The association of PTPN22 (rs2476601) and IL2RA (rs11594656) polymorphisms with T1D in Egyptian children

BackgroundType 1 diabetes mellitus (T1D) is a T cell-mediated autoimmune disease characterized by the destruction of pancreatic β cells. PTPN22 and IL2RA polymorphisms have been found to be associated with several autoimmune diseases including T1D.AimsWe aimed to elucidate the role of PTPN22 and IL2RA polymorphisms in predisposition of T1D in Egyptian children.MethodsWe studied 150 children and adolescents with T1D and 165 healthy controls. The PTPN22 (rs2476601) and IL2RA (rs11594656) polymorphisms were genotyped using polymerase chain reaction.ResultsWe found that carriers of the T allele of PTPN22 were significantly more likely to develop T1D (OR = 2.2, 95% CI = 1.2–4, P = 0.01). Also, the carrier of TT genotype and T allele of IL2RA more likely to develop T1D (OR = 2.8, 1.4, respectively, P = 0.03). There was a statistically significant association between T allele of PTPN22 gene and females ⩽10 years old at the onset of diabetes (OR = 4, 95% CI = 1.2–13.4, P = 0.019).ConclusionThis study suggests a possible association between the T allele of PTPN22 gene and TT genotype of IL2RA with T1D in studied Egyptian children, especially, females with early onset diabetes who carried the 1858T allele.     

Association between interleukin‐21 gene polymorphisms (rs12508721) and HBV‐related hepatocellular carcinoma

Interleukin‐21 (IL‐21), as a multifunctional cytokine, plays an important role in many diseases, such as cancer, inflammatory and autoimmune diseases. We aimed to investigate the relationship between polymorphisms of IL‐21 gene and susceptibility of hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) in a Chinese population. Studied subjects were divided into three groups: 100 patients with HBV‐related HCC, 115 patients with chronic HBV infection and 127 healthy controls. Genomic DNA was isolated from peripheral blood, and the polymerase chain reaction–ligase detection reaction (PCR‐LDR) method was used to genotype the SNPs (rs2221903, rs907715 and rs12508721) within IL‐21 gene. Our results showed that IL‐21 polymorphisms were associated with the risk of HCC and chronic HBV infection when compared with healthy controls. The rs2221903A/G AG genotype was associated with a higher risk of chronic HBV infection when compared with healthy controls [AG versus AA + GG, P = 0.036, OR = 1.898, 95%CI = 1.038–3.471]. The rs12508721C/T TT genotype was related with a lower risk of chronic HBV infection and HBV‐related HCC than in healthy controls [TT versus CT + CC, P = 0.026, OR = 0.451, 95%CI = 0.221–0.920; P = 0.049, OR = 0.482, 95%CI = 0.231–1.005]. No significant difference in the genotype and allele distrubutions of rs907715G/A SNP was observed in the HBV‐related HCC group, chronic HBV‐infected group and the healthy control group when compared to each other. Our findings suggest that the rs12508721T/C and rs2221903A/G polymorphisms of IL‐21 gene are associated with the susceptibility of HBV‐related HCC and chronic HBV infection. The genetic variant may in fact cause protection against the HBV‐related HCC. However, the function in these SNPs of IL‐21 gene needs to clarify the mechanisms involved in the pathogenesis of HBV‐related HCC further.     

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.     

Association of PTPN22+1858C/T polymorphism with Type 1 diabetes in the North Indian population

A nonsynonymous SNP +1858C/T (rs2476601) in the protein tyrosine phosphatase, nonreceptor type 22(PTPN22) gene leading to Arg 620 Trp substitution is known to be associated with susceptibility to type 1 diabetes (T1D) and several other autoimmune diseases. We studied this polymorphism in 145 T1D patients and 210 healthy controls from North India. The minor allele +1858T was observed to be significantly increased among patients as compared to healthy controls (2.76% vs 0.5%, P = 0.027, OR = 5.93; 95% CI = 1.4–24.8). The association was also observed at the level of heterozygous C/T genotype (5.5% vs 0.95%, P = 0.026, OR = 6.07; 95% CI = 1.43–25.6). The T allele and C/T genotype were predominantly found among patients who were positive for both glutamic acid decarboxylase 65 (GAD65) and insulin antigen 2 (IA2) autoantibodies and showed significantly increased frequencies (10%, P = 0.034, OR = 11.67; 95% CI = 1.58–84.1 and 20%, P = 0.031, OR = 13.0; 95% CI = 1.66–97.5, respectively) as compared to patients negative for these autoantibodies (0.95% and 1.9%, respectively). The results suggest that the PTPN22+1858T allele is positively associated with T1D in the North Indian 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.     

The level of thymic stromal lymphopoietin and its gene polymorphism are associated with rheumatoid arthritis

ObjectiveTo study the correlation between TSLP gene SNPs and RA in a Han Chinese population.MethodsThe genotypes of TSLP genes rs11466749, rs11466750 and rs10073816 among 197 RA patients and 197 controls were analysed by direct sequencing. ELISA was used to detect the plasma TSLP level. Logistic regression analysis was also conducted to identify risk factors for RA.ResultsThe rs11466749 locus GG genotype (OR = 5.30, 95% CI: 1.76–15.95, P < 0.01), dominant model (OR = 1.68, 95% CI: 1.03–2.73, P = 0.04), recessive model (OR = 5.15, 95% CI: 1.72–15.43, P < 0.01), and G allele (OR = 2.02, 95% CI: 1.33–3.09, P < 0.01) were associated with an increased risk of RA. The rs1073816 locus AA genotype (OR = 4.58, 95% CI: 1.49–14.01, P < 0.01), dominant model (OR = 1.75, 95% CI: 1.09–2.79, P = 0.03), recessive model (OR = 4.27, 95% CI: 1.40–13.00, P = 0.03) and A allele (OR = 1.94, 95% CI: 1.29–2.91, P < 0.01) were associated with an increased risk of RA. The rs1073816 locus GA genotype (OR = 0.29, 95% CI: 0.18–0.45, P < 0.01), dominant model (OR = 0.32, 95% CI: 0.21–0.49, P < 0.01) and A allele (OR = 0.45, 95% CI: 0.32–0.63, P < 0.01) were related to a decreased risk of RA susceptibility. The rs1466749 locus GG genotype, rs11466750 AA genotype, and rs10073816 GG genotype were independent risk factors for RA (P < 0.05). The AUC of plasma TSLP level in the diagnosis of RA was 0.8661 (95% CI: 0.8301–0.9002, P < 0.001). There were statistically significant differences in plasma TSLP levels among subjects with different genotypes at rs11466749, rs11466750, and rs10073816 in the TSLP gene (P < 0.05).ConclusionPlasma TSLP levels are a potential molecular marker of RA. SNPs at rs11466749, rs11466750 and rs10073816 of the TSLP gene are related to the susceptibility of the Han Chinese population to RA.     

IL‐1A rs1800587, IL‐1B rs1143634 and IL‐1R1 rs2234650 polymorphisms in Iranian patients with systemic sclerosis

Systemic Sclerosis (SSc) is a systemic autoimmune disorder, with ambiguous pathogenesis. Genetic and environmental factors were proved to be correlated with SSc aetiology. Single nucleotide polymorphisms (SNPs) in cytokine genes can alter the structure and function of the cytokines and consequently may increase the susceptibility to a specific disease. In this study, we investigated SNPs of the IL‐1 gene cluster in Iranian SSc patients. We obtained blood samples from 170 SSc patients and 213 healthy individuals. Cytokine genotyping results were obtained by polymerase chain reaction with sequence‐specific primers (PCR‐SSP). IL‐1A rs1800587, IL‐1B rs1143634 and IL‐1R1 rs2234650 were evaluated for SNP study. The frequency of the IL‐1B rs1143634 CT genotype was significantly lower in SSc patients compared to the controls (OR = 0.584; 95% CI = 0.385–0.886; P‐value = 0.023), so we propose that CT genotype of this allele might be protective. According to our haplotype analysis, CCC haplotype frequency is higher in the control group compared to SSc patients (OR = 1.575; 95% CI = 1.176–2.111; P‐value = 0.008) and in contrast, CTC haplotype frequency is lower in the control group compared to SSc patients (OR = 0.152; 95% CI = 0.047–0.484; P‐value = 0.002), so they might decrease and increase the susceptibility of having SSc, respectively. In addition, we reported two significant diplotypes frequency differences among SSc patients and healthy individuals. It is highly important that there is not much resemblance between the IL‐1 gene cluster polymorphism in different populations, so we can indicate that SNPs may play critical roles when they are combined with other genetic and environmental factors.     

Analysis of PTPN22, ZFAT and MYO9B polymorphisms in Turner Syndrome and risk of autoimmune disease

Turner syndrome (TS) is one of the most common sexual chromosome abnormalities and is clearly associated with an increased risk of autoimmune diseases, particularly thyroid disease and coeliac disease (CD). Single‐nucleotide polymorphism analyses have been shown to provide correlative evidence that specific genes are associated with autoimmune disease. Our aim was to study the functional polymorphic variants of PTPN22 and ZFAT in relation to thyroid disease and those of MYO9B in relation to CD. A cross‐sectional comparative analysis was performed on Mexican mestizo patients with TS and age‐matched healthy females. Our data showed that PTPN22 C1858T (considered a risk variant) is not associated with TS (X² = 3.50, p = .61, and OR = 0.33 [95% CI = 0.10–1.10]). Also, ZFAT was not associated with TS (X² = 1.2, p = .28, and OR = 1.22 [95% CI = 0.84–1.79]). However, for the first time, rs2305767 MYO9B was revealed to have a strong association with TS (X² = 58.6, p = .0001, and OR = 10.44 [95% C = 5.51–19.80]), supporting a high level of predisposition to CD among TS patients. This report addresses additional data regarding the polymorphic variants associated with autoimmune disease, one of the most common complications in TS.     

Polymorphisms of inflammation‐related genes and colorectal cancer risk: a population‐based case–control study in China

The previous studies found that chronic inflammation related to an increased risk of colorectal cancer (CRC). This study aims to explore the associations of polymorphisms in inflammation‐related genes (IL10, IL10RA, IL6R, TNFRSF1A, TNFRSF1B, LTA and IL4) and their interactions with the risk of colorectal cancer among Chinese population. A population‐based case–control study including 299 cases and 296 controls was conducted from January 2001 to December 2009. Multivariate unconditional logistic regression was used to analyse the association of nine SNPs in inflammation‐related genes with the risk of CRC, colon cancer and rectal cancer, respectively. Generalized multifactor dimensionality reduction (GMDR) was implemented to explore the gene–gene interactions among all SNPs on CRC. A decreased risk of colorectal cancer in subjects with rs1800872 AC genotype of IL10 (OR = 0.643, 95%CI = 0.453, 0.912) or AC/CC genotype (OR = 0.636, 95%CI = 0.457, 0.885) was observed, compared with those with AA genotype. Meanwhile, similar associations were observed between rs1800872 and rectal cancer. Additionally, in rs1061624 of TNFRSF1B gene, AG genotype (OR=0.566; 95% CI= 0.362, 0.885) and AG/GG genotype (OR=0.638; 95% CI=0.420, 0.971) were significantly associated with a decreased risk of rectal cancer, respectively. Our findings indicated that mutants in IL10 and TNFRSF1B genes may change the CRC risk. However, there is no interaction between inflammation‐related genes on CRC risk.     

Association of MIR146A rs2910164 variation with a predisposition to sporadic breast cancer in a Pakistani cohort

Single‐nucleotide polymorphisms (SNPs) in genes coding for microRNAs (miRNAs) play a pivotal role in the progression of breast cancer (BC). We investigated the association of miR‐146a rs2910164 GC polymorphism with the risk of BC in the Pakistani population. The miR‐146a rs2910164 polymorphism was genotyped in 300 BC cases and 300 age‐ and gender‐matched healthy controls using T‐ARMS‐PCR. Genotype and allele frequencies were calculated and the association between genotypes and the risk of BC was calculated by odds ratio (OR) and confidence interval (95%). A significant difference in genotypic frequencies (χ² = 63.10; P = <0.0001) and allelic frequencies (OR = 0.3955 (0.3132–0.4993); P = < 0.0001) was observed between cases and controls. Furthermore, we also found that miR‐146 rs2910164 CC homozygote increased the risk of BC in the dominant (OR = 0.2397 (0.1629–0.3526); P = 0.0001; GG vs. GC + CC) and recessive (OR = 2.803 (1.865–4.213); P = <0.0001; CC vs. GC + GG) inheritance models. In summary, miR‐146a rs2910164 GC is significantly associated with BC in the Pakistani population. To our knowledge, this is the first study that assessed MIR146a rs2910164 G > C SNP in Pakistani population. By analyzing the secondary structure of MIR146A variant, a significant structural modification was noted. Study with a larger sample size is needed to further confirm of these findings.     

Association of ABCG2 polymorphisms with ischemic stroke in a Chinese population

ATP‐binding cassette, superfamily G, member 2 (ABCG₂) has been shown to play an important role in the development of ischemic stroke in European and African American populations. The aim of the present study is to test the hypothesis that there are associations between ABCG₂ polymorphisms and ischemic stroke risk in a Chinese population. We conducted a case–control study including 967 participants with ischemic stroke and 939 stroke‐free controls. The rs2231137C > T and rs2231142G > T were genotyped using a TaqMan real‐time polymerase chain reaction assay. We found the rs2231137C > T and rs2231142G > T in ABCG₂ were significantly associated with ischemic stroke (sex‐, age‐, BMI‐, SBP‐, DBP‐adjusted OR = 1.252; 95% CI, 1.035–1.515; P‐value = 0.021 and OR = 1.526; 95% CI, 1.085–2.146; P‐value = 0.015, respectively). By haplotype analyses, the haplotype T‐G still had a strongly significant association with ischemic stroke (OR = 0.806; 95% CI, 0.692–0.939; P‐value = 0.00568). Our findings identified the rs2231137C > T and rs2231142G > T polymorphisms of the ABCG₂ as risk factors for ischemic stroke in a Chinese population.     

Association of cytotoxic T‐lymphocyte associated protein 4 gene polymorphisms with the risk and prognosis of oesophageal cancer in a high‐incidence region from northern China

The most important anti‐tumour immune response is mediated by T lymphocytes. Cytotoxic T lymphocyte‐associated protein 4 (CTLA4) plays a critical role in the immune surveillance against tumours as an inhibitory immune checkpoint molecule of T‐cell activation. This study was designed to explore the association of CTLA4 polymorphisms with the susceptibility to oesophageal squamous cell carcinoma (ESCC) and prognosis of patients with ESCC in a high‐incidence population from northern China. CTLA4 rs5742909 C/T and rs231775 G/A single nucleotide polymorphisms (SNPs) were genotyped using polymerase chain reaction–ligase detection reaction (PCR‐LDR) method in 577 ESCC patients and 580 controls. Upper gastrointestinal cancer family history increased the risk of ESCC (the sex‐, age‐ and smoking status‐adjusted OR = 1.383, 95%CI = 1.094–1.749). The genotype frequencies of these two SNPs in the patients with ESCC were similar to that in the controls. Survival analyses were conducted in 204 patients with ESCC with five‐year survival information. The mean survival time of ESCC patients with rs231775 SNP A/A genotype in age over 60 years group was 23.2 months, significantly shorter than that of those with G/G genotype (47.3 months). The A/A genotype was associated with increased death risk of patients with ESCC older than 60 years (adjusted HR = 4.544, 95%CI = 1.913–10.790). CTLA4 rs231775 SNP might be used as genetic marker of worse prognosis for patients with ESCC over 60 years in a high‐incidence population from northern China.     

IL‐23R gene polymorphism rs2201841 is associated with psoriatic arthritis

We examined rs2201841 within IL‐23R gene in Serbian patients with psoriasis and healthy controls. G allele frequency was significantly increased in the group of patients with psoriatic arthritis compared with controls (0.481 vs 0.308). Carriage of G allele increases risk to develop psoriatic arthritis (P = 0.009, OR = 3.311, 95% CI 1.29–8.70).     

PTPN22 Polymorphism is Related to Autoimmune Disease Risk in Patients with Turner Syndrome

Individuals with Turner syndrome (TS) clearly have an increased risk for autoimmune diseases. Recently, an allelic variation (C1858T) of the PTPN22 gene was revealed to be associated with the development of autoimmunity. Thus, the aim of this study was to determine the frequency of the PTPN22 C1858T polymorphism in women with Turner syndrome (TS) compared to controls. Case–control study comprises 142 women with TS (cases) and 180 healthy and fertile women without a history of autoimmune disease (controls). Detection of the PTPN22 C1858T polymorphism (rs2476601) was performed by TaqMan real‐time PCR. The chi‐square test was used to compare allele and genotype frequencies between groups and to estimate the Hardy–Weinberg equilibrium. All P‐values were two‐tailed, and 95% confidence intervals (CIs) were calculated. A P‐value <0.05 was considered statistically significant. Genotypes CC, CT and TT of the PTPN22 C1858T polymorphism presented frequencies of, respectively, 67.6%, 28.2% and 4.2% in the TS, and 82.8%, 16.1% and 1.1% in the control group (P = 0.0043). Alleles C and T were present in, respectively, 81.7% and 18.3% of the patients with TS (P = 0.001, OR = 2.22, 95% CI = 1.39‐3.54) and in 90.8% and 9.2%, respectively, of the controls. The data suggest that in Brazilian patients with TS, the PTPN22 C1858T polymorphism may be an important genetic factor predisposing to autoimmune disease risk.     

Interleukin 10 gene promoter polymorphisms (rs1800896, rs1800871 and rs1800872) and haplotypes are associated with the activity of systemic lupus erythematosus and IL10 levels in an Iranian population

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with unknown aetiology. According to the role of interleukin 10 (IL10) in SLE pathogenesis, the genetic alterations in its promoter region could be associated with elevated IL10 levels and exacerbated disease. Here, we investigated the association of genotype and haplotype frequencies of three IL10 gene promoter polymorphisms with susceptibility to SLE, IL10 plasma levels and disease activity of patients in an Iranian population. A total of 116 SLE patients and 131 healthy subjects were enrolled. The PCR‐RFLP technique was used to detect IL10 promoter genotypes at the positions of ?1082 (G/A), ?819 (C/T) and ?592 (C/A) in association with IL10 plasma levels and SLEDAI scores. The GG genotype of ?1082 polymorphism was associated with the increased risk of SLE [OR = 2.65, 95% CI (1.21–5.82), p‐value = 0.046]. The CC genotype in ?819 region was associated with SLE susceptibility [OR = 3.38, 95% CI (1.26–9.07), p‐value = 0.034] and C allele was introduced as risk allele [OR = 1.86, 95% CI (1.15–3.01), p‐value = 0.009] in this region. IL10 plasma levels were overexpressed in CC genotype carriers of ?592 SNP and decreased in AA genotype carriers of ?1082. IL10 was also increased in SLE patients with CGT (?592/?1082/?819) haplotype. The SLEDAI score was higher among CC genotype carriers at the position of ?592 and TT genotype carriers at the region of ?819. SLEDAI was also elevated among patients with CGC (?592/?1082/?819) and CAC (p = 0.011) haplotypes. The present study suggests that the IL10 –819(C/T), ?1082(G/A) and ?592(C/A) polymorphisms and the haplotypes are associated with SLE susceptibility, increased disease activity and elevated IL10 levels. While this is the first time to report such an association in an Iranian population, further studies are needed to confirm these findings.     

TNFSF4 polymorphisms are associated with systemic lupus erythematosus in the Malaysian population

Tumour necrosis factor superfamily 4 (TNFSF4) gene has been reported to be associated with systemic lupus erythematosus (SLE) susceptibility due to its encoding for OX40L protein that can increase autoantibody production and cause imbalance of T‐cell proliferation. The purpose of this study was to investigate the association of TNFSF4 rs2205960, rs1234315, rs8446748 and rs704840 with SLE in the Malaysian population. A total of 476 patients with SLE and 509 healthy controls were recruited. Real‐time polymerase chain reaction (PCR) was applied to genotype the selected single nucleotide polymorphisms (SNPs). Allelic and genotypic frequencies of each SNP were calculated for each ethnic group, and association test was performed using logistic regression. The overall association of each SNP in Malaysian patients with SLE was determined with meta‐analysis. The frequency of minor T allele of TNFSF4 rs2205960 was significant in Chinese and Indian patients with SLE, with P values of 0.05 (OR = 1.27, 95% CI: 1.00–1.61) and 0.004 (OR = 3.16, 95% CI: 1.41–7.05), respectively. Significant association of minor G allele of rs704840 with SLE was also observed in Chinese (P = 0.03, OR = 1.26, 95% CI: 1.02–1.56). However, after Bonferroni correction, only T allele of rs2205960 remained significantly associated with Indian cohort. Overall, minor G allele of rs704840 showed significant association with SLE in the Malaysian population with P values of 0.05 (OR = 1.20, 95% CI: 1.00–1.43). We suggested TNFSF4 rs704840 could be the potential SLE risk factors in the Malaysian population.     

CD28 and PTPN22 are associated with susceptibility to rheumatoid arthritis in Egyptians

ObjectiveLimited data are available on the genetics of rheumatoid arthritis (RA) in Egyptians. Therefore, we investigated whether the confirmed genetic risk factors for RA in Europeans and/or Asians contribute to RA susceptibility in Egyptians.Subjects and methodsA set of seven single-nucleotide polymorphisms (SNPs) in the vicinity of CD28, TNFAIP3, PTPN22, PADI4 and HLA-DRA were tested in a large multi-centric RA cohort in Egypt, consisting of 394 cases and 398 matched controls. Patients were stratified based on the positivity of either anti-citrullinated protein antibodies (ACPAs) or rheumatoid factor (RF).ResultsSignificant association was evident for three SNPs in this cohort: the CD28 (rs1980422) variant showed a strong association in the whole cohort (P = 0.000119) and in seropositive subsets of the disease (P_ACPA+ = 0.004; P_RF+ = 0.0005). Upon stratification, the PTPN22 (rs2476601) and TNFAIP3(rs5029939) variants showed association only with ACPA positive (P_ACPA+ = 0.00573) and negative (P_ACPA− = 0.00999) phenotypes, respectively.ConclusionOur results suggest that CD28(rs1980422) and PTPN22(rs2476601) contribute to RA-susceptibility in Egyptians. Failure to replicate the association of PADI4(rs2240340)/(PADI4_94) in Egyptian RA patients provides further support for the notion that genetic architecture of RA is different in multiple populations of European, Asian, African, and Middle Eastern ancestries. Further investigation using large-scale studies is thus needed to maximize the power of genetic association.     

Type 1 diabetes linked PTPN22 gene polymorphism is associated with the frequency of circulating regulatory T cells

Dysfunction of FOXP3-positive regulatory T cells (Tregs) likely plays a major role in the pathogenesis of multiple autoimmune diseases including type 1 diabetes (T1D). Whether genetic polymorphisms associated with the risk of autoimmune diseases affect Treg frequency or function is currently unclear. Here, we analysed the effect of T1D-associated major HLA class II haplotypes and seven single nucleotide polymorphisms in six non-HLA genes [INS (rs689), PTPN22 (rs2476601), IL2RA (rs12722495 and rs2104286), PTPN2 (rs45450798), CTLA4 (rs3087243), and ERBB3 (rs2292239)] on peripheral blood Treg frequencies. These were determined by flow cytometry in 65 subjects who had progressed to T1D, 86 islet autoantibody-positive at-risk subjects, and 215 islet autoantibody-negative healthy controls. The PTPN22 rs2476601 risk allele A was associated with an increase in total (p = 6 × 10⁻⁶) and naïve (p = 4 × 10⁻⁵) CD4+CD25+CD127lowFOXP3+ Treg frequencies. These findings were validated in a separate cohort comprising ten trios of healthy islet autoantibody-negative children carrying each of the three PTPN22 rs2476601 genotypes AA, AG, and GG (p = 0.005 for total and p = 0.03 for naïve Tregs, respectively). In conclusion, our analysis implicates the autoimmune PTPN22 rs2476601 risk allele A in controlling the frequency of Tregs in human peripheral blood.     

NEDD9 rs760678 polymorphism and the risk of Alzheimer's disease: A meta-analysis

The NEDD9 rs760678 polymorphism has been extensively investigated for association to Alzheimer's disease (AD), however, results of different studies have been inconsistent. The objective of this study is to assess the relationship of NEDD9 rs760678 polymorphism and AD risk by using meta-analysis. Systematic searches of electronic databases Pubmed and Embase, as well as hand searching of the references of identified articles were performed. Statistical analyses were performed using software Revman 4.2 and STATA 11.0. A total of 4436 cases and 4420 controls in 11 case–control studies were included. The results indicated that the homozygote GG had a 13% decreased risk of AD, when compared with the C allele carriers (CC + CG) (OR = 0.87, 95%CI = 0.77–0.99, P = 0.04 for GG vs. CG + CC). In the subgroup analysis by ethnicity, significant decreased risk was associated with homozygote GG or G allele carriers in Caucasians (OR = 0.84, 95%CI = 0.74–0.96, P = 0.008 for GG vs. CG + CC; OR = 0.79, 95%CI = 0.69–0.91, P = 0.001 for GG vs. CC; OR = 0.90, 95%CI = 0.84–0.96, P = 0.002 for G vs. C), but not in Asians. This meta-analysis suggests that the GG genotype of NEDD9 rs760678 polymorphism would be a protective factor for AD in Caucasians but not in Asians. To further evaluate the effect of gene–gene and gene–environmental interactions between NEDD9 rs760678 polymorphism and the risk of AD, more studies with larger number of subjects are required.     

Levels of Interleukin‐(IL)‐12p40 are Markedly Increased in Brucellosis Among Patients with Specific IL‐12B Genotypes

Brucellosis remains a major zoonosis worldwide. Brucella antigens induce the production of T‐helper 1 (Th1) cytokines such as interleukin‐12 (IL‐12) in humans. We aimed to investigate the association of two single nucleotide polymorphisms (SNPs) in the gene encoding the IL‐12p40 cytokine (IL‐12B) with brucellosis and to examine the functionality of these SNPs through measuring serum levels of IL‐12p40. We genotyped IL‐12B gene rs3212227, A>C; rs6887695 G>C polymorphisms in a case‐control study on a total of 281 subjects including 153 patients with active brucellosis and 128 healthy controls, using RFLP and serum IL‐12p40 levels, were assessed by ELISA. The rs3212227 minor allele (C) and homozygote genotype (CC) were more frequent in controls compared with patients with brucellosis (P = 0.006, OR = 0.608, 95%CI = 0.429–0.861 for the C allele; P = 0.024, OR = 0.443, 95% CI: 0.218–0.900 for the CC genotype). Comparison of IL‐12B genotypes and serum levels of the IL‐12p40 revealed that rs3212227 AA genotype, with higher frequency in patients than in controls, was associated with increased levels of the cytokine (P = 0.0001). Furthermore, the distribution of haplotype and genotype combinations in our study suggested that rs3212227C/rs6887695C haplotype or CC/GC or CC/CC genotype combinations may protect controls against Brucella infection by contributing to a functional downregulation of the serum IL‐12p40 production in vivo, as shown by ELISA (P < 0.05). Overall, our study demonstrated that rs3212227 A variant was associated with higher levels of serum IL‐12p40 and could possibly contribute to an inherited predisposition to brucellosis.