HLA-E gene polymorphism associates with ankylosing spondylitis in Sardinia

Introduction  

Ankylosing spondylitis (AS) is a severe, chronic inflammatory disease strongly associated with HLA-B27. The presence of additional HLA risk factors has been suggested by several studies. The aim of the current study is to assess the occurrence of an additional HLA susceptibility locus in the region between HLA-E and HLA-C in the Sardinian population.     

Determination of IL-23 receptor gene polymorphism in Iranian patients with ankylosing spondylitis

Introduction

The result of recent genome-wide association studies revealed that, in addition to HLA-B27, a few non-HLA genes are associated with susceptibility to ankylosing spondylitis (AS) in Caucasian populations. According to these studies, IL-23R is one of the genes that is associated with AS. In this study, we evaluated five important single nucleotide polymorphisms (SNPs) of the IL-23R gene which confers susceptibility to AS, and its effects on the severity of the disease in HLA-B27 positive and negative patients and several subtypes of HLA-B27.

Materials and methods

The study population consisted of 294 AS patients and 352 age-, sex-, and ethnicity-matched healthy controls. All patients were examined by rheumatologists, and met modified,NewYork criteria for the disease. Five SNPs (rs1004819, rs11209032, rs1495965, rs11465804, and rs1004819) of the IL-23R gene were genotyped using the Real-Time PCR TaqMan genotyping method.

Results

We found that only rs1004819 has a significant association with AS, and that the remaining four SNP alleles are not associated with AS. Also, there was no association between these five polymorphisms and BASDAI, BASFI, and BASMI indices. Two haplotypes, ACGAT and ACGAG, were found to be associated with the heritability of AS. In addition, two significant, protective diplotypes (D8, \(\frac{{GCGAG}}{{GTGGG}}\); and D9, \(\frac{{ACGAG}}{{GCGAG}}\)) were discovered.

Conclusion

This study supported our previous findings regarding the differences between the genetic patterns of AS in Iranian patients compared with those in other parts of the world.

     

Association of IL1R polymorphism with HLA-B27 positive in Iranian patients with ankylosing spondylitis

Ankylosing spondylitis (AS) is one of the most common causes of inflammatory arthritis, with an estimated prevalence of 0.1-0.9%. Genetic factors have been strongly implicated in its aetiology, and heritability as assessed by twin studies has been estimated to be >90%. HLA- B27 is almost essential for inheritance of AS; it is not merely sufficient for explaining the pattern of familial recurrence of the disease. This study's purpose is to investigate the association of ankylosing spondylitis with single-nucleotide polymorphisms (SNPs) in the IL-1 family: IL-1a (-889C/T) rs1800587, IL-1b (-511C/T) rs16944, IL-1b (+3962C/T) rs1143634, IL-1R (Pst-1 1970C/T) rs2234650 and IL-1RA (Mspa-1 11100C/T) rs315952. 99 unrelated Iranian AS patients and 217 healthy control subjects were selected. Cytokine typing was performed by the polymerase chain reaction with sequence-specific primers assay. The allele and genotype frequencies of the polymorphisms were determined: The IL1α rs1800587, IL1β rs16944 and IL1β rs1143634 were not significantly associated with AS. Genotype frequencies at IL1R rs2234650 differed between cases and controls (χ(2)=8.85; p=0.01); the IL1R rs2234650 C/T and T/T genotypes were less common in AS patients than controls. The IL1R rs2234650 C/T genotype was inversely associated with AS comparing with the IL1R rs2234650 C/C genotype (OR=0.48; p=0.005). IL1R rs2234650 C/T genotype was less common in patients than controls (OR=0.37; p=0.02).Furthermore IL1R rs2234650 T allele was strongly associated with HLA-B2702 patients rather than HLA-B2705 but was not associated with HLA-B27 negative patients (OR=0.33; p=0.01). Polymorphisms of IL1α rs1800587, IL1β rs16944 and IL1β rs1143634 were not significantly associated with ankylosing spondylitis but inversely in this study IL1R rs2234650 was significantly associated and carriage of T allele in IL1R rs2234650 seems to be protective, while carriage of C allele result in two fold higher risk of developing AS.     

Lack of association between the G+2044A polymorphism of interleukin-13 gene and chronic obstructive pulmonary disease: a meta-analysis

Numerous studies have investigated association of interleukin-13 (IL-13) G+2044A polymorphism with COPD susceptibility; however, the results were inconsistent and inconclusive. To evaluate the association between the IL-13 G+2044A polymorphism and susceptibility to COPD, a meta-analysis of published case–control studies was performed. Based on PubMed and Chinese database, this research selected studies that examined the association of the IL-13 G+2044A polymorphism with COPD. A genetic model-free approach was used to assess whether the combined data showed this association. Then a subgroup analysis was also performed, with stratifications for race, study design, and sample size. Six studies (total 1,213 COPD patients and 801 control subjects) for the IL-13 G+2044A polymorphism with COPD were included in the meta-analysis (G- vs A-allele: OR 1.12, 95 % CI 0.96–1.32, P = 0.15; genotypes GG+GA vs genotype AA: OR 0.99, 95 % CI 0.49–2.00, P = 0.98; genotype GG vs genotypes GA+AA: OR 1.18, 95 % CI 0.97–1.44, P = 0.09; genotype GA vs genotypes GG+AA: OR 0.85, 95 % CI 0.70–1.04, P = 0.11). This meta-analysis demonstrates that the IL-13 G+2044A polymorphism does not confer susceptibility to COPD. More detailed data about individual and environment, larger sample sizes with unbiased genotyping methods and matched controls in different populations are required.     

Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spondylitis in the Korean population

The PD-1 (programmed death 1) molecule is a negative regulator of T cells. PDCD1 (programmed cell death 1) has been reported to have a genetic association in systemic lupus erythematosus and rheumatoid arthritis in Caucasians. However, there are no reports on the association between this gene and ankylosing spondylitis (AS). The present study investigated the association of the PD-1 polymorphisms and the haplotypes with AS in a Korean population sample. In a case-control association study, two single-nucleotide polymorphisms, PD-1.5 C/T and PD-1.9 T/C, were genotyped in 95 AS patients and 130 healthy controls. The T allele of the PD-1.9 polymorphism was more frequent in the Korean male population with AS than in the Korean male controls (21.0% versus 6.9%, odds ratio 1.89, 95% confidence interval 1.483 to 2.408). The frequency of the CT haplotype (PD-1.5 C/T and PD-1.9 T/C) was higher in the AS patients (19%) than the controls (5.4%) (odds ratio 1.83, 95% confidence interval 1.559 to 2.521). The PD-1 polymorphism was demonstrated in Korean AS patients. The results suggest a genetic association between the PD-1 polymorphism and susceptibility to AS.     

PTPN22 1858C>T gene polymorphism in patients with SLE: association with serological and clinical results

To assess the association between PTPN22 1858C>T gene polymorphism and susceptibility to, and clinical presentation of, systemic lupus erythematosus (SLE). Our study included 135 SLE patients (120 women and 15 men; mean age 45.1 years; mean course of disease from 0.5 to 31 years) and 201 healthy subjects. The PTPN22 1858C>T gene polymorphism was genotyped by polymerase chain reaction restriction fragment length polymorphism. A significantly higher incidence of genotype CT in patients with SLE (36.3 %) was found, compared with the control group (24.9 %). The frequencies of C1858 and T1858 alleles were 78.1 and 21.9 % in SLE patients and 86.1 and 13.9 % in controls, respectively. Significantly higher SLE susceptibility was observed in patients carrying at least one T allele (p = 0.009; OR 1.86; 95 % CI 0.14–3.05). Significant association of the PTPN22 T1858 allele (CT + TT vs.CC) and secondary antiphospholipid syndrome was observed (p = 0.049). In SLE patients carrying the T1858 allele, higher levels of antiphospholipid antibodies (anticardiolipin antibodies and/or lupus anticoagulant) were found (p = 0.030; OR 2.17; 95 % CI 1.07–4.44).     

强直性脊柱炎患者咽部菌群变化

目的 探讨强直性脊柱炎患者的咽部菌群变化。方法 筛选入组7例强直性脊柱炎患者和7例健康者咽拭子样本,提取咽部DNA,扩增16S rRNA基因,在Illumina平台测序,对测序结果进行生物信息学分析。结果 从ACE指数、Chao1指数、Shannon指数和Simpson指数综合来看强直性脊柱炎患者的咽部菌群Alpha多样性差异不大。Beta多样性分析显示两组研究对象咽部菌群样本可被区分。强直性脊柱炎患者咽部菌群组成和含量发生显著改变,主要变化包括：拟杆菌门（Bacteroidetes）和放线菌门（Actinobacteria）显著降低。拟杆菌门中普雷沃杆菌属（Prevotella）相关的纲目科属水平都显著降低。放线菌门变化落实到属水平,放线菌属（Actinomyces）显著降低,丙酸杆菌属（Propionibacterium）和棒状杆菌属（Corynebacterium）显著增高。厚壁菌门（Firmicutes）中,芽胞杆菌纲（Bacilli）所属的与链球菌属（Streptococcus）相关的纲目科属水平显著增加,而梭状芽胞杆菌纲（Clostridia）包含的韦荣球菌属（Veillonella）、消化球菌属（Peptococcus）显著下降。此外,变形菌门中出现弧菌属（Vibrio）的增加和弯曲菌属（Campylobacter）的降低等变化。结论 强直性脊柱炎患者（本次研究样本）的咽部菌群出现紊乱,以普雷沃杆菌属、放线菌属、韦荣球菌属、消化球菌属和弯曲菌属等显著降低,丙酸杆菌属、棒状杆菌属、链球菌属和弧菌属等显著增加为主要特征。     

Lack of association between methylenetetrahydrofolate reductase gene A1298C polymorphism and breast cancer susceptibility

Published data on the association between methylenetetrahydrofolate reductase gene (MTHFR) A1298C polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline, PubMed, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between the MTHFR A1298C polymorphism and breast cancer risk. The pooled ORs were performed for co-dominant model (AC vs. AA, CC vs. AA), dominant model (CC+AC vs. AA), and recessive model (CC vs. AC+AA), respectively. A total of 26 studies including 12,244 cases and 15,873 controls were involved in this meta-analysis. Overall, no significant associations were found between MTHFR A1298C polymorphism and breast cancer risk when all studies pooled into the meta-analysis (AC vs. AA: OR=0.99, 95% CI 0.94-1.05; CC vs. AA: OR 0.99, 95% CI 0.90-1.09; dominant model: OR=0.99, 95% CI 0.95-1.04; and recessive model: OR=0.98, 95% CI 0.90-1.08). In the subgroup analysis by ethnicity or study design, still no significant associations were found for all comparison models. In conclusion, this meta-analysis suggests that the MTHFR A1298C polymorphism may be not associated with breast cancer development. However, large sample and representative population-based studies with homogeneous breast cancer patients and well matched controls are warranted to confirm this finding.     

Analysis of CTLA4 gene 49A/G polymorphism association with development of allergic rhinitis

CTLA4 gene 49A/G polymorphism was analyzed in 44 patients with allergic rhinitis and 70 nominally healthy donors of the Uzbek population. The unfavorable allele rate of this polymorphism in general studied groups and control groups did not differ significantly; it was 73.3 and 72.9% respectively. A comparative analysis of the distribution of CTLA4 gene 49A/G polymorphism in groups of patients with allergic rhinitis, depending on the clinical course and patient’s gender, with the control groups did not reveal statistically significant differences. However, in patients with year-round forms of allergic rhinitis, the rate of the functionally unfavorable allele 49A/G of CTLA4 gene was almost 1.29 times higher than the same rate in the group with the seasonal form and the slightly higher than the rate in the control group.     

Psychological correlates of self-reported functional limitation in patients with ankylosing spondylitis

Introduction  

Functional status is an integral component of health-related quality of life in patients with ankylosing spondylitis (AS). The purpose of this study was to investigate the role of psychological variables in self-reported functional limitation in patients with AS, while controlling for demographic and medical variables.     

Lack of association between the Val158Met catechol-O-methyltransferase gene polymorphism and methamphetamine dependence

OBJECTIVES: About 25,000 serious methamphetamine abusers live in the Czech Republic among the total population of 10 million. Dependence on methamphetamine is markedly related to the brain neurotransmitter dopamine, metabolised by catechol-O-methyltransferase enzyme. The main aim of the study was to ascertain whether the Val158Met catechol-O-methyltransferase gene polymorphism is associated with methamphetamine dependence in this Central European country. Methods: One hundred and twenty-three subjects dependent on methamphetamine (women N=44), parents of sixty-seven dependent individuals, and four hundred healthy controls (women N=250) were involved into the study. We performed a population-based as well as family-based genetic association studies. Results: We did not find any significant association between the Val158Met catechol-O-methyltransferase gene polymorphism and methamphetamine dependence using the population-based or family-based design (p=0.41-0.66; Chi-Square Test or UNPHASED program, Version 3.1.4, respectively). We found a trend toward a statistically significant difference between the Val allele carriers and Met/Met homozygotes in the frequence of psychotic symptoms induced by methamphetamine (more frequent in Val carriers; p=0.062; Chi-Square Test). Conclusion: Further research involving haplotype analysis and other dopamine-related genetic polymorphisms in large populations is needed. More attention should also be paid to possible role of the Val158Met catechol-O-methyl-transferase gene polymorphism in individual clinical subtypes of dependence on methamphetamine involving e.g. psychotic features or violence.     

闽南地区HLA-B27基因亚型与强直性脊柱炎相关性研究

目的对闽南地区人群中HLA-B27阳性标本进行回顾性调研及分型检测,探讨闽南地区HLAB27亚型分布情况,分析HLA-B27亚型与强直性脊柱炎(AS)的相关性。方法采用PCR-SBT(测序法)基因分型技术,对流式细胞术(FCM)检测为阳性的186例标本进行HLA-B*27基因分型。结果 186例HLA-B27阳性(FCM法)标本中,再用PCR-SBT法检测,HLA-B*27基因型均为阳性;而基因亚型分布,174例为B*27:04亚型,占93.5%,有8例B*27:05亚型,占4.3%,B*27:15亚型2例,占1.1%,另外B*27:06和B*27:07各1例,均占0.5%。186例中有103例确诊为AS患者,其中98例为B*27:04亚型,占95.1%,3例为B*27:05亚型,占2.9%,B*27:07和B*27:15亚型各1例,均占1.0%。结论闽南地区HLA-B27阳性的强直病患者以B*27:04为主,其次为B*27:05。AS患者与其他B27基因携带者,在亚型分布上没有明显的差异。     

Lack of association between an ecNOS gene polymorphism and diabetic nephropathy in type 2 diabetic patients with proliferative diabetic retinopathy.

The development of diabetic nephropathy shows remarkable variation among individuals. Therefore, not only hyperglycemia but also genetic factors may contribute to the development of diabetic nephropathy. The aim of the present study was to examine the contribution of the 27-bp repeat polymorphism in intron 4 of the endothelial constitutive nitric oxide synthase gene (ecNOS4) to the development of diabetic nephropathy. For this purpose, we analyzed this polymorphism in 167 Japanese type 2 diabetic patients with proliferative diabetic retinopathy consisting of 102 patients with diabetic nephropathy (with macroalbuminuria) and 65 patients without diabetic nephropathy (with normoalbuminuria). The genotype and allele frequencies were not significantly different between patients with diabetic nephropathy and those without diabetic nephropathy (ecNOS4 "b/b" 79.4% vs. 84.6%, ecNOS4 "b/a" 20.6% vs. 15.4%, "b" allele 89.7% vs. 92.3%, "a" allele 10.3% vs. 7.7%). We conclude that the ecNOS4 polymorphism does not contribute to the development of diabetic nephropathy.     

Isolation of proteoglycan-specific T lymphocytes from patients with ankylosing spondylitis

Three T-cell lines and clones of the OKT4 phenotype have been isolated from the peripheral blood of three patients with ankylosing spondylitis. Antigen specificities of T cells were determined with purified protein derivative-(PPD) and cartilage-derived antigens, namely proteoglycans from human articular cartilage and intervertebral disc, bovine nasal cartilage, and rat chondrosarcoma and human type II collagen from cartilage. A cell line from one patient reacted with proteoglycans from human articular cartilage and human intervertebral disc, but the other two cell lines (each from a different patient) and four clones from one of the latter two lines proved to be highly specific for the human articular cartilage proteoglycan. From a study of four proteoglycan specific clones isolated from one patient, it is clear that removal of chondroitin sulfate had no effect on immunoreactivity but digestion of proteoglycan with pronase or alkali/sodium borohydride treatment abolished all reactivity. A OKT4-positive T-cell clone isolated from a healthy adult which was reactive to PPD was used to compare the antigen specificity of cells: this clone showed no reactivity to any of the other putative antigens listed above.     

Incidence and predictors of morphometric vertebral fractures in patients with ankylosing spondylitis

Introduction

Ankylosing spondylitis (AS) is associated with an increased incidence of vertebral fractures (VFs); however the actual incidence and predictors of morphometric VFs are unknown. The present study examined the incidence and predictors of new VFs in a large AS cohort.

Methods

In total, 298 AS patients who fulfilled the modified New York criteria were enrolled and spinal radiographs were evaluated biennially. Clinical and laboratory data and radiographic progression were assessed according to the Bath AS Disease Activity Index, erythrocyte sedimentation rate, C-reactive protein (CRP), and the Stoke AS spine score (SASSS). VF was defined according to the Genant criteria. The incidence of VFs at 2 and 4 years was evaluated using the Kaplan-Meier method. The age-specific standardized prevalence ratio (SPR) for AS patients in comparison with the general population was calculated.

Results

Of 298 patients, 31 (10.8%) had previous VFs at baseline. A total of 30 new VFs occurred in 26 patients over 4 years. The incidence of morphometric VFs was 4.7% at 2 years and 13.6% at 4 years. Multivariate logistic regression analysis showed that previous VFs at baseline and increased CRP levels at 2 years were predictors of new VFs (odds ratio (OR) =12.8, 95% confidence interval (CI) = 3.6-45.3 and OR = 5.4, 95% CI = 1.4–15.9). The age-specific specific standardized prevalence ratio of morphometric VFs in AS was 3.3 (95% CI 2.1–4.5).

Conclusions

The incidence of morphometric VFs increased in AS. Previous VFs and increased CRP levels predicted future VFs. Further studies are needed to identify the effects of treatment interventions on the prevention of new VFs.     

G/A polymorphism in intronic sequence affects the processing of MAO-B gene in patients with Parkinson disease

Monoamine oxidase B (MAO-B) plays an important role in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. Increased levels of MAO-B mRNA and enzymatic activity have been reported in platelets from patients with Parkinson’s and Alzheimer’s diseases, however the triggers of enhanced mRNA levels are unknown. Our results demonstrate for the first time that G/A dimorphism in intron 13 sequence creates splicing enhancer thus stimulating intron 13 removal efficiency. The increased MAO-B protein levels might serve as a surrogate marker for - Parkinson disease.     

Absence of polymorphism between HLA-B27 genomic exon sequences isolated from normal donors and ankylosing spondylitis patients

Ninety percent of individuals with ankylosing spondylitis (AS) express HLA-B27. To determine if HLA-B27 coding sequences from normal vs AS individuals show differences that might relate to the etiology of the disease, the gene coding for this allele was cloned from three different partial genomic libraries. These libraries were made with DNA from three different cell lines expressing HLA-B27: MRWC (HLA-B27, 14), obtained from an AS patient; KCA (HLA-B27, w44), obtained from a known normal individual; and MVL (HLA-B27, 27), a homozygous consanguineous cell line of unknown origin. To increase the number of clones coding for the HLA-B locus, partial libraries were made using a complete Eco RI digestion of genomic DNA in the lambda vector 607. The libraries were screened with two probes; one probe hybridizes to all HLA-A, B, C class I genes, and the other to a small subpopulation of class I genes, including the B locus. DNA from clones hybridizing with both probes was transfected into murine L cells. Cell surface expression of HLA-B27 on murine L cells was detected with a polymorphic monoclonal antibody (ME1) specific for HLA-B27, 7, 22. DNA from those clones positive for HLA-B27 by transfection was subcloned into the Xba I site of M13mp18 and the DNA sequence for exons 2 through 4 (encoding domains alpha 1, alpha 2, and alpha 3) was determined by the dideoxy technique by using synthetic oligonucleotide primers or the M13 primer. The resulting sequences show no difference between HLA-B27 alpha 1, alpha 2, alpha 3 domains from a known AS patient and a known normal individual.