Polymorphisms in three genes are associated with hemorrhagic stroke.
ABSTRACT: BACKGROUND:Multiligand receptor for advanced glycation end products (RAGE), osteoprotegerin, and Golgb1 genes may be implicated in atherosclerosis and vascular diseases. Single nucleotide polymorphisms (SNPs) rs1035798 in RAGE gene, rs2073617 and rs2073618 in TNFRSF11B, and rs3732410 in Golgb1 will be investigated on whether there is an association with hemorrhagic stroke (HS) in Chinese population. METHODS:A total of 600 subjects including 199 HS patients and 401 controls were assayed. These samples were divided into two groups: the ?50 year and >50 year groups. Genotyping of SNPs was determined using the SEQUENOM MassARRAY matrix-assisted laser desorption ionization-time-of-flight-mass spectrometry. The association between genotype and HS risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) with multivariate unconditional logistic regression analyses. RESULTS:Our data showed that in the ?50 year group, the rs1035798 major allele homozygote C/C in RAGE gene was associated with an increased risk of HS, while Golgb1 rs3732410 minor allele homozygote G/G was associated with a decreased risk of HS. In the >50 year group, the major allele homozygote G/G of rs2073618 was found to be associated with an increased risk of HS. CONCLUSIONS:The polymorphisms rs1035798 of RAGE gene, rs2073618 of TNFRSF11B, and rs3732410 of Golgb1 might be involved in the risk of HS at different stage of ages.
Project description:Patients with rheumatoid arthritis (RA) have accelerated atherosclerosis, but there is limited information about the genetic contribution to atherosclerosis in this population. Therefore, we examined the association between selected genetic polymorphisms and coronary atherosclerosis in patients with RA.Genotypes for single-nucleotide polymorphisms (SNPs) in 152 candidate genes linked with autoimmune or cardiovascular risk were measured in 140 patients with RA. The association between the presence of coronary artery calcium (CAC) and SNP allele frequency was assessed by logistic regression with adjustment for age, sex, and race. To adjust for multiple comparisons, a false discovery rate (FDR) threshold was set at 20%.Patients with RA were 54±11 years old and predominantly Caucasian (89%) and female (69%). CAC was present in 70 patients (50%). A variant in rs2073618 that encodes an Asn3Lys missense substitution in the osteoprotegerin gene (OPG, TNFRSF11B) was significantly associated with the presence of CAC (OR=4.09, p<0.00026) and withstands FDR correction.Our results suggest that a polymorphism of the TNFRSF11B gene, which encodes osteoprotegerin, is associated with the presence of coronary atherosclerosis in patients with RA. Replication of this finding in independent validation cohorts will be of interest.
Project description:The etiology of otosclerosis is unknown. The etiopathogenesis of otosclerosis seems similar to that occurring in Paget's disease of bone, for which mutations or polymorphisms in several genes have been identified. Among these, TNFRSF11B gene encoding the osteoprotegerin is produced at high levels in the normal inner ear and at low level in active otosclerotic stapes footplates. The aim of this work was to verify the presence of a correlation between the rs2073618 (N3K) polymorphism in the TNFRSF11B gene and otosclerosis. Mutational screening in the TNFRSF11B gene was performed by direct sequencing. SNPs analysis was performed by PCR and by specific restriction enzyme assay with HpaI. The significance of the association was analyzed by statistical specific software. No causative mutation has been identified but the data suggested a strong correlation between the rs2073618 (N3K) polymorphism and otosclerosis. This correlation, however, has been excluded in a case-control study. This study excluded the association between the N3K polymorphism and otosclerosis in Campania region population.
Project description:Osteoporosis (OP) is highly prevalent in rheumatoid arthritis (RA) and is influenced by genetic factors. Single-nucleotide polymorphism (SNP) rs2073618 in the <i>TNFRSF11B</i> osteoprotegerin (<i>OPG</i>) gene has been related to postmenopausal OP although, to date, no information has been described concerning whether this polymorphism is implied in abnormalities of bone mineral density (BMD) in RA. We evaluated, in a case-control study performed in Mexican-Mestizo women with RA, whether SNP rs2073618 in the <i>TNFRSF11B</i> gene is associated with a decrease in BMD. RA patients were classified as follows: (1) low BMD and (2) normal BMD. All patients were genotyped for the <i>rs2073618</i> polymorphism by PCR-RFLP. The frequency of low BMD was 74.4%. Higher age was observed in RA with low BMD versus normal BMD (62 and 54 years, resp.; <i>p</i> < 0.001). Worse functioning and lower BMI were observed in RA with low BMD (<i>p</i> = 0.003 and <i>p</i> = 0.002, resp.). We found similar genotype frequencies in RA with low BMD versus RA with normal BMD (GG genotype 71% versus 64.4%, GC 26% versus 33%, and CC 3% versus 2.2%, resp.; <i>p</i> = 0.6). We concluded that in Mexican-Mestizo female patients with RA, the rs2073618 polymorphism of the <i>TNRFS11B</i> gene is not associated with low BMD.
Project description:Purpose:Diabetic foot is a complication of long-lasting diabetes mellitus affecting up to 15% of patients, both in type 1 and type 2 diabetes. Osteoprotegerin is involved in osteogenesis and calcification. The aim of the study was to assess the role of selected osteoprotegerin gene variants in diabetes patients with diabetic foot. Methods:The study involved 300 patients with diabetes and diabetic foot and 968 healthy controls. The study group was formed by 243 patients with diabetic foot of neuropathic origin, 102 with diabetic foot of neuroischemic origin and 77 with Charcot neuroarthropathy. Results:Compared to controls, rs1872426 and rs1485286 showed correlation with diabetic foot in diabetes subjects. Significant associations between rs2073618, rs1872426, rs7464496 and rs1485286 in men were reported. The aforementioned correlations were also present in type 2 diabetes patient subgroup. Variant rs1485286 was associated to diabetic foot of neuropathic origin. Sex-specificity for females was present for rs6993813 in patients with diabetic foot of neuropathic origin and type 1 diabetes. Variants rs1872426, rs2073617 and rs1485286 were correlated with CN. We found that age, body weight, body mass index, waist circumference, hip circumference and waist-hip ratio were among the basic risk factors of diabetic foot. Conclusions:The following variants TNFRSF11B (rs2073618, rs2073617, rs1872426, rs1032128, rs7464496, rs11573829 and rs1485286), COLEC10 (rs6993813, rs3134069) and TNFSF11 (rs9533156) present differences in allele frequencies in diabetic foot patients and show correlation with gender, diabetes type and diabetic foot etiology.
Project description:BACKGROUND The aim of this study was to investigate the association between T950C (rs2073617) and G1181C (rs2073618) polymorphisms of the osteoprotegerin gene (OPG) and the susceptibility of peri-implantitis in the Chinese Han population. MATERIAL AND METHODS 110 patients with peri-implantitis and 116 healthy persons from the Chinese Han population were included in this study using a case-control design; rs2073617 and rs2073618 in OPG were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The linkage disequilibrium (LD) and haplotype analysis were performed with Haploview software. Hardy-Weinberg equilibrium (HWE) was assessed in the control group based on the genotype distributions of OPG polymorphisms. The genotype, allele, and haplotype distribution differences between the case and control groups were analyzed by chi-square test, and the relative risk of PD was expressed by odds ratio (OR) and 95% confidence interval (CI). RESULTS The study results showed that people carrying the CC genotype of rs2073618 were more likely to have peri-implantitis than GG genotype carriers (OR=2.18, 95% CI=1.03-4.62, p=0.04). In addition, patients with the C allele had 1.47 times the risk of suffering from peri-implantitis (OR=1.47, 95% CI=1.01-2.13, p=0.04), but not rs2073617 polymorphism. The G-C haplotype frequency of rs2073618-rs2073617 in OPG was significantly correlated to the increased susceptibility of peri-implantitis (OR=2.27, 95% CI=1.20-4.30). CONCLUSIONS OPG rs2073618 polymorphism may be related to the risk of peri-implantitis, but not rs2073617. Moreover, haplotype is also a non-ignorable risk factor.
Project description:BACKGROUND AND AIMS:A recent meta-analysis revealed that the genotype PNPLA3 rs738409 GG is associated with a higher risk of hepatic steatosis (HS) in Caucasian patients with chronic hepatitis C (CHC). However, controversial results were found regarding Asian populations. Furthermore, previous studies have shown a negative association between interferon lambda 3 (IFNL3) rs12979860 CC and HS in Caucasian CHC patients, but there have been no reports indicating any such association in Asian populations. In this study, then, we investigated the association of PNPLA3 and IFNL3 polymorphisms with HS in Asian CHC patients. METHODS:We enrolled consecutive CHC patients who underwent liver biopsy prior to antiviral therapy. We excluded those patients with decompensated liver disease, any co-existing chronic liver disease, or HIV or HBV co-infection. RESULTS:1080 CHC patients were enrolled, and HS was found in 453 (41.9%) patients. The frequency distribution of the G allele was significantly associated with HS (P<0.001), and this conferred a higher risk to G allele homozygotes (OR: 2.06, 95% CI: 1.46-2.88, P <0.001) than to G allele carriers (OR: 1.98, 95% CI: 1.52-2.58, P<0.001). There was a borderline significant difference in the prevalence of HS in rs12979860 CC versus non-CC (40.8% versus 49.3%, P = 0.059). After adjustment for age, sex, body mass index, diabetes, and excessive alcohol intake, the rs738409 G allele homozygote carriers still carried a higher risk for HS (OR: 1.93, 95% CI: 1.35-2.77, P = 0.003). CONCLUSION:The PNPLA3 rs738409 GG genotype is positively associated with HS, while the IFNL3 rs 12979860 CC genotype may be negatively associated with HS, in Asian CHC patients.
Project description:Golgin subfamily B member 1 (GOLGB1) gene encodes the coat protein 1 vesicle inhibiting factor, giantin. Previous study showed that mutations of the GOLGB1 gene are associated with dozens of human developmental disorders and diseases. However, the biological function of GOLGB1 gene in chicken is still unclear. In this study, we detected a novel 65-bp insertion/deletion (indel) polymorphism in the chicken GOLGB1 intron 5. Association of this indel with chicken growth and carcass traits was analyzed in a yellow chicken population. Results showed that this 65-bp indel was significantly associated with chicken body weight (p < 0.05), highly significantly associated with neck weight, abdominal fat weight, abdominal fat percentage and the yellow index b of breast (p < 0.01). Analysis of genetic parameters indicated that "I" was the predominant allele. Except for the yellow index b of breast, II genotype individuals had the best growth characteristics, by comparison with the ID genotype and DD genotype individuals. Moreover, the mRNA expression of GOLGB1 was detected in the liver tissue of chicken with different GOLGB1 genotypes, where the DD genotype displayed high expression levels. These findings hinted that the 65-bp indel in GOLGB1 could be assigned to a molecular marker in chicken breeding and enhance production in the chicken industry.
Project description:The soluble receptor for advanced glycation end-products (sRAGE) is shown to mitigate pro-inflammatory effects triggered by ligation of RAGE with N(?)-carboxymethyl-lysine (CML)-AGE or other ligands. We examined the associations among host, lifestyle, and genetic determinants of CML-AGE or sRAGE and risk of pancreatic cancer in the prospective ATBC Study. We obtained baseline exposure information, data on serological and genetic biomarkers from 141 patients with pancreatic cancer and 141 subcohort controls. Stepwise linear and logistic regression models were used for data analysis. Multiple linear regression analyses showed that CML-AGE concentrations were independently inversely correlated with the minor allele of rs640742 of DDOST, physical activity, alcohol consumption, diastolic blood pressure (BP), and positively correlated with heart rate, serum sRAGE and HDL concentrations (P < 0.05). sRAGE concentrations were independently inversely correlated with the 82Ser allele of rs2070600 of RAGE, age, body mass index, heart rate, and serum HDL; and positively correlated with serum CML-AGE, sucrose consumption, and diastolic BP (P < 0.05). The minor allele of rs1035786 of RAGE was associated with reduced risk of pancreatic cancer (any T compared with CC: multivariate OR = 0.61, 95% CI: 0.38-0.98). We identified host metabolic profile, lifestyle and genetic factors that explained approximately 50% of variability of CML-AGE or sRAGE in Finnish men smokers. The association between RAGE SNPs and pancreatic cancer risk warrants further investigation.
Project description:Accumulating evidence has suggested that receptor for advanced glycation end products (RAGE) is involved in the development and progression of human abdominal aortic aneurysms (AAAs). However, the association between RAGE gene polymorphisms and AAA has not yet been determined. The present study was aimed at analyzing the potential association between the RAGE gene polymorphisms and AAAs. A cohort of 381 patients and 436 age-matched healthy controls were genotyped to detect the three RAGE polymorphisms (-374 T/A, -429 T/C, and G82S) using SNaPshot. Our study demonstrated a significant difference in the genotype and allele frequencies of the RAGE G82S polymorphism between the AAA patients and the controls. Further stratification by gender and smoking status revealed that the presence of the RAGE 82S allele confers a higher risk for developing AAA in men and smokers. Moreover, AAA patients with the variant 82S allele of RAGE presented with reduced serum soluble RAGE (sRAGE) production, and this decrease was more significant in men and smokers with AAA. Our study provides preliminary evidence that the 82S allele of RAGE is a risk factor for AAA. This new piece of knowledge regarding RAGE may be clinically important for the prevention and therapy of AAAs.
Project description:Single-nucleotide polymorphisms (SNPs) located in the promoter region of the receptor for advanced glycation end products (RAGE) gene have been linked to the activity of RAGE. However, contrary to our expectation, we previously detected no correlation between SNPs within the RAGE promoter and ulcerative colitis (UC) risk in a case-control study. Here, we investigated the methylation of the RAGE promoter and analyzed the collective contribution of methylation and SNPs to UC risk. We found that RAGE promoter hypomethylation was more common in UC patients compared to controls (70% vs. 30%, respectively), as determined via bisulfite sequencing PCR (BSP) and methylation-specific PCR (MSP). Furthermore, we investigated the cooperativity of promoter methylation and SNPs and found that either of two SNPs (rs1800624 or rs1800625) and promoter methylation jointly contributed to UC risk (30 UC patients vs. 30 controls, P?<?0.05). There was no correlation between UC risk and either methylation or SNPs when analyzed separately. This lack of correlation is likely due to promoter methylation repressing gene transcription, whereas SNPs in the RAGE promoter region activate RAGE transcription. We found that variant allele carriers with promoter hypomethylation were at an increased risk for UC (rs1800624, OR = 10, 95% CI: 1.641-60.21, P?=?0.009; rs1800625, OR = 4.8, 95% CI: 1.074-21.447, P?=?0.039). Furthermore, our data revealed that the RAGE mRNA levels in variant allele carriers with promoter hypomethylation were significantly higher compared to those with promoter hypermethylation (P?<?0.05) as well as to those in wild-type allele individuals exhibiting promoter hypomethylation (P?<?0.05). We therefore speculate that the methylation status and SNPs present in the RAGE promoter region alter RAGE transcription, thereby impacting UC risk. We also propose that the methylation status and RAGE promoter genotype could jointly serve as clinical biomarkers to assist in UC risk assessment.