associated with cervical cancer risk (OR 8.75, CI 1.27–374.1), whereas the TT genotype was associated with a significantly decreased risk of HSIL (OR 0.66, CI 0.01–0.32) and LSIL (OR 0.11, CI 0.026–0.45). Our results suggest that genotyping the 46359CT polymorphism in DNMT3B may help identify women who are genetically susceptible to cervical cancer development. Additional studies with larger sample sizes are necessary to confirm our findings.     

Polymorphisms in the aurora-A gene is not associated with lung cancer in the Turkish population

Lung cancer, a complex neoplasm of lung tissue, is influenced by several environmental and genetic factors which could be changed in each individual. Aurora-A gene is related to mitotic events such as: chromosome instability, cell cycle regulation, spindle formation, and kinetechore-microtubule connections. This centrosomic serine/threonine kinase provides a strong connection between mitotic errors and carcinogenesis. The genomic alterations such as single nucleotide polymorphisms (SNPs) can exist in molecular pathways of lung cancer. Therefore, we evaluated the role of genetic polymorphisms of Aurora-A gene in the lung cancer in the Turkish population. Genotypes of five Aurora-A polymorphisms (F31I, V57I, 6328G/A, P50L, and S104L) were determined in 102 healty controls and 102 new diagnosed lung cancer cases. All samples were genotyped with DNA sequence technique. There were not any genotype variations in P50L, S104L, and 6328G/A polymorphisms. The frequencies of both genotypes F31I and V57I in lung cancer patients were not significantly different from those in controls (p > 0.05). A multivariable logistic regression analysis including patient characteristics, such as age and gender, did not change the results.     

A C597-->A polymorphism in the Norrie disease gene is associated with advanced retinopathy of prematurity in premature Kuwaiti infants

Retinopathy of prematurity (ROP) is a retinal vascular disease which occurs in infants with a short gestational age and low birth weight and may lead to retinal detachment and blindness. In some premature infants, ROP progresses to advanced stages despite rigorous intervention, but in the majority, it spontaneously regresses before the threshold stage. Genetic factors, e.g. mutations in the Norrie disease (ND) gene, have been implicated in determining the progression of ROP to advanced stages. We have identified a novel C597A polymorphism of the ND gene; we screened this and another mutation in the ND gene, C110G, in 210 premature Kuwaiti infants using PCR-RFLP, DNA sequence analysis and DNA enzyme immunoassay hybridization to investigate their association with advanced-stage ROP. In this cohort of premature Kuwaiti newborns, 115 of 210 babies had no eye problems and served as controls, while 95 were found to have ROP. In 71 of the 95 ROP cases, the disease spontaneously regressed at or before stage 3, while in 24 of 95 ROP cases, the disease progressed to advanced stages 4 or 5. The incidence of the AA genotype of the C597A polymorphism was considerably higher in advanced-stage ROP cases (83.3%) compared to spontaneously regressing ROP cases (0%) and the normal controls (10.4%) (p < 0.0001). For the other genotypes, no significant difference was detected between the controls and ROP cases. In the case of the C110G mutation in the ND gene, no significant differences were detected between the controls and ROP cases, and the majority of subjects had a CC genotype in all three groups.     

The Per2 polymorphism rs10462023 is associated with the risk of stroke in a Chinese population

The key clock protein Period2 (Per2) has been suggested to play an essential role in regulating endothelial function. It also regulates the expression of plasminogen activator inhibitor-1, but its role in stroke development has not been studied. To explore the possible association between Per2 and ischemic stroke (IS), 479 Chinese IS patients and 306 healthy controls were recruited, and five tag single nucleotide polymorphisms representing the Per2 locus were genotyped using the Sequenom MassARRAY system. A significant difference was observed in the genotypic distribution (p = 0.014) and allele frequency (p = 0.005) of rs10462023, with carriers of the G allele being more prone to developing IS. After adjusting for possible risk factors including smoking, alcohol use, and history of hypertension and diabetes, a significant association was still apparent. Haplotype analysis also supported the association between Per2 and IS. This study suggests that Per2 variations are associated with IS and may represent genetic risk factors for IS in a Chinese population.