PTPN22 polymorphisms,but not R620W,were associated with the genetic susceptibility of systemic lupus erythematosus and rheumatoid arthritis in a Chinese Han population

ObjectivesThe present study aimed to detect a possible association between PTPN22 gene polymorphisms and rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in a Chinese Han population.Methods7 PTPN22 SNPs were genotyped in 358 patients with RA and 713 patients with SLE, as well as 564 RA controls and 672 SLE controls by Restriction Fragment Length Polymorphism (RFLP). Association analyses were conducted on the whole data set. Significant relationships were also examined between clinical features and SNPs for both RA and SLE.ResultsRs2476601 was lack of polymorphism with a ⩽0.1% frequency in both SLE and RA patients and healthy controls in our study. The two SNPs rs1217414 and rs3811021 of PTPN22 shown strong association with both SLE (rs1217414T: p_adj = 6.07e−004, OR = 0.57; rs3811021C: p_adj = 4.68e−005, OR = 0.65) and RA (rs1217414T: p_adj = 2.01e−008, OR = 0.26; rs3811021C: p_adj = 0.028, OR = 0.70). And the rs3765598 revealed a strong risk factor for SLE (p = 9.38e−009, p_adj = 6.57e−008, OR = 1.93), but not for RA (p = 0.48, OR = 1.12). Moreover, protective haplotype ACTTC in RA (p = 7.73e−016, p_adj = 5.51−015, OR[95%CI] = 0.02[0.002–0.10]) and SLE (p = 8.29e−018, p_adj = 5.80e−017, OR[95%CI] = 0.11[0.06–0.21]) were observed. In addition, the distribution of risk haplotypes ACGTC and GCTTT in RA (ACGTC: p = 0.0006, p_adj = 0.004, OR[95%CI] = 1.85[1.29–2.63]; GCTTT: p = 2.62e−005, p_adj = 1.85e−004, OR[95%CI] = 2.40[1.57–3.65]) and SLE (ACGTC: p = 0.0006, p_adj = 0.004, OR[95%CI] = 1.85[1.29–2.63]; ACGTC: p = 7.74e−011, p_adj = 6.81e−010, OR[95%CI] = 2.21[1.12–3.34]; GCTTT: p = 2.40[1.57–3.65], p_adj = 2.26e−006, OR[95%CI] = 2.64[1.79–3.87]) were significant different from that in controls. Furthermore, significant association was observed between the PTPN22 rs3765598 and antinuclear antibodies 1 (ANA1) in SLE.ConclusionsOur data provide strong evidence that the rs1217414 and rs3811021 in PTPN22 gene might be common protective factors contributed to SLE and RA susceptibility in the Chinese Han population. While, the rs3765598 might increase the genetic susceptibility of SLE, but not RA.     

Evaluation of TLR2, TLR4, and TOLLIP polymorphisms for their role in tuberculosis susceptibility

Previous studies indicated that single‐nucleotide polymorphisms (SNPs) of genes coding for toll‐like receptors (TLRs) and toll‐interacting protein (TOLLIP) may be involved in the pathogenesis of pulmonary tuberculosis (PTB). This study was designed to investigate potential associations between the polymorphisms in TLR2, TLR4, and TOLLIP and susceptibility to latent tuberculosis infection (LTBI) or subsequent PTB in a Chinese Han population. A total of 209 PTB and 201 LTBI patients and 204 healthy control subjects (HCS) were enrolled in our study. We performed a logistic regression including sex and age as covariates to test the effect of genotype. Genotyping was conducted using the improved multiplex ligase detection reaction (iMLDR). Eleven markers in TLR2, TLR4, and TOLLIP were assessed. No significant association between polymorphisms of TLR2 and TLR4 with PTB or LTBI was detected. For TOLLIP, rs5743899 (p = 0.005, OR = 1.83, 95% CI: 1.20–2.80) CC genotype were risk factors for PTB progression. Moreover, rs5743867 under addictive (p = 0.005, OR = 1.54, 95% CI: 1.14–2.07) and recessive model (p = 0.004, OR = 1.86, 95% CI: 1.22–2.83) were also risk factors for PTB susceptibility. Our results indicate that polymorphisms in TOLLIP affected the risk of PTB disease.     

Association of Helicobacter pylori infection with Toll‐like receptor‐4 Thr399Ile polymorphism increased the risk of peptic ulcer development in North of Iran

Toll‐like receptor‐4 (TLR4) polymorphisms may influence host immune response against Helicobacter pylori (H. pylori). This study aimed to investigate whether TLR4 polymorphisms are associated with H. pylori susceptibility and risk of peptic ulcer development or not. The TLR4 + 3725 G/C polymorphism was studied using polymerase chain reaction with confronting two‐pair primers (PCR–CTPP). In addition, TLR4 Asp299Gly and Thr399Ile polymorphisms were evaluated by PCR‐restriction fragment length polymorphism (RFLP). There was no significant difference in TLR4 + 3725 G/C and Asp299Gly genotype frequencies between non‐peptic ulcer (NPUD) and peptic ulcer (PUD) individuals in the context of peptic ulcer development and susceptibility to infection with H. pylori. Nevertheless, a significant association with increased risk for PUD development was observed for polymorphism TLR4 Thr399Ile [odds ratio (OR) = 4.2; 95% confidence interval (CI) = 1.35–13.26; p = 0.01]. Correspondingly, TLR4 Thr399Ile polymorphism was associated with H. pylori susceptibility (OR = 0.27; 95% CI = 0.08–0.88; p = 0.04). In addition, TLR4 Thr399Ile polymorphism increased 4.2‐fold, the risk of peptic ulcer development in individuals infected by H. pylori carrying CT + TT genotype. Our results showed that TLR4 Thr399Ile polymorphism along with H. pylori infection may play critical roles in peptic ulcer development in North of Iran.     

Investigation of Cytotoxic T‐lymphocyte antigen 4 Polymorphisms in Gastric Cardia Adenocarcinoma

To assess the potential effects of Cytotoxic T‐lymphocyte antigen 4 (CTLA4) gene polymorphisms on susceptibility to gastric cardia adenocarcinoma (GCA), we genotyped four polymorphisms (rs733618 A>G, rs16840252 C>T, rs231775 G>A and rs3087243 G>A) in CTLA4 and calculated odds ratios (ORs) with the corresponding 95% confidence intervals (95% CIs) for the genotype and allele distributions between GCA cases and controls. The CTLA4 genotypes were determined by the polymerase chain reaction–ligase detection reaction (PCR‐LDR) analysis in 330 GCA patients and 608 unrelated cancer‐free controls. In this case–control study, there was no significant difference in the genotype and allele distributions of four CTLA4 polymorphisms between GCA patients and controls. However, haplotype association analysis indicated that compared with CTLA4 G_rs733618C_rs16840252G_rs231775C_rs3087243, CTLA4 G_rs733618C_rs16840252A_rs231775G_rs3087243 and A_rs733618C_rs16840252G_rs231775A_rs3087243 haplotypes conferred increased risks of GCA (OR = 6.46, 95% CI = 1.33–31.28; P = 0.012; both); however, CTLA4 A_rs733618C_rs16840252A_rs231775G_rs3087243 and A_rs733618T_rs16840252G_rs231775G_rs3087243 haplotypes conferred decreased risks of GCA (P = 0.001 and P = 0.011, respectively). These results highlight that the rare CTLA4 haplotypes may affect the development of GCA in the Chinese population.     

Identification of susceptibility SNPs in CTLA-4 and PTPN22 for scleritis in Han Chinese

The aim of this study was to determine the association between 13 single nucleotide polymorphisms (SNPs) in the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes with scleritis in a Chinese Han population. We recruited 432 scleritis patients and 710 healthy controls. Four tag SNPs of CTLA4 and nine tag SNPs of PTPN22 were selected using Haploview. Genotyping was performed with the Sequenom MassArray® iPLEX GOLD Assay. Genotype and allele frequency differences were analyzed by χ² test and Bonferroni correction. Haplotype analysis was performed to further evaluate the association of these two genes with scleritis. In this study, CTLA4/rs3087243 G allele frequency and GG genotype frequency were significantly increased in scleritis patients compared to healthy controls [corrected P-value (Pc) = 0·02, odds ratio (OR) = 1·475, 95% confidence interval (CI) = 1·175–1·851; Pc = 0·04, OR = 1·546, 95% CI = 1·190–2·008, respectively]. None of the tested SNPs in the PTPN22 gene showed an association with scleritis. Haplotype analysis revealed a lower frequency of a CTLA4 TCAA haplotype (order of SNPs: rs733618, rs5742909, rs231775, rs3087243) (Pc = 4·26 × 10^–3, OR = 0·618, 95% CI = 0·540–0·858) and a higher frequency of a PTPN22 TTATACGCG haplotype (order of SNPs: rs3789604, rs150426536, rs1746853, rs1217403, rs1217406, rs3789609, rs1217414, rs3789612, rs2488457) (Pc = 2·83 × 10^–4, OR = 1·457, 95% CI = 1·210-1·754) in scleritis patients when compared to healthy controls. In conclusion, our findings indicate that CTLA4 and PTPN22 might confer genetic susceptibility to scleritis in a Chinese Han population.     

Association of interleukin 22 gene polymorphisms and serum IL‐22 level with risk of systemic lupus erythematosus in a Chinese population

The aim of this study was to investigate the association between the single‐nucleotide polymorphisms (SNPs) of the interleukin 22 (IL‐22) gene and systemic lupus erythematosus (SLE) in a Chinese population. Three IL‐22 SNPs (rs2227485, rs2227513 and rs2227491) were genotyped using SNaPshot SNP genotyping assays and identified by sequencing in 314 SLE patients and 411 healthy controls. The IL‐22 level of serum was assessed by enzyme‐linked immunosorbent assay (ELISA) kits. Data were analysed by spss version 17.0 software. We found that rs2227513 was associated with an increased risk of SLE [AG versus AA: adjusted odds ratio (aOR) = 2·24, 95% confidence interval (CI) = 1·22–4·12, P = 0·010; G versus· A: adjusted OR = 2·18, 95% CI = 1·20‐3·97, P = 0·011]. Further analysis in patients with SLE showed that the AG genotype and G allele were associated with an increased risk of renal disorder in SLE (G versus A: aOR = 3·09, 95% CI = 1·30–7·33, P = 0·011; AG versus· AA: aOR = 3·25, 95% CI = 1·35–7·85, P = 0·009). In addition, the concentration of IL‐22 was significantly lower in the rs2227513 AG genotype compared with AA genotype (P = 0·028). These results suggest that rs2227513 polymorphism might contribute to SLE susceptibility, probably by decreasing the expression of IL‐22.     

Association of Nod‐like receptor protein‐1 (rs2670660) and Toll‐like receptor‐4 (rs4986790) with non‐segmental vitiligo: A case–control study in South Indian population

Non‐segmental vitiligo (NSV) is an autoimmune skin disease. Genetics plays a predominant part in disease pathogenesis. Nucleotide‐binding and oligomerization domain (NOD)‐like receptors and pyrin‐containing protein (NLRP) and Toll‐like receptors (TLR) are pattern recognition receptors in mediating innate immunity. They participate in presenting pathogens and mediating the immune responses. NLRP and TLRs are involved in mediating immune response in various dermatological diseases. Understanding the influence of genetic polymorphisms of NLRP and TLRs associated with immune homeostasis might help us to understand the complex etiopathogenesis of NSV. Thus, we aimed to study the association of NLRP‐1 (rs2670660) and TLR‐4 (rs4986790) and the synergistic effects on disease spectrum, disease activity of NSV in South Indian population. This research was designed as a case–control genetic study with 264 patients and 264 controls. Genotyping of NLRP‐1 (rs2670660) and TLR‐4 (rs4986790) was performed by Taqman 5’ allele discrimination assay and ARMS‐PCR. Plasma levels of proteins were measured by enzyme‐linked immunosorbent assay (ELISA). A statistically significant difference was observed with the frequency of homozygous GG genotype of NLRP‐1 (rs2670660) (17.8% in cases vs. 5.3% in controls) (p < 0.0001; OR‐3.73; 95% CI‐1.94–7.14). Allele G was significantly frequent in 38% of the cases than in controls with 30% (p = 0.004; OR‐1.46; 95% CI‐1.13–1.89). Plasma NLRP‐1 level was significantly higher in patients compared to controls (p < 0.05). Amongst cases, the plasma NLRP‐1 levels did not show any difference with respect to their genotypes (p > 0.05). In TLR‐4 (rs4986790), no significant difference in the frequency of genotypes and allele between cases and controls (p = 0.80) was observed; nevertheless, plasma TLR‐4 was analogous between cases and controls (p > 0.05). Influence of genotype on plasma TLR‐4 showed no significant difference in TLR‐4 levels between GG and ancestral genotype AA, whilst heterozygous AG genotype showed a significant increase of TLR‐4 compared to AA and GG (p = 0.02) amongst NSV cases. The obtained results suggest that NLRP‐1 (rs2670660), and not TLR‐4 ((rs4986790), is associated with increased risk of NSV in South Indian population.     

Association of TLR4 and TLR5 gene polymorphisms with Graves’ disease in Chinese Cantonese population

Graves’ disease (GD) is postulated to be caused by the combined effects of susceptibility genes and environmental triggers. Toll like receptors (TLRs) play a role in the activation of innate and adaptive immune responses in mammalians. The aim of this study was to evaluate the potential association of TLR4 and TLR5 gene polymorphisms with GD in Chinese Cantonese population. Four single nucleotide polymorphisms (SNPs), rs11536889 and rs7873784 in TLR4, rs2072493 and rs5744174 in TLR5, were evaluated in 332 GD patients and 351 unrelated controls from Chinese Cantonese population. The minor allele C of TLR5 rs5744174 decreased the risk to GD in females (OR_{C vs. T} = 0.63; p = 0.003; p_trend = 0.003). Under a dominant model, rs5744174 conferred a protective effect in all cases (OR_{CC/CT vs. TT} = 0.65; p = 0.009) or female subset (OR_{CC/CT vs. TT} = 0.57; p = 0.002). Under a co-dominant model, rs5744174 also conferred a protective effect in all cases (OR_{TC vs. TT} = 0.64; p = 0.008) and females (OR_{TC vs. TT} = 0.57; p = 0.002). The haplotype A-C of TLR5 (rs2072493–rs5744174) decreased the risk of GD in females (OR = 0.62; p = 0.002). The other three SNPs were not found associated with GD. This study provided evidence that polymorphisms in TLR5 might be associated with decreased susceptibility of GD in females.     

Association of single nucleotide polymorphisms in TPM1 rs11071720, rs3803499, rs12148828, and rs1972041 with the risk of nonsyndromic cleft lip with or without cleft palate in a sample of the Iranian population,a preliminary report

Several lines of evidence support an association between tropomyosin 1 (TPM1) and the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P). The present study aimed to investigate the association between TPM1 polymorphisms and the risk of NSCL/P in an Iranian population. This case‐control was done on 105 NSCL/P patients and 110 unrelated healthy controls. TPM1 rs11071720, rs3803499, rs12148828, and rs1972041 polymorphisms were genotyped by the polymerase chain reaction‐restriction fragment length polymorphism method. The finding showed that rs11071720 polymorphism significantly increased the risk of NSCL/P in homozygous codominant (odds ratio [OR] = 2.54, 95% confidence interval [CI] = 1.14–5.69, p = 0.023, TT vs. CC), recessive (OR = 2.33, 95% CI = 1.06–5.18, p = 0.021, TT vs. CT + CC), and allele (OR = 1.53, 95% CI = 1.02–2.30, p = 0.030, T vs. C). The rs12148828 polymorphism was associated with protection against NSCL/P in codominant (OR = 0.27, 95% CI = 0.15–0.48, p < 0.001, TC vs. TT) and allele (OR = 0.38, 95% CI = 0.22–0.64, p < 0.001, C vs. T). Regarding rs3803499, the findings proposed that this polymorphism significantly increased the risk of NSCL/P in codominant (OR = 3.86, 95% CI = 1.19–12.56, p = 0.025, CC vs. TT) and recessive (OR = 3.74, 95% CI = 1.09–14.15, p = 0.018, CC vs. CT + TT). No significant association was practical between rs1972041 polymorphism and NSCL/P. In conclusion, the findings proposed that TPM1 polymorphisms may contribute to the etiology of NSCL/P in a sample of the Iranian population.     

TLR9 gene polymorphism (rs187084, rs352140): association with acute rejection and estimated glomerular filtration rate in renal transplant recipients

The Toll‐like receptors (TLRs) are related to innate immunity. TLR9, a member of TLRs, is expressed in immune cell–rich tissues and mediates cellular response. We investigated the association between TLR9 polymorphisms and kidney allograft outcomes. To investigate whether TLR9 polymorphisms are associated with acute rejection after renal transplantation, two single nucleotide polymorphisms (SNPs) of TLR9 gene (rs187084 ‐1486; rs352140, G2848A) were selected and genotyped by direct sequencing in 342 renal transplant recipients. SNPStats, SNPAnalyzer, Helixtree and Haploview version 4.2 were used to analyse genetic data. Multiple logistic regression models (codominant, dominant, recessive and log‐additive) were used to evaluate odds ratios (ORs), 95% confidence intervals (CIs) and P values. Both SNPs, TLR9 rs187084 ‐1486 and rs352140 G2848A, of recipients were associated with the risk of acute rejection in renal transplantation. C allele of rs187084 ‐1486 and A allele of rs352140 G2848A were protective genotype for acute rejection (OR 0.6, 95% CI 0.40–0.92; P = 0.018, OR 0.64, 95% CI 0.42–0.98; P = 0.04, respectively). rs187084 ‐1486 CT and rs352140 G2848A GA genotype were associated with a lower eGFR after a year of renal transplantation. TLR9 polymorphisms, rs187084 and rs352140, of recipients were associated with the risk of acute rejection in renal transplantation. The patients with rs187084 ‐1486 CT and rs352140 G2848A GA genotype showed a lower eGFR after a year of renal transplantation.     

Perinatal risk factors for sensitization, atopic dermatitis and wheezing during the first year of life (PIPO study)

Objective To evaluate the influence of perinatal environmental factors on early sensitization, atopic dermatitis and wheezing during the first year. Methods Information on pregnancy‐related factors, parental atopic history, environmental factors and the clinical course of the infant until age one was gathered by questionnaires, as part of a prospective birth cohort study (Prospective study on the Influence of Perinatal factors on the Occurrence of asthma and allergies [PIPO‐study]). Quantification of total and specific IgE was performed in 810 children and their parents. Results Early sensitization was found in 107/810 (13%) of the infants. Multiple regression analysis showed that specific IgE in fathers was a risk factor for early sensitization in their daughters (adjusted odds ratios (OR_adj) 2.21 (95% confidence interval (CI) 1.10–4.49); P=0.03), whereas in boys, day care attendance was shown to be protective for early sensitization (OR_adj 0.38 (95% CI 0.20–0.71); P=0.001). Atopic dermatitis occurred in 195/792 infants (25%). Specific IgE in the mother (OR_adj 1.52 (95% CI 1.06–2.19); P=0.02) and in the infant (OR_adj 4.20 (95% CI 2.63–6.68); P<0.001) were both risk factors for the occurence of atopic dermatitis, whereas postnatal exposure to cats was negatively associated with atopic dermatitis (OR_adj 0.68 (0.47–0.97); P=0.03). Postnatal exposure to cigarette smoke (OR_adj 3.31 (95% CI 1.79–6.09); P<0.001) and day care attendance (OR_adj 1.96 (95% CI 1.18–3.23); P=0.009) were significantly associated with early wheezing, which occurred in 25% (197/795) of the infants. Conclusion The effect of paternal sensitization and day care attendance on sensitization is gender dependent. Maternal sensitization predisposes for atopic dermatitis, whereas postnatal exposure to cats had a protective effect.     

Association analysis of Toll-like receptor 4 polymorphisms with autoimmune pancreatitis

Autoimmune pancreatitis (AIP) is characterized by lymphoplasmocytic inflammation, high serum IgG4 concentrations, and a favorable response to corticosteroid treatment. Although long-term follow-up studies have shown that a relapse rate of 30–40% can occur in AIP after remission with corticosteroids, there are few genetic characteristic predictors of relapse in AIP patients. Toll-like receptor (TLR) is an important mediator in both innate and adaptive immunity. Polymorphisms in TLR4 gene have been linked with several autoimmune and allergic diseases. We therefore investigated the genetic association between TLR4 polymorphisms and AIP susceptibility and relapse in a Japanese population. Eight SNPs in TLR4 (rs10759930, rs1927914, rs1927911, rs12377632, rs2149356, rs11536889, rs7037117, and rs7045953) were genotyped in 59 patients with AIP and 126 healthy controls using a TaqMan assay. Analysis of allelic frequencies revealed no statistical association with either susceptibility or relapse of AIP. These data indicate that TLR4 polymorphisms do not play an important role in the development of AIP.     

The association of CTLA‐4 A49G polymorphism with colorectal cancer risk in a Chinese Han population

Cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) is expressed in T cells and plays an important role in the regulation of T cell. CTLA‐4 has long been considered to be associated with various kinds of diseases. With the attempt to examine the association between CTLA‐4 A49G polymorphism and colorectal cancer risk in a Chinese Han population, we employed TaqMan assay to genotype the CTLA‐4 A49G polymorphism in 311 colorectal cancer cases and 389 cancer‐free controls. We found evidence of the association between CTLA‐4 A49G polymorphism and colorectal cancer risk (GG vs. AA: OR = 2.01, 95% CI = 1.29–3.07, P = 0.002; GA vs. AA: OR = 2.32, 95% CI = 1.53–3.57, P = 0.001; GA + GG vs. AA: OR = 2.16, 95% CI = 1.46–3.21, P = 0.001). Next, we performed a meta‐analysis to comprehensively examine the association between CTLA‐4 A49G polymorphism and colorectal cancer risk. We found a significant association between CTLA‐4 A49G polymorphism and colorectal cancer risk among Asians, which is consistent with our result. However, we found no evidence for the association between CTLA‐4 A49G polymorphism and colorectal cancer risk among Caucasians. In conclusion, we demonstrated that the CTLA‐4 A49G polymorphism increased the susceptibility of colorectal cancer in Asian population.     

Genetic polymorphisms in pattern recognition receptors and risk of periodontitis: Evidence based on 12,793 subjects

Pattern recognition receptors (PRRs) constitute a pivotal arm of innate immunity. Many studies investigated the association between PRRs polymorphisms and periodontitis risk, which showed inconclusive results. The aim of the meta-analysis was to evaluate the precise association between five widely-evaluated polymorphisms (CD14 −260C/T (rs2569190), Toll-like receptor (TLR) 2 2408G/A (rs5743708), TLR4 896A/G (rs4986790), TLR4 1196C/T (rs4986791), mannose-binding lectin (MBL) codon 54 (rs1800450)) within the PRRs and susceptibility to either chronic (CP) or aggressive periodontitis (AgP). Overall, no significant association was found for the PRRs polymorphisms with either CP or AgP. In the subgroup analyses, TLR4 896G and 1196T alleles yielded a 32% (OR = 1.32, 95% CI: 1.04–1.68) and a 37% increased CP risk (OR = 1.37, 95% CI: 1.05–1.80) in Caucasians, respectively. Further stratified analyses revealed links between CD14, MBL2 polymorphisms and the severity of CP. This meta-analysis suggested that the periodontitis susceptibility was partly controlled by PRRs polymorphisms involved in the innate immunity.     

Association of CD33 rs3865444:C˃A polymorphism with a reduced risk of late‐onset Alzheimer's disease in Slovaks is limited to subjects carrying the APOE ε4 allele

CD33 rs3865444:C>A single nucleotide polymorphism (SNP) has been previously associated with the risk of late‐onset Alzheimer's disease (LOAD); however, the results have been inconsistent across different populations. CD33 is a transmembrane receptor that plays an important role in AD pathogenesis by inhibiting amyloid β42 uptake by microglial cells. In this study, we aimed to validate the association between rs3865444 and LOAD risk in the Slovak population and to evaluate whether it was affected by the carrier status of the major LOAD risk allele apolipoprotein (APOE) ε4. CD33 rs3865444 and APOE variants were genotyped in 206 LOAD patients and 487 control subjects using the polymerase chain reaction–restriction fragment length polymorphism method and direct sequencing, respectively. Logistic regression analysis revealed a significant association of rs3865444 A allele with a reduced LOAD risk that was only present in APOE ε4 allele carriers (AA + CA versus CC: p = .0085; OR = 0.45; 95% CI = 0.25?0.82). On the other hand, no such association was found in subjects without the APOE ε4 (p = .75; OR = 0.93; 95% CI = 0.61?1.42). Moreover, regression analysis detected a significant interaction between CD33 rs3865444 A and APOE ε4 alleles (p = .021 for APOE ε4 allele dosage and p = .051 for APOE ε4 carriage status), with synergy factor (SF) value of 0.49 indicating an antagonistic effect between the two alleles in LOAD risk. In conclusion, our results suggest that CD33 rs3865444:C?A substitution may reduce the risk of LOAD in Slovaks by antagonizing the effect conferred by the major susceptibility allele APOE ε4.     

A PEAR1 polymorphism (rs12041331) is associated with risk of coronary artery aneurysm in Kawasaki disease

Kawasaki disease (KD) is an acute systemic vasculitis that is most seriously complicated by coronary artery aneurysm (CAA). The polymorphisms of platelet endothelial aggregation receptor 1 (PEAR1), notably rs12041331 and rs12566888, were found to be closely related to cardiac disease. However, little is known regarding the connection between PEAR1 and KD. In this study, we genotyped PEAR1 rs12566888 and rs12041331 in 637 healthy infants and 694 KD patients (74 with CAA). Subsequently, odds ratio (OR) and 95% confidence interval (CI) were calculated to assess the strength of their relationships. No significant differences in the frequency of rs12566888 or rs12041331 in PEAR1 were observed between KD and healthy controls. However, regardless of the statistical combination of rs12566888 genotype, the rs12041331 recessive inheritance model was associated with an increased risk of CAA after Bonferroni correction (for rs12041331, AA vs. GG/GA: adjusted OR = 2.37, 95% CI = 1.41–4.01, P = 0.009; combination of two recessive genotypes vs. combination of 0–1 recessive genotypes: adjusted OR = 2.39, 95% CI = 1.42–4.04, P = 0.009). This study suggests for the first time that PEAR1 polymorphisms did not indicate susceptibility for KD occurrence but the rs12041331 polymorphism was associated with increased risk of CAA formation in KD, and the functions of the gene warrant further research.     

Telomere length,telomere‐related genes,and breast cancer risk: The breast cancer health disparities study

Telomeres are involved in maintaining genomic stability. Previous studies have linked both telomere length (TL) and telomere‐related genes with cancer. We evaluated associations between telomere‐related genes, TL, and breast cancer risk in an admixed population of US non‐Hispanic white (1,481 cases, 1,586 controls) and U.S. Hispanic and Mexican women (2,111 cases, 2,597 controls) from the Breast Cancer Health Disparities Study. TL was assessed in 1,500 women based on their genetic ancestry. TL‐related genes assessed were MEN1, MRE11A, RECQL5, TEP1, TERC, TERF2, TERT, TNKS, and TNKS2. Longer TL was associated with increased breast cancer risk [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38, 2.55], with the highest risk (OR 3.11, 95% CI 1.74, 5.67 p interaction 0.02) among women with high Indigenous American ancestry. Several TL‐related single nucleotide polymorphisms had modest association with breast cancer risk overall, including TEP1 rs93886 (OR 0.82, 95% CI 0.70,0.95); TERF2 rs3785074 (OR 1.13, 95% CI 1.03,1.24); TERT rs4246742 (OR 0.85, 95% CI 0.77,0.93); TERT rs10069690 (OR 1.13, 95% CI 1.03,1.24); TERT rs2242652 (OR 1.51, 95% CI 1.11,2.04); and TNKS rs6990300 (OR 0.89, 95% CI 0.81,0.97). Several differences in association were detected by hormone receptor status of tumors. Most notable were associations with TERT rs2736118 (OR_adj 6.18, 95% CI 2.90, 13.19) with estrogen receptor negative/progesterone receptor positive (ER?/PR+) tumors and TERT rs2735940 (OR_adj 0.73, 95% CI 0.59, 0.91) with ER?/PR? tumors. These data provide support for an association between TL and TL‐related genes and risk of breast cancer. The association may be modified by hormone receptor status and genetic ancestry. © 2013 Wiley Periodicals, Inc.     

Association between IFNL4 rs368234815 polymorphism and sustained virological response in chronic hepatitis C patients undergoing PEGylated interferon/ribavirin therapy: A meta-analysis

Background and aimsMany studies have been published on the association between IFNL4 rs368234815 single-nucleotide polymorphism (SNP) and sustained virological response (SVR) in chronic hepatitis C (CHC) patients undergoing treatment with PEGylated interferon (PEG-IFN) plus ribavirin (RBV). Because of the variable and sometimes inconsistent results, we performed a meta-analysis to estimate the association between these factors.MethodsWe conducted a search of the literature published prior to July 1, 2014. The pooled results were analyzed as the odds ratios (ORs) and corresponding 95% confidence intervals (CIs) using random-effect model.ResultsThe pooled results revealed that the rs368234815 TT/TT genotype was significantly correlated with SVR in HCV-1/4-infected Caucasian patients (OR = 4.65, 95% CI = 3.36–6.42, P < 0.00001) but not in HCV-2/3-infected Caucasian patients (OR = 1.44, 95% CI: 0.89–2.33, P = 0.13). Conversely, the rs368234815 ΔG/ΔG genotype was significantly linked to treatment failure in Caucasian patients (OR = 0.49, 95% CI: 0.38–0.64, P < 0.00001), regardless of the HCV genotype.ConclusionThe results of the meta-analysis suggest that IFNL4 rs368234815 polymorphism may be a predictor of SVR in Caucasian HCV-1/4-infected patients.     

TNFRSF1A polymorphisms and their role in multiple sclerosis susceptibility and severity in the Slovak population

Tumour necrosis factor (TNF)‐mediated signalling plays a key role in inflammatory and neurodegenerative processes leading to the development of multiple sclerosis (MS). Recent studies have highlighted the role of tumour necrosis factor receptor superfamily member 1A (TNFRSF1A) gene encoding the type 1 TNF receptor in the genetic predisposition to MS. This study aimed to validate the association of TNFRSF1A rs1800693 and rs4149584 polymorphisms with susceptibility to MS in the Slovak population and analyse their influence on age at disease onset, severity, and disability progression. Polymerase chain reaction–restriction fragment length polymorphism method was used to genotype both TNFRSF1A polymorphisms in 541 MS patients and 724 healthy controls. Logistic regression analysis revealed a significantly increased risk of developing MS for the carriers of rs1800693 C allele (TC + CC vs. TT: pcorr = 0.005; OR = 1.61; 95% CI = 1.23–2.12), irrespective of sex and carriage of the major MS risk allele HLA‐DRB1*15:01. On the other hand, no association could be found between rs4149584 and MS risk (GA + AA vs. GG: pcorr = 1.00; OR = 1.25; 95% CI = 0.71–2.21). Moreover, neither polymorphism was significantly associated with age at disease onset, MS Severity Score (MSSS) or MS Progression Index (PI) in any of the inheritance models. In conclusion, our results provide support for a sex‐ and HLA‐DRB1*15:01‐independent association of TNFRSF1A rs1800693 SNP with MS susceptibility, but not with age at disease onset, severity or rate of disability accumulation.     

Toll-like receptor 1 gene polymorphisms in childhood IgA nephropathy: a case-control study in the Korean population

Toll‐like receptors (TLRs) are innate immune mediators that stimulate nuclear factor kappa B and the inflammatory cytokines. TLR1 is expressed in renal tubular epithelial cells when the kidney is injured, but the role of TLR1 gene in glomerulonephritis has not been clearly elucidated. We aimed to investigate the association of TLR1 polymorphisms with immunoglobulin A nephropathy (IgAN) in children. One hundred and ninety pediatric patients with biopsy‐proven IgAN and 283 healthy control subjects were enrolled. Two single nucleotide polymorphisms of TLR1 gene [rs4833095 (missense, Asn248Ser) and rs5743557 (promoter, ?414C/T)] were selected and genotyped by direct sequencing. For rs4833095, the C/T genotype in the codominant model (vs. the T/T genotype) [odds ratio (OR) = 2.11, 95% confidence interval (CI): 1.21–3.69, P = 0.009] and the genotype containing C allele (C/T and C/C) in the dominant model (vs. the T/T genotype) (OR = 1.97, 95% CI: 1.16–3.34, P = 0.012) were associated with an increased risk of IgAN. For rs5743557, the T/T genotype in the codominant model (vs. the C/C genotype) (OR = 1.74, 95% CI: 1.02–2.96, P = 0.041) appeared to be associated with IgAN risk. In haplotype analysis, the CT haplotype revealed an association with IgAN (codominant model, OR = 1.38, 95% CI: 1.06–1.80, P = 0.017; dominant model, OR = 1.76, 95% CI: 1.16–2.67, P = 0.008). After Bonferroni correction, the association of the genotypes of rs4833095 and the CT haplotype with IgAN risk remained significant. These findings suggest that TLR1 gene polymorphisms may affect IgAN susceptibility in Korean children.