Linkage analysis of candidate genes as susceptibility loci for osteoarthritis-suggestive linkage of COL9A1 to female hip osteoarthritis

OBJECTIVE: To examine 11 candidate genes as susceptibility loci for osteoarthritis (OA). METHODS: A total of 481 families have been ascertained in which at least two siblings have had joint replacement surgery of the hip, or knee, or hip and knee for idiopathic OA. Each candidate gene was targeted using one or more intragenic or closely linked microsatellite marker. The linkage data were analysed unstratified and following stratification by sex and by joint replaced (hip or knee). RESULTS: The analyses revealed suggestive linkage of the type IX collagen gene COL9A1 (6q12-q13) to a subset of 132 families that contained affected females who were concordant for hip OA (female-hip) with a P-value of 0.00053 and logarithm of the odds (LOD) score of 2.33 [corrected P-value of 0. 0016, corrected LOD score of 1.85]. CONCLUSIONS:COL9A1 may therefore be a susceptibility locus for female hip OA. In addition, there was weak evidence of linkage to HLA/COL11A2 (6p21.3) in female hip OA with a corrected P-value of 0.016.     

Effects of interleukin (IL)-17A and IL-17F in human rheumatoid arthritis synoviocytes

Rheumatoid arthritis (RA) is a chronic inflammatory disease where the contribution of T cells is now supported by clinical results. Among the cytokines produced by T cells, interleukin (IL)-17A (previously known as IL-17) and IL-17F constitute the signature cytokines of the newly described Th17 T helper cell subset. While the effects of IL-17A on RA synoviocytes been well described, those of IL-17F remain less studied. The present review describes the effects of IL-17A and IL-17F on synoviocytes and their contribution to RA pathogenesis. Although IL-17F is less active than IL-17A when used alone, IL-17A and IL-17F induce in synoviocytes a rather similar expression pattern in the presence of tumour necrosis factor α. They enhance their response by stabilising mRNA of cytokines and enhancing receptor expression. They increase the migration, chemokine gene expression and invasiveness of synoviocytes. They contribute to disease chronicity by inhibiting synoviocyte apoptosis. Finally, they enhance metalloprotease secretion leading to cartilage damage. These properties support the combined inhibition of IL-17A and -F to control RA inflammation and joint destruction.     

IL-17A and IL-17F genes variants and susceptibility to childhood asthma in Tunisia

Objectives: IL-17A and IL-17F are new pro-inflammatory cytokines implicated in neutrophilic inflammation and thus, involved in the pathogenesis of asthma. We investigated the possible association among asthma and IL-17A -197G/A (rs2275913), IL-17F 7488A/G (rs763780) and IL-17F 7383A/G (rs2397084).

Methods: The study was performed in 171 patients with asthma (mean age 9.5?years, 105 boys, and 66 girls) and 171 healthy individuals matched with patients in age and sex. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to detect genes’ polymorphisms.

Results: IL-17A -197G/A and IL-17F 7383A/G were associated with asthma in children (p?=?0.008, p?=?0.001, respectively). No association was found with IL-17F 7488A/G polymorphism. Haplotype analysis revealed a significant association between GA and AG haplotypes and asthma (p?=?0.004, p?=?0.02). When patients were stratified according to the atopic status, no significant association was detected with any of the three studied variants.

Conclusion: Our results suggested that SNPs in IL-17A and IL-17F confer susceptibility to childhood asthma in Tunisia.     

Association of polymorphisms in the IL1B and IL2 genes with susceptibility and severity of systemic sclerosis

OBJECTIVE: To investigate possible associations of 9 single-nucleotide polymorphisms in the IL10, IL1B, IL1A, IL1RN, IL2, LTA, and IL6 genes with susceptibility to systemic sclerosis (SSc), and with clinical subtype of SSc patients. METHODS: A total of 78 patients with SSc [diffuse SSc (dcSSc), n = 31; limited SSc, (lcSSc), n = 47] and 692 healthy blood donors were genotyped for the following polymorphisms: IL10 T-3575A, IL10 A-1082G, IL1B C-31T, IL1B C-511T, IL1A C-889T, IL1RN A9589T, IL2 T-384G, LTA T-91G, and IL6 G-174C. RESULTS: Alleles in IL1B-31 and IL1B-511 showed a significantly different distribution between cases and controls. Carriers of at least one copy of the IL1B-31-C allele had an increased risk of SSc [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.6-5.2, p < 0.001], while a similar strong association was also evident for IL1B-511-T carriers (OR 3.1, 95% CI 1.7-5.7, p < 0.001). Interestingly, carriers of the IL2-384-G allele were significantly more frequent among patients with lcSSc (80.8%), compared to patients with the diffuse subtype (45.1%) (OR 5.1, 95% CI 1.8-14.3, p = 0.001) and in subjects positive to anticentromere antibodies (OR 4.2, 95% CI 1.5-11.9, p = 0.007). Lastly, the distribution of the IL2-384 genotype showed statistically significant differences between controls and patients with lcSSc (OR 3.5, 95% CI 1.7-7.4, p < 0.001). There were no differences between patients with dcSSc and controls. CONCLUSION: IL1B and IL2 gene polymorphisms may be involved in susceptibility to SSc. Moreover, the IL2-384-G allele may be a marker for the limited phenotype of SSc.     

IL-10基因多态性与乙肝肝硬化易感性的相关性研究

探讨白细胞介素10(IL-10)基因多态性与乙型肝炎肝硬化易感性的关系.采用聚合酶链反应-限制性片段长度多态性(PCR-PFLP)分析方法,检测100例乙肝肝硬化患者及124例健康对照组IL-10基因启动子-1082G/A、-592A/C位点的基因多态性,并确定了其基因型和等位基因频率的分布.肝硬化组与对照组IL-10基因启动子-592A/C位点基因型分布频率和等位基因频率差异无显著性(P＞0.1),肝硬化组-1082G/A位点AA基因型频率及A等位基因频率高于对照组(P＜0.05),G等位基因相对于A等位基因患肝硬化的机会比为0.373(95%CI:0.166～0.838).IL-10基因多态性与肝硬化易感性相关,基因启动子-1082G/A位点AA基因型携带者肝硬化易感性高.     

Association study of IFNAR2 and IL10RB genes with the susceptibility and interferon response in HBV infection

Summary. A recent genome‐wide association study discovered that two polymorphisms, interferon (IFN) alpha receptor 2 (IFNAR‐2) F8S and interleukin 10 receptor (IL10RB) K47E, were associated with susceptibility to hepatitis B virus (HBV) infection in Africa. Here, we reevaluate the effects of the two polymorphisms on HBV susceptibility in the Chinese Han population, and extended the study to look at their association with IFN response in chronic hepatitis B (CHB). We included 341 patients with CHB and 341 unrelated controls presenting with asymptotic HBV self‐limited infection, who were well matched in age and sex. In the CHB group, 101 patients had been treated with peg‐IFN‐alpha‐2a for 48 weeks and followed up for 24 weeks to determine the clinical response, resulting 34 individuals with sustained virological response (SVR) and 67 individuals with nonsustained response (NR). Subgroups in the CHB group were divided according to the viral loads, HBeAg and maternal HBsAg status. The association with the susceptibility to HBV infection was only observed for IL10RB K47E when we compared the individuals with persistent HBV infection through nonmaternal transmission to the controls with asymptomatic self‐limited HBV infection. Further, we found that the IFNAR2‐8SS genotype was associated with HBeAg negative patients (OR = 0.316, 95% CI: 0.121–0.825, P = 0.019) and that the IFNAR2‐8F allele was associated with the risk to high viral loads (OR = 1.667, 95% CI: 1.148–2.420, P = 0.007). In addition, the IFNAR2‐8FF genotype predisposed to higher MxA gene induction and correlated with sustained IFN response (OR = 0.348, 95% CI: 0.129–0.935, P = 0.036). Haplotype analysis based on polymorphisms of three single‐nucleotide polymorphisms, MxA ?88 G/T, IFNAR‐2 F8S and IL10RB K47E showed that the haplotype distribution was significantly different between the SVR and NR groups (P = 0.040). This study suggests that IFNAR2 may play an important role in determining IFN response and clinical phenotypes of HBV infection in the Chinese Han population.     

Genetic association analysis of LRCH1 as an osteoarthritis susceptibility locus

OBJECTIVE: A genetic association with knee osteoarthritis (OA) of a single nucleotide polymorphism (SNP) in intron 1 of the LRCH1 gene was recently reported in a UK Caucasian case-control sample and confirmed in a Newfoundland Caucasian sample. Our objective was to assess whether the SNP was associated with OA in our large UK Caucasian sample. METHODS: The SNP was genotyped in 1521 cases that had undergone elective joint replacement of the hip (1098 cases), of the knee (340 cases) or of the hip and knee (83 cases) due to end-stage primary OA. The SNP was also genotyped in 736 controls of similar ages in the cases. RESULTS: There was no significant difference (all P-values >0.05) in genotype or allele frequencies between our cases and our controls. There was also no significant difference when the cases were stratified by sex, by joint replaced or by sex combined with joint replaced. CONCLUSION: Our data on 2257 individuals implies that the LRCH1 intron 1 SNP is not a risk factor for OA aetiology of the knee or of the hip in our UK Caucasian sample.     

A genome-wide search identifies potential new susceptibility loci for Crohn's disease

Chronic inflammatory bowel disease (IBD) presents as two major clinical forms, Crohn's disease (CD) and ulcerative colitis (UC). Genetic epidemiological studies and animal models suggest that inherited factors play significant roles in the susceptibility to both forms of IBD. From four genome-wide scans, putative susceptibility loci on chromosome 16 (IBD1 for CD), and on chromosomes 1, 3, 4, 6, 7, 10, and 12 for IBD, have been identified. Several other groups, including ours, have confirmed linkage to the loci on chromosomes 12 and 16. The aim of this study is to identify other potential susceptibility loci for CD with a genome-wide search approach. In our sample of 222 individuals from 46 families (20 Jewish and 26 non-Jewish), with a total of 65 sibpairs diagnosed with CD, we observed a novel locus with suggestive linkage [multipoint logarithm of the odds score (Mlod) > 2] at chromosome 14q11.2 (Mlod = 2.8, p = 0.0002). In addition, suggestive linkage was observed in our Jewish families at chromosome 17q21-q23 (Mlod = 2.1, p = 0.01) and chromosome 5q33-q35 (Mlod = 2.2, p = 0.0003). The syntenic regions of the latter locus are mapped within two putative loci on mouse chromosomes 11 and 18, which were identified in a mouse IBD model induced by dextran sulfate sodium (29). Our preliminary results provide potential evidence for several susceptibility loci contributing to the risk of CD. The observation of man-mouse synteny may accelerate the identification of CD susceptibility gene(s) on human chromosome 5.     

The expression of interleukin (IL)-17 and IL-17 receptor and MMP-9 in human pituitary adenomas

The IL-17 plays a crucial role in the invasion of tumors. However, the effects of IL-17 on the invasion of human pituitary adenomas are still unknown. The current study is designed to investigate the possible involvement of IL-17 in the invasion of adenomas. By collecting invasive and non-invasive pituitary adenomas, the mRNA and protein levels of IL-17, IL-17R and MMP-9 are investigated. The results obtained from IHC showed that the strong positive rate and the total positive rate of IL-17, IL-17R and MMP-9 expression cells in the non-invasive group were 17.1 and 51.43%, 14.3 and 54.3%, 17.1 and 57.1%, respectively. In contrast, the strong positive rate and the total positive rate of the invasive group were significantly higher than that of the non-invasive group, which were 37.5 and 82.5%, 52.5 and 87.5%, 67.5 and 92.5%, respectively. Meanwhile, the serum IL-17 level in the invasive pituitary adenomas patients was significantly higher than in the non-invasive groups (P < 0.05). Furthermore, the mRNA levels of IL-17, IL-17R and MMP-9 were also higher in the invasive group than in the non-invasive group with statistical differences (P < 0.05), and where the expression levels of IL-17 and IL-17R had positive correlation with that of MMP-9 in the invasive group. These results suggested that IL-17 may promote the invasion of pituitary adenomas.     

Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD

BACKGROUND: Interleukin (IL)-17F, produced in IL-23R-expressing Th17 cells, is a novel member of the IL-17 cytokine family. Given the association of IL23R with inflammatory bowel disease (IBD), we characterized the role of IL-17F in IBD including its intestinal gene expression and the effect of the IL17F p.His161Arg polymorphism on disease susceptibility and phenotype of Crohn's disease (CD) and ulcerative colitis (UC). In addition, we analyzed the IL17F p.His161Arg polymorphism for potential epistasis with IL23R and NOD2/CARD15 variants. METHODS: Intestinal IL-17F mRNA expression was measured by quantitative polymerase chain reaction (PCR). Genomic DNA from 1682 individuals (CD: n = 499; UC: n = 216; controls: n = 967) was analyzed for the presence of the IL17F p.His161Arg polymorphism, the 3 NOD2 variants, p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008, and 10 CD-associated IL23R variants. RESULTS: Intestinal IL-17F mRNA expression was 4.4-fold increased in inflamed colonic lesions compared to uninflamed biopsies in CD (P = 0.016) but not in UC. However, the mean intestinal IL-17F mRNA expression was higher in UC than in CD (P < 0.0001). The IL17F p.His161Arg substitution was observed with similar frequencies in IBD patients and controls and was not associated with a certain disease phenotype, but weakly associated with a low body mass index (BMI; P = 0.009) and an earlier age of disease onset (P = 0.039) in UC. There was no evidence for epistasis between the IL17F p.His161Arg polymorphism and IBD-associated single nucleotide polymorphisms within the IL23R gene. CONCLUSIONS: Intestinal IL17F gene expression is increased in active CD. The IL17F p.His161Arg polymorphism is not associated with IBD susceptibility and has no epistatic interaction with CD-associated IL23R variants.