Haplotype-based case-control study of estrogen receptor alpha (ESR1) gene and pregnancy-induced hypertension.

Hypotheses about pregnancy-induced hypertension (PIH) have been proposed to explain the vascular damage that characterizes this disease. Reports indicate that estrogens and estrogen receptors play important physiological roles in cardiovascular diseases. There have been studies examining the association between coronary artery disease and the estrogen receptor alpha (ESR1) gene. The aim of the present work was to assess the association between PIH and single-nucleotide polymorphisms (SNPs) in the human ESR1 gene, by conducting a haplotype-based case-control study. Based on a database search at the web site of the National Center of Biotechnology Information, we chose five SNPs in the human ESR1 gene, and performed an association study using 95 PIH patients and 200 age-matched non-PIH subjects. The frequency of rs2881766 genotypes and alleles differed significantly between the two groups. There was no significant difference in overall distribution of genotypes or alleles of the other four SNPs. The T allele of rs2881766 was significantly more prevalent in the PIH group than in the non-PIH group. Haplotype-based case-control analysis revealed that there was a significant difference in overall distribution of the combinations rs2881766-rs1643821-rs988328 and rs2881766-rs1643821 between the PIH group and the non-PIH group (all or body mass index [BMI]-matched). One susceptibility haplotype for PIH and two resistance haplotypes for PIH were revealed by comparison between the PIH group and the non-PIH (BMI-matched) control group. In conclusion, the T allele of rs2881766 could be a useful genetic marker of PIH. The G-A-T haplotype of rs2881766-rs1643821-rs988328 and the G-A haplotype of rs2881766-rs1643821 appear to be resistance markers of PIH.     

Haplotype-based case-control study of the association between the guanylate cyclase activator 2B (GUCA2B, Uroguanylin) gene and essential hypertension.

Uroguanylin (gene name: guanylate cyclase activator 2B, GUCA2B) is a peptide regulator of intestinal salt and water transport. It has been reported that the uroguanylin knockout mouse exhibits elevated blood pressure. Therefore, the GUCA2B gene is thought to be a susceptibility gene for essential hypertension (EH). Despite extensive studies, however, the relationship between the GUCA2B gene and EH has not yet been defined. The aim of this study was to assess the association between the human GUCA2B gene and EH. Using four single nucleotide polymorphisms (SNPs), we conducted a genetic association study in 281 EH patients and 279 age-matched normotensive (NT1) individuals. To derive more reliable data, we performed a duplicate case-control study in which we recruited another normotensive group (NT2). There was no significant difference in the overall distribution of alleles for any of the SNPs between the EH and NT1 groups, or between the EH and NT2 groups. Therefore, these four SNPs cannot be the genetic markers for EH. The occurrences of the C-A haplotype (rs883062-rs1047047) and the C-A-G haplotype (rs883062-rs1047047-rs2297566) were significantly higher in the EH group than in the NT1 group (p<0.0001) or the NT2 group (p<0.0001). These results suggest that the C-A haplotype and the C-A-G haplotype of the GUCA2B gene are the genetic markers for EH, and that GUCA2B or a neighboring gene might be a susceptibility gene for EH.     

A genome-wide meta-analysis of nodular sclerosing Hodgkin lymphoma identifies risk loci at 6p21.32

Nodular sclerosing Hodgkin lymphoma (NSHL) is a distinct, highly heritable Hodgkin lymphoma subtype. We undertook a genome-wide meta-analysis of 393 European-origin adolescent/young adult NSHL patients and 3315 controls using the Illumina Human610-Quad Beadchip and Affymetrix Genome-Wide Human SNP Array 6.0. We identified 3 single nucleotide polymorphisms (SNPs) on chromosome 6p21.32 that were significantly associated with NSHL risk: rs9268542 (P = 5.35 × 10(-10)), rs204999 (P = 1.44 × 10(-9)), and rs2858870 (P = 1.69 × 10(-8)). We also confirmed a previously reported association in the same region, rs6903608 (P = 3.52 × 10(-10)). rs204999 and rs2858870 were weakly correlated (r(2) = 0.257), and the remaining pairs of SNPs were not correlated (r(2) < 0.1). In an independent set of 113 NSHL cases and 214 controls, 2 SNPs were significantly associated with NSHL and a third showed a comparable odds ratio (OR). These SNPs are found on 2 haplotypes associated with NSHL risk (rs204999-rs9268528-rs9268542-rs6903608-rs2858870; AGGCT, OR = 1.7, P = 1.71 × 10(-6); GAATC, OR = 0.4, P = 1.16 × 10(-4)). All individuals with the GAATC haplotype also carried the HLA class II DRB1*0701 allele. In a separate analysis, the DRB1*0701 allele was associated with a decreased risk of NSHL (OR = 0.5, 95% confidence interval = 0.4, 0.7). These data support the importance of the HLA class II region in NSHL etiology.     

Cytokine Gene Polymorphisms in Chinese Children with Idiopathic Nephrotic Syndrome

Background: Cytokines play a role in the progression of idiopathic-nephrotic syndrome (INS). Objectives: To investigate the association of different cytokine genes polymorphisms with INS incidence and response to steroid therapy in Chinese children. Methods: 182 children with INS and 100 healthy controls were enrolled in this study. Blood genomic DNAs were used to analyze20 single nucleotide polymorphisms (SNPs) in 8 cytokine genes includingIL-21, IL-18, IL-6, IFN-γ, IL-4, IL-10, IL-17F, IL-17A d by multi-PCR with next-generation sequencing. Results: Among 182 children with INS, 89 (48.6%) were steroid-sensitive (SS), 73 (39.9%) were steroid-dependent (SD) and 21 (11.5%) were steroid-resistant (SR). In 20 SNPs, IL-4-rs2243283 exhibited a significantly different genotype distribution between INS and the healthy controls (CC is a risk genotype: 66.5% of INS VS 51% of the control; OR=1.91, p=0.012). Patients carrying AG genotype (rs2275913, IL-17A) had a significantly higher risk of steroid-dependent response (69.1% of SD VS 46.4% of SS; OR=2.58, p=0.014). Similarly, patients carrying A allele of IL-10-rs1800872 (39.0% of SD VS 26.7% of SS; OR=1.76, p=0.018) and C allele of IL-10-rs1800896 (12.3% of SD VS 3.9% of SS; OR=3.44, p=0.004) had a higher risk of steroid-dependent response. However, none of these 20 SNPs showed a significant difference between SS group and SR group. Conclusion: Among the 20 cytokine gene SNPs, IL-4-rs2243283 might increase the susceptibility to INS in Chinese children; rs2275913 of IL-17A, rs1180972, and rs1800896 of IL-10 show association with the steroid -response in Chinese INS children.     

Associations between CLCNKA_B tag SNPs with essential hypertension and interactions between genetic and environmental factors in an island population in China

Abstract

Objective: Essential hypertension (EH) is known as the result from the interaction of environmental and genetic factors. We selected tag SNPs of CLCNKA_B genes as gene markers, to elucidate the relationship between CLCNKA_B and EH, and to determine the possible interaction among tag SNPs and dietary factors in island of China. Methods: A case-control study was conducted in Changshan islands of China, blood samples of 806 participants were genotyped, and the general characteristics and dietary habits of them were collected. Unconditional logistic regression (ULR) was used to assess the effects of CLCNKA_B tag SNPs and dietary factors on EH. Generalized multifactor dimensionality reduction (GMDR) was used to test gene–environment interaction for EH risk. Results: Four SNPs were identified as the tag SNPs of CLCNKA_B. Recessive model for rs5253 and rs2275166 were marginal associated with the decrease risk of EH (OR?=?0.36, 95% CI?=?0.12–1.07 for rs5253; OR?=?0.40, 95% CI?=?0.16–1.05 for rs2275166). In GMDR, the five-factor interaction model of rs1010069, salt, marine products, meat and edible oil consumption was the best model, with a maximum CVC of 10/10 and a TBA of 0.638 (p?=?0.001). In ULR, compared with subjects carried wild genotypes and null dietary risk factor, those with three or more dietary risk factors and mutation genotypes had 5.90-fold EH risk (95% CI:2.24–15.53). Conclusion: Though the single loci of tag SNPs of CLCNKA_B are not enough to significantly increase the EH susceptibility, the combination of CLCNKA tag SNP, salt, marine products, meat and edible oil consumption is associated with elevated risk.     

Haplotype-based case study of human CYP4A11 gene and cerebral infarction in Japanese subject

OBJECTIVE: CYP4A11 is an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid, which is involved in regulation of vascular tone in the brain. Recent evidence indicates that the polymorphism of the CYP genes is associated with cerebral infarction (CI). The aim of the present study was to assess the association between the human CYP4A11 gene and CI using a haplotype-based case-control study divided by gender. METHODS: Three SNPs of the human CYP4A11 gene (rs2269231, rs1126742, and rs9333025) were selected and genotyped for 174 CI patients and 293 controls. The data were assessed for three separate groups: total subjects, men and women. RESULTS: In men, the genotype distribution of rs9333025 significantly differed between the CI patients and control subjects (P = 0.047). The distribution of the dominant model of rs9333025 (GG vs. GA + AA) significantly differed between both the total and the men groups (P = 0.033, P = 0.028, respectively). Logistic regression analysis adjusted for the history of hypertension and diabetes mellitus also showed that the GG genotype was significantly more frequent in the CI patients than in the controls, both for the total and men groups (P < 0.001, P = 0.008, respectively). The overall distribution of the haplotypes constructed with the 3 SNPs showed significant differences between the CI and the control in total group (P = 0.049). The T-C-G haplotype was significantly more frequent in control subjects than in the CI patients in the total group (P = 0.020). CONCLUSIONS: The GG genotype of rs9333025 could be a genetic marker for CI in Japanese men. In addition, the T-C-G haplotype might also be a protective marker for CI in Japanese.     

Association of polymorphisms in NOS3 with the ankle-brachial index in hypertensive adults

We investigated the association of 14 polymorphisms in the endothelial nitric oxide synthase gene (NOS3) with ankle brachial index (ABI) in non-Hispanic white hypertensives belonging to hypertensive sibships. Subjects (n=659, mean age 61+/-9 years, 54% women) underwent measurement of ABI using a standard protocol, and the lowest of 4 ABI values was used in the analyses. Non-synonymous SNPs with a minor allele frequency >0.02 and tag SNPs selected based on a measure of linkage disequilibrium (r(2)) were genotyped. We reduced the chance of false positives by testing for replication, randomly selecting 1 hypertensive sib from each sibship to create Subset 1 (n=330) and Subset 2 (n=329). Multivariable linear regression models were used to assess the associations of single NOS3 polymorphisms and haplotypes with ABI after adjustment for covariates (age, sex, body mass index, smoking, total cholesterol, HDL cholesterol, and diabetes). Two specific SNPs in significant LD with each other (rs891512 and rs1808593) were significantly associated with ABI in both subsets. Based on a sliding window approach with a window size of 2, estimated haplotypes from 2 SNP pairs (rs2070744-rs3918226 and rs1808593-rs7830) were also significantly associated with ABI in both subsets. In conclusion, specific NOS3 SNPs and haplotypes were associated with inter-individual variation in ABI, a non-invasive marker of peripheral arterial disease, in replicate subsets of hypertensive subjects. These findings motivate further investigation of the role of NOS3 variants in determining susceptibility to peripheral arterial disease.     

Polymorphism of the C-reactive protein (CRP) gene is related to serum CRP Level and arterial pulse wave velocity in healthy elderly Japanese.

The objective of this study was to clarify relationships between the C-reactive protein (CRP) gene and both the serum level of CRP and arterial pulse wave velocity (PWV), using haplotype analysis of healthy elderly Japanese. Five single-nucleotide polymorphisms (SNPs) of the human CRP gene (rs1341665, rs3091244, rs1800947, rs1130864 and rs1205) were used to genotype 315 healthy elderly Japanese subjects (mean age, 77.9 +/- 4.1 years; male/female ratio, 0.96). Linkage disequilibrium was analyzed for the five SNPs. The frequency of each haplotype and diplotype was estimated using the expectation/maximization (EM) algorithm. There were statistically significant associations between the CRP level and two CRP genotypes; the p value for the T allele of rs3091244 (CT + AT + TT vs. CC + CA + AA) was 0.002 (95% confidential interval [CI], 2.1-24), and the p value for the T allele of rs1130864 (TT + TC vs. CC) was 0.002 (95% CI, 2.1-24). The only genotype that was significantly associated with arterial PWV was the C allele of rs1800947, with a p value of 0.039. The haplotype was constructed using rs1341665, rs3091244 and rs1800947, in that order. There was a significant association between the CRP level and the T-T-G haplotype, with a p value of 0.002 (95% CI, 2.1-24). There was a significant association between arterial PWV and the C-C-C haplotype, with a p value of 0.039. We concluded that rs3091244, rs1130864 and the T-T-G haplotype are genetic markers for elevated basal CRP levels. rs1800947 and the C-C-C haplotype appear to be susceptibility markers for atherosclerosis, but this requires confirmation.     

Genetic susceptibility and haplotype analysis between Fcgamma receptor IIB and IIIA gene with systemic lupus erythematosus in Chinese population

The objective of this study is to understand the role of FcgammaRIIB and FcgammaRIIIA gene in susceptibility to systemic lupus erythematosus (SLE), and to examine possible susceptible haplotypes between two genes. A total of 119 patients with SLE from 95 nuclear families, aged from 14 to 78 years, were selected according to 1997 criteria of American College of Rheumatology. In addition, 316 family members of these patients were also genotyped. A family-based association study was used to explore the relationship between gene polymorphism and SLE. We studied 13 single-nucleotide polymorphisms (SNPs) encoding non-synonymous substitution in the FcgammaRIIB and FcgammaRIIIA gene (four SNPs in the FcgammaRIIB gene and nine SNPs in the FcgammaRIIIA gene) with respect to genetic susceptibility to SLE. All SNPs were genotyped by restriction fragment length polymorphism method. Among 13 SNPs, univariate (single-marker) family-based association tests showed that variant alleles at only four SNPs (rs10917661 and rs1050501, in exon 2 and exon 5 of FcgammaRIIB gene, rs403016 and rs428888, in exon3 of FcgammaRIIIA gene respectively) were significantly associated with genetic susceptibility to SLE. Furthermore, the haplotype-specific FBATs showed 50Ter-225Thr (34.1%, in FcgammaRIIB gene) and 72Arg-118Asn (40%, in the FcgammaRIIIA gene) haplotype were more frequently transmitted in SLE than other haplotypes (Z = 3.539, P = 0.00042; Z = 2.678, P = 0.007412 respectively). But haplotypes were not found between FcgammaRIIB and FcgammaRIIIA gene Our results suggest that there were meaningful haplotype in FcgammaRIIIA and FcgammaRIIB gene respectively. FcgammaRIIIA and FcgammaRIIB genes in the pathogenesis of SLE may play an independent role in Chinese population.     

Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia

Disrupted-in-schizophrenia 1 (DISC1) is a promising schizophrenia candidate gene expressed predominantly within the hippocampus. We typed 12 single-nucleotide polymorphisms (SNPs) that covered the DISC1 gene. A three-SNP haplotype [hCV219779 (C)-rs821597 (G)-rs821616 (A)] spanning 83 kb of the gene was associated with schizophrenia in a family-based sample (P = 0.002). A common nonconservative SNP (Ser704Cys) (rs821616) within this haplotype was associated with schizophrenia (P = 0.004). Based on primary expression of DISC1 in hippocampus, we hypothesized that allelic variation at Ser704Cys would have a measurable impact on hippocampal structure and function as assayed via specific hippocampus-related intermediate phenotypes. In addition to overtransmission in schizophrenia, the Ser allele was associated with altered hippocampal structure and function in healthy subjects, including reduced hippocampal gray matter volume and altered engagement of the hippocampus during several cognitive tasks assayed with functional magnetic resonance imaging. These convergent data suggest that allelic variation within DISC1, either at Ser704Cys or haplotypes monitored by it, increases the risk for schizophrenia and that the mechanism of this effect involves structural and functional alterations in the hippocampal formation.     

新疆维吾尔族人心肌梗死与前列环素合酶基因单体型的相关性

目的 探讨前列环素合酶基因(CYP8A1)单体型与新疆维吾尔族人心肌梗死(MI)的相关性.方法 采用聚合酶链反应-限制性片段长度多态性方法 ,对210例MI患者和206例健康体检者CYP8A1基因的3个单核苷酸多态性(SNP)(rs5602,rs5629和rs45498106)进行基因分型和单体型构建,应用病例对照单体型分析的方法 进行相关性分析.结果 MI组CPY8A1基因rs5629的CC基因型频率为71.42%,明显高于对照组(61.65%,P=0.035),而rs5602和rs45498106基因型在两组间分布差异无统计学意义;MI组A-C-T单体型频率为0.60%,明显低于对照组(4.02%,P=0.001),但MI组C-T-T单体型频率为7.40%,明显高于对照组(3.31%,P=0.011).logistic回归分析结果 显示,调整吸烟、高血压和高胆固醇血症等因素后发现,rs5629CC基因型(P=0.021,OR=1.665,95%C/ :1.024～2.156)和C-T-T单体型仍是MI的独立危险因素(P=0.011,OR=1.876,95%CI:1.410-3.171).结论 CYPSA1基因rs5629位点CC基因型可能与新疆维吾尔族人MI的发生相关;C-T.T单体型可能为新疆维吾尔族人MI的易感标志;A-c-T单体型可能为新疆维吾尔族人群MI的保护因子.     

Fibroblast growth factor 23 (FGF23) gene polymorphisms are associated with essential hypertension risk and blood pressure levels in Chinese Han population

In this case-control study, 246 EH patients and 157 healthy controls were selected from Chinese Han population to explore the associations between the fibroblast growth factor 23 (FGF23) gene polymorphisms and essential hypertension (EH).The SequenomMassarray system was used for the genotyping of three FGF23 gene Tag single-nucleotide polymorphisms, namely rs7955866, rs13312756, and rs3812822. The primers were designed by Assay Designer 3.1 software, and then the samples were added to a 384-well plate for the polymerase chain reaction amplification, shrimp alkaline phosphatase reaction, and desalting after extension. The distributions of the alleles, genotypes, and haplotypes were compared between the two groups. Confounding factors (sex, age, BMI, smoking, and drinking) were adjusted in the non-logistic regression, and the results showed that rs7955866 and rs3812822 polymorphisms were independently associated with the risk of developing EH (P < 0.05). The statistical analysis of the haplotype of rs7955866-rs13312756-rs3812822 showed that haplotype ACC could increase the risk of developing EH (P = 0.046; OR = 1.513, 95%CI: 1.005–2.278). The analysis of the control group showed that carrying rs7955866 A allele (P = 0.031) and rs3812822 C allele (P = 0.025) was associated with the increase of systolic blood pressure (SBP). The insulin (INS) level in the peripheral blood was significantly different between the case and control groups (P = 0.014). After confounding factors were excluded, the results showed that the serum INS level was also an independent risk factor of developing EH (P = 0.044; OR = 1.604, 95%CI: 1.014–2.539). In summary, our results suggest that FGF23 gene polymorphisms are associated with the risk of developing EH in Chinese Han population.     

Association of the multidrug-resistance-associated protein gene (ABCC2) variants with intrahepatic cholestasis of pregnancy

BACKGROUND/AIMS: We hypothesized that common genetic variation at ABCC2 influences ICP susceptibility. Hence we studied the association of single nucleotide polymorphisms (SNPs) of promoter, coding and non-coding regions of ABCC2 and intrahepatic cholestasis of pregnancy (ICP). METHODS: 70 ICP patients and 112 healthy pregnant women in the third trimester of their pregnancies were included in a cross sectional study. Four tag SNPs (rs717620 A/G; rs2756105 C/T; rs2002042 C/T; rs3740066 A/G) encompassing 70 kb in chr.10 and representing 46 polymorphic sites (r(2) > 0.8) were genotyped. Besides, 2 additional SNPs (rs17222723 A/T and rs8187710 G/A) were included. RESULTS: In univariate analysis, rs2002042 and rs3740066 were significantly associated with ICP (p < 0.04 and 0.01, respectively) but after multiple testing correction, only rs3740066 remained significantly associated with disease status (p < 0.03). We also observed a positive association between the rs3740066 and ALT, AST, alkaline phosphatase and total and conjugated bilirubin concentrations. Consistent with the analysis of individual markers, we observed that haplotype frequency of the ABCC2 gene in ICP patients significantly differed from controls (p < 0.03). CONCLUSIONS: We found an association between the rs3740066 in exon 28 of ABCC2 gene and ICP. The risk of disease for homozygous AA carriers is 4-fold higher (OR 4.44 CI 95% 1.83-10.78, p < 0.001) in comparison with GG carriers.     

Association of rheumatoid arthritis risk with EGFR genetic polymorphisms in Taiwan’s Han Chinese population

The involvement of the epidermal growth factor receptor (EGFR) in the pathogenesis of cancer is well documented. In contrast, its role in rheumatoid arthritis (RA) development is not that well defined although previous studies suggested the possible link between autoimmune diseases and malignancy. Therefore, we aimed to examine whether there is a link between the EGFR genetic polymorphisms and the RA. Our study gauged the effects of EGFR (rs11543848 and rs17337023) single-nucleotide polymorphisms (SNPs) on RA among Taiwan’s Han Chinese population. Polymorphism of EGFR gene was analyzed in 188 RA patients and 128 control subjects. Genotyping for EGFR SNPs was performed by restriction fragment length polymorphism (RFLP) assay. Our data confirmed statistically significant increased risk of RA development in subjects with A carrier at rs17337023 SNP (P?<?0.0001), and subjects with A allele at rs17337023 SNP (odds ratio [OR]?=?1.52; 95% confidence interval [CI]?=?1.10–2.09). Furthermore, comparison of haplotype frequencies between patients and controls suggested GA and AT haplotypes were more “at-risk” for RA development (P?<?0.0001 and P?<?0.01, respectively). However, comparisons of the clinical features of RA patients according to different genotypes and haplotypes revealed no significant difference. In conclusion, our data yield the new information on EGFR polymorphisms (rs11543848 and rs17337023) with the susceptibility of RA development and polymorphism revealed by this study merit further investigation.     

Lack of association between COPD and transforming growth factor-beta1 (TGFB1) genetic polymorphisms in Koreans.

OBJECTIVE: Many genetic variations have been suggested as genetic risk factors for the development of chronic obstructive pulmonary disease (COPD), including single nucleotide polymorphisms in the transforming growth factor-beta1 (TGFB1) gene. We attempted to elucidate the association between TGFB1 genetic polymorphisms and COPD among Koreans. DESIGN: The genotypes of 102 male patients with COPD and 159 volunteers with similar distributions of age, sex and smoking intensity, as well as normal pulmonary function, were determined for three previously associated TGFB1 single nucleotide polymorphisms (SNPs), -10807G/A (rs2241712) and -509T/C (rs1800469), located in or near the promoter, and 29T/C (rs1982073), located in exon 1 of the TGFB1 gene. RESULTS: No significant associations between COPD and the three TGFB1 SNPs could be identified. In addition, the haplotypes composed of three TGFB1 SNPs were not associated with the presence of COPD. CONCLUSION: These results differ from previous reports involving Caucasians, and might reflect racial differences in the pathogenesis of COPD.     

Human leukocyte antigen class I region single-nucleotide polymorphisms are associated with leprosy susceptibility in Vietnam and India

Experimental evidence suggested the existence of unidentified leprosy susceptibility loci in the human leukocyte antigen (HLA) complex. To identify such genetic risk factors, a high-density association scan of a 1.9-mega-base (Mb) region in the HLA complex was performed. Among 682 single-nucleotide polymorphisms (SNPs), 59 were associated with leprosy (P <.01) in 198 Vietnamese single-case leprosy families. Genotyping of these SNPs in an independent sample of 292 Vietnamese single-case leprosy families replicated the association of 12 SNPs (P <.01). Multivariate analysis of these 12 SNPs showed that the association information could be captured by 2 intergenic HLA class I region SNPs (P = 9.4 × 10??)-rs2394885 and rs2922997 (marginal multivariate P = 2.1 × 10?? and P = .0016, respectively). SNP rs2394885 tagged the HLA-C*15:05 allele in the Vietnamese population. The identical associations were validated in a third sample of 364 patients with leprosy and 371 control subjects from North India. These results implicated class I alleles in leprosy pathogenesis.     

Clinical associations of the genetic variants of CTLA‐4, Tg,TSHR, PTPN22, PTPN12 and FCRL3 in patients with Graves’ disease

Objective Graves’ disease (GD) is an organ‐specific autoimmune disorder. Both immune‐modulating genes and thyroid‐specific genes are involved in its genetic pathogenesis. It remains unclear, however, how the interactions of various susceptibility genes contribute to the pathogenesis and clinical severity of the disease. The purpose of this study was to investigate the relationships between GD and single nucleotide polymorphisms (SNPs) from CTLA‐4, PTPN22, PTPN12, FCRL3 (general autoimmunity genes regulating T and B cells) and the TSHR and Tg genes (disease‐specific genes). Furthermore, we evaluated the influences these SNPs have on the risk and severity of GD. Design and methods This cross‐sectional clinical study was performed in 436 GD patients and 316 healthy, gender‐matched individuals. Twenty‐eight SNPs from CTLA‐4, PTPN22, PTPN12, FCRL3, TSHR and Tg genes were genotyped and their associations with the risk and severity of GD were analysed. Results The CTLA‐4 rs231779, Tg rs2069550 and PTPN22 rs3789604 SNPs were associated with GD, with additive risk effects present in rs231779 and rs2069550. The ACACC and ACGCT haplotypes, composed of five SNPs in the CTLA‐4 gene (rs4553808, rs5472909, rs231775, rs231777 and rs231779), were protective and risk haplotypes respectively. The AA genotype of PTPN22 rs3789604 and AA genotype of FCRL3 rs7528684 were correlated with a reduced risk of GD, while the CC genotype of TSHR rs2239610 was associated with higher serum concentrations of FT4 and TRAb. Logistic analysis confirmed the contribution of CTLA‐4 rs231779 to the development of GD. Conclusions These preliminary results demonstrate that the immune‐regulatory gene CTLA‐4 and the thyroid‐specific gene Tg contribute to the risk of Graves’ disease with additive effects, while PTPN22 rs3789604 and FCRL3 rs7528684 polymorphisms are protective against the disease. In addition, the TSHR rs2239610 SNP is related to the severity of Graves’ disease.     

Association of Genetic Polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the Clinical Forms of Dengue in Patients from Veracruz,Mexico

Dengue manifestations range from a mild form, dengue fever (DF), to more severe forms such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The ability of the host to present one of these clinical forms could be related to polymorphisms located in genes of the Toll-like receptors (TLRs) which activate the pro-inflammatory response. Therefore, the genotyping of single nucleotide genetic polymorphisms (SNPs) in TLR3 (rs3775291 and rs6552950), TLR4 (rs2737190, rs10759932, rs4986790, rs4986791, rs11536865, and rs10983755), TLR7 (rs179008 and rs3853839), and TLR8 (rs3764880, rs5741883, rs4830805, and rs1548731) was carried out in non-genetically related DHF patients, DF patients, and general population (GP) subjects. The SNPs were analyzed by real-time PCR by genotyping assays from Applied Biosystems^®. The codominance model showed that dengue patients had a lower probability of presenting the TLR4-rs2737190-G/G genotype (odds ratio (OR) (95% CI) = 0.34 (0.14–0.8), p = 0.038). Dengue patients showed a lower probability of presenting TLR4-rs11536865-G/C genotype (OR (95% CI) = 0.19 (0.05–0.73), p = 0.0092) and had a high probability of presenting the TACG haplotype, but lower probability of presenting the TGCG haplotype in the TLR4 compared to GP individuals (OR (95% CI) = 0.55 (0.35–0.86), p = 0.0084). In conclusion, the TLR4-rs2737190-G/G and TLR4-rs11536865-G/C genotypes and TGCG haplotype were associated with protection from dengue.     

TNFSF4 gene polymorphism rs3861950 but not rs3850641 is associated with the risk of cerebral infarction in a Chinese population

Tumor necrosis factor superfamily member 4 (TNFSF4) plays a key role in the process of atherosclerosis, a common risk factor for both myocardial and cerebral infarctions. Recent studies indicate that the single nucleotide polymorphism (SNP) rs3850641 in TNFSF4 is associated with higher risk of myocardial infarction, but little is known about the association between TNFSF4 variation and cerebral infarction (CI). A case-control study involving 385 CI patients and 385 age-matched, sex-matched non-CI controls was conducted in a Chinese population, only the most common subtype, atherosclerosis CI, was recruited. Two SNPs of TNFSF4, rs3850641 and rs3861950, were genotyped by the TaqMan SNP genotyping method, and verified partly by genomic DNA sequencing. The results revealed a significant allelic association between rs3861950 and CI (Odds ration = 1.733, 95 % confidence interval = 1.333–2.254, P = 0.000). Genotypic association analysis demonstrated that the CC genotype of rs3861950 confers susceptibility to CI (Odds ration = 2.896, 95 % confidence interval = 1.368–6.132), and it was associated with a significantly higher risk of ischemic stroke (Odds ration = 3.520, 95 % confidence interval = 1.546–8.015, P = 0.003) after adjusting for the other confirmed risk factors such as the history of hypertension, diabetes, CAD, smoking and alcohol drinking. While the odds ratio of the T allele to the C allele was 1.733 (95 % confidence interval: 1.333–2.254). However, there was no significant association between rs3850641 and CI (Odds ration = 1.288, 95 % confidence interval = 0.993–1.670, P = 0.056). TNFSF4 gene polymorphism rs3861950, but not rs3850641, is associated with the risk of atherosclerosis CI in a Chinese population.