Étude des polymorphismes des gènes de l’interleukine-1 et de l’antagoniste du récepteur de l’interleukine-1 chez des patients atteints de polyarthrite rhumatoïde

Objectives

One of the most important pro-inflammatory cytokines in the pathophysiology of rheumatoid arthritis (RA) is interleukin 1 (IL-1). The purpose of this study is to evaluate the association between IL-1B (-511), IL-1 (+3953), IL-1 RN variable number of tandem repeat (VNTR) polymorphisms and the occurrence in Algerian patients with rheumatoid arthritis. We also analyze their correlations with clinical and biological phenotypes.

Patients and methods

One hundred and forty-seven patients with RA (119 women, 28 men) and 127 controls (70 women, 57 men) were included in the study. The analysis of two polymorphisms of IL-1B-511 and IL-1B+3953 was done by PCR-RFLP. Analysis of IL1-RN VNTR polymorphism was performed by PCR.

Results

No significant difference in genotype, allelic and haplotype distribution at the three polymorphisms was observed between RA patients and controls. However, the genotype (T/T) polymorphism of IL-1B-511 is more frequent in the group of patients with positive ACPA compared with negative ACPA group (Pc = 0.01, OR = 4.65). Moreover, we noted that the haplotype (IL-1RN* 1/IL-1B-511T/IL-1B+3953C) was more frequent (Pc = 0.03, OR = 2.05) in the positive ACPA group.

Conclusion

The association between the allele 1 of IL-1 RN VNTR, T allele of IL1B-511 and C allele of IL1-B +3953 polymorphisms seems to predispose to the synthesis of ACPA and therefore to the occurrence of ACPA positive RA. Further studies with a larger number of patients are needed to define the real role of IL-1 in the susceptibility to or severity of RA.     

Haplotypes of the IL-1 gene cluster are associated with gastroesophageal reflux disease and Barrett’s esophagus

Objectives

Gastroesophageal reflux (GERD) is a one of the major public health problem that can lead to reflux esophagitis (RE), Barrett’s esophagus (BE), and esophageal adenocarcinoma (EAC). The aim of our study was to determine the impact of IL-1 gene polymorphisms on the development of GERD, RE and BE.

Methods

Three hundred and thirty-three Czech patients with gastroesophageal reflux and 165 healthy controls were included in this case-control study. Four polymorphisms in the genes of the IL-1 cluster [IL-1A(-889C/T), IL-1B(−511C/T), IL-1B(+3953C/T), and IL-1RN(VNTR)] were analyzed.

Results

Significant differences were found in IL-1RN 1/2 genotype between patients with GERD/RE and controls and in IL-1B+3953 T allele between patients with BE and healthy subjects. In addition, complex analysis revealed differences in IL-1 haplotype frequencies between the groups. Specifically, the haplotype TCCL was significantly more frequent (p = 0.016) in GERD patients than in controls and the haplotype CCCL more frequent (p = 0.008) in RE patients than in controls. However, in patients with BE, frequency of haplotype TCTL was lower (p = 0.05) and haplotypes CTCL and TCCL were higher (p = 0.03 and p = 0.02) in comparison with the controls.

Conclusions

Our results suggest that IL-1 haplotypes may be associated with susceptibility to GERD, RE and BE.     

Association between interleukin-10 -1082A/G, -819C/T and -592C/A polymorphisms with deep venous thrombosis

Background

Deep venous thrombosis (DVT) and inflammation are two closely related entities. The objective of this study was to evaluate a possible association between interleukin-10 (IL-10) -1082A/G, -819C/T and -592C/A polymorphisms with DVT.

Methods

A case-control study was carried out in 660 patients with DVT and 660 age- and gender-matched healthy controls. Polymerase chain reaction restriction fragment length polymorphism (PCR–RFLP) assay was applied to identify the polymorphisms mentioned.

Results

Patients with DVT had a significantly lower frequency of IL-10 -1082GG genotype [odds ratio (OR) = 0.59, 95% confidence interval (CI) = 0.39, 0.89; P = 0.01] than healthy controls. When stratifying by family history of DVT, it was found that patients with positive family history of DVT had a significantly lower frequency of IL-10 -1082GG genotype (OR = 0.13, 95% CI = 0.02, 0.95; P = 0.04). When stratifying by smoking status, presence of varicose veins, type 2 diabetes mellitus and any hormone administration before, no significant differences were found in any groups.

Conclusions

This study provides evidence that IL-10 -1082A/G polymorphism associated with risk of DVT. However, no association of the IL-10 -592C/A or -819C/T polymorphism with DVT risk was found. Additional well-designed large studies were required for the validation of our results.     

Are GP patients’ needs being met? Unfulfilled information needs among native-Dutch and Turkish-Dutch patients

Objective

This study aims to assess unfulfilled information needs of native-Dutch and Turkish-Dutch general practitioner (GP) patients in the Netherlands. In addition, the relation between perceived and recorded information provision by GPs is studied.

Methods

Unfulfilled information needs of native-Dutch (N = 117) and Turkish-Dutch patients (N = 74) were assessed through pre- and post-consultation questionnaires. Audiotapes of GP consultations were made to code GPs’ information provision.

Results

Turkish-Dutch patients experience more unfulfilled information needs than native-Dutch patients, in particular those who identify equally with Dutch and Turkish culture. Overall, perceived information provision is hardly related to recorded information provision.

Conclusion

GPs insufficiently provide Turkish-Dutch patients and, to a lesser extent, native-Dutch patients as well, the information they need.

Practice implications

GPs should be trained in giving adequate, tailored information to patients with various ethnic and cultural backgrounds.     

Association of myasthenia gravis with polymorphisms in the gene of histamine N-methyltransferase

Introduction

Histamine N-methyltransferase (HNMT) is the main metabolizing enzyme of histamine. Histamine modulates immune responses and plays a role in the pathogenesis of autoimmune disorders.

Methods

The non-synonymous HNMT C314T polymorphism and the A939G single-nucleotide polymorphism (SNP) influencing HNMT mRNA stability were genotyped in 213 patients with myasthenia gravis (MG) and 342 healthy controls.

Results

The carrier frequency of the A allele of the A939G SNP was over-represented among patients with anti-AchR and anti-Titin antibodies (P = 0.05 and P = 0.004, respectively); the presence of the minor G allele was protective against anti-AchR and anti-Titin positive MG (OR = 0.67 and OR = 0.54, respectively). The combination of the G allele carrier status with wild-type C314C homozygosity was also protective against MG (OR = 0.55, P = 0.008) and against the development of anti-AchR antibodies (OR = 0.37, P = 0.01).

Discussion

The A939G HNMT polymorphism is associated with autoimmune MG, while no association with C314T SNP was found.     

Association between functional Fc receptor-like 3 (FCRL3) −169 C/T polymorphism and susceptibility to seropositive rheumatoid arthritis in Asians: A meta-analysis

Objective

The aim of this study was to determine whether the functional Fc receptor like-3 (FCRL3) −169 C/T polymorphism confers susceptibility to rheumatoid arthritis (RA).

Methods

A meta-analysis was conducted on the associations between the FCRL3 −169 C/T polymorphism and RA.

Results

A total of 17 comparison studies including 11,170 patients and 11,142 controls were considered in the meta-analysis. The meta-analysis showed no association between RA and the FCRL3 −169 C allele in study subjects (OR = 1.046, 95% CI = 0.997–1.098, p = 0.068). Stratification by ethnicity indicated an association between the FCRL3 −169 C allele and RA in Asians (OR = 1.101, 95% CI = 1.035–1.174, p = 0.002), but not in Europeans. Stratification of patients according to the presence of rheumatoid factor (RF) revealed a different significant association between the C allele and RA in RF-positive and RF-negative RA patients. Stratification by ethnicity indicated an association between the FCRL3 −169 C allele and RF-positive RA in Asians (OR = 1.093, 95% CI = 1.004–1.189, p = 0.040), but not in Europeans.

Conclusions

This meta-analysis demonstrates that the FCRL3 −169 C/T polymorphism may confer susceptibility to seropositive RA in Asians.     

Human SA gene polymorphisms are associated with non-high-density lipoprotein cholesterol in postmenopausal women: A pilot study

Objective

The purpose of the study is to evaluate the associations between polymorphisms of the human SA (SAH) gene, an acyl-CoA synthetase gene, with dyslipidemia and phenotypes of the insulin resistance syndrome in postmenopausal women.

Methods

One hundred and forty-two postmenopausal women were recruited for the study. Each subject received anthropometric and blood pressure measurements, fasting sampling for lipids, and a 75-g oral glucose tolerance test for insulin resistance. Genotypes of two polymorphisms in the promoter region (c.-962ins/del, c.-451G > A), one missense variant (c.1077G > C, p.K359N) in exon 8, and one in intron 12 (A > G) of the SAH gene, were determined.

Results

There were significant differences in genetic distribution of the SAH gene promoter I/D polymorphism between the two groups of subjects by non-high-density lipoprotein cholesterol (non-HDL-C) levels (p = 0.004). The subjects with the DD genotype was associated with high levels of non-HDL-C (>160 mg/dL) as compared with the ID or II genotypes (p = 0.002). Furthermore, three haplotypes were constructed based on the promoter I/D and the exon 8 G/C polymorphisms. Homozygosity for SAH haplotype 3 was associated with increased adiposity, insulin resistance, and elevated levels of non-HDL-C in the post menopausal women. The subjects with haplotype 3 had double the risk to have higher non-HDL-C levels than those with haplotype 1.

Conclusion

Our results suggest that the polymorphisms of the SAH gene are associated with non-HDL-C levels in postmenopausal women. Further studies with larger sample sizes or different populations are warranted to confirm our preliminary findings.     

A multicenter,prospective, quasi-experimental evaluation study of a patient education program to foster multiple sclerosis self-management competencies

Objective

To determine the impact of the self-management training program “S.MS” for new multiple sclerosis (MS) patients.

Method

Multicenter, prospective, quasi-experimental study with 31 MS patients in the intervention group (training program) and 33 participants in the control group (CG) (brochures). Data were collected before, after and 6 months after the interventions. Analysis of change was done by ANCOVA with repeated measurements.

Results

At baseline, participants in CG were younger at the time of diagnosis, suffered more frequently from relapsing–remitting MS and took more MS-medication on a permanent basis. The intervention had a stable significant effect on each dimension of self-management ability, on total self-management ability (ES = 0.194, p < 0.001), on anxiety (ES = 0.193, p = 0.001), and on disease-specific quality of life (ES = 0.120, p = 0.007). Regarding depression, a significant interaction effect of time and intervention could be observed (ES = 0.106, p = 0.011). No effect was found on disease-specific knowledge. High participant acceptance was reported.

Conclusion

“S.MS” participation was associated with a significant and sustained improvement of self-management abilities, anxiety and disease-specific quality of life in a quasi-experimental study design. Using RCT or CRT-designs would be desirable to further improve the evidence of treatment effectiveness.

Practice implications

This study provides substantial evidence that “S.MS” fosters patients’ self-management ability.     

The nuclear factor-kB functional promoter polymorphism is associated with endometriosis and infertility

Introduction

An aberrant immunologic mechanism has been suggested to be involved in the pathogenesis of endometriosis. Nuclear factor-kB (NF-kB) plays a key role in the immune and inflammatory response and modulates cell proliferation, apoptosis, adhesion, invasion, and angiogenesis in many cell types involved in the development of endometriosis. We hypothesized a possible relationship between the NFKB1 promoter regulatory polymorphism and endometriosis and/or infertility.

Methods

A genetic association study comprising 172 infertile women with endometriosis, 77 women with idiopathic infertility and 189 controls was performed. Detection of the −94 insertion/deletion ATTG (rs28362491) polymorphism in the NFKB1 gene was done using the RFLP–PCR (Restriction Fragment Length Polymorphism–Polymerase Chain Reaction) technique. The results were statistically analyzed, and a p-value <0.05 was considered significant.

Results

Single-marker analysis revealed a significant association between the −94 insertion/deletion ATTG polymorphism and endometriosis-related infertility (p = 0.014, OR = 1.47, 95% CI = 1.09–1.97), especially in moderate/severe disease cases. Considering the idiopathic infertility group, a significant association was also found (p = <0.001, OR = 2.01, 95% CI = 1.35–2.98), suggesting that the −94 insertion/deletion ATTG polymorphism is associated with endometriosis and/or infertility.

Conclusion

In the population sample studied, the −94 insertion/deletion ATTG polymorphism in the NFKB1 gene was positively associated both with moderate/severe endometriosis and idiopathic infertility.     

The variant of CD11b,rs1143679 within ITGAM, is associated with systemic lupus erythematosus and clinical manifestations in Brazilian patients

Background/aims

Immune responses mediated by complement receptors (CR) are impaired in patients with systemic lupus erythematosus (SLE). Regarding CR3 (CD11b/CD18), the CD11b subunit is encoded by the ITGAM gene and a single nucleotide polymorphism (G230A; rs1143679) in ITGAM changes an arginine to a histidine at position 77 (R77H). We assessed whether the variant R77H, rs1143679 within ITGAM, is associated with the risk to developing SLE and the clinical manifestations of Brazilian SLE patients.

Methods

The rs1143679 was genotyped by SSP-PCR in 157 patients with SLE and 147 healthy individuals. Clinical and laboratorial manifestations were obtained from the official medical records according the criteria of the American College of Rheumatology.

Results

The 77H variant was associated with susceptibility to SLE (OR = 1.8); the frequencies of the minor allele A were 0.25 (SLE) and 0.15 (healthy) (p < 0.01). In addition, the minor allele A was associated with lupus nephritis (p = 0.02) and antiphospholipid antibodies (p = 0.04).

Conclusion

These results showed that the rs1143679 variant is also associated with the risk to SLE in our population and with the risk to specific clinical manifestations, as nephritis and presence of antiphospholipid antibodies. These results may have implications for discussing the association of this polymorphism with the IC deposition in SLE.     

Positive affect dimensions and their association with inflammatory biomarkers in patients with chronic heart failure

Background

In cardiac patients positive affect has found to be associated with improved clinical outcomes, with reduced inflammation being one of the potential mechanisms responsible.

Methods

Positive affect was assessed using The Global Mood Scale (GMS), Positive and Negative Affect Schedule (PANAS), and Hospital Anxiety and Depression Scale (HADS) in patient with chronic heart failure (N = 210; 67 ± 9 years, 79% men). Markers of inflammation (TNFα, sTNFr1, sTNFr2, IL-6 and CRP) were measured and averaged at three consecutive time points.

Results

The positive affect dimensions of the GMS and PANAS were significantly associated with lower averaged levels of sTNFr2, TNFα and IL-6 (p < .1), even after adjustment for clinical and lifestyle confounders. Positive affect of the HADS was significantly associated with lower averaged levels of hsCRP (p < .1), but was no longer significant after correction for lifestyle confounders and depressive symptoms.

Conclusion

Positive affect is associated with reduced inflammation in patients with heart failure.     

Impact of genetic polymorphisms on the pathogenesis of idiopathic achalasia: Association with IL33 gene variant

Aim

To investigate the association of single nucleotide polymorphisms (SNPs) of genes involved in the regulation of immune responses, IL33, IL1RL1, IL23R, and IL10, with idiopathic achalasia in an Italian cohort of patients.

Materials and methods

A panel of eleven polymorphisms were genotyped in 116 unrelated idiopathic achalasic patients and 371 healthy subjects, by using TaqMan genotyping assays.

Results

Significant differences of allele (P = 0.0065, OR = 1.59, CI = 1.14–2.22) and genotype (P = 0.0097, OR = 1.74, CI = 1.14–2.65) frequencies of the IL33 rs3939286 variant were found between achalasic patients and controls. No association of the other investigated SNPs was detected. No differences in genotype and allele distribution were found with respect to clinical characteristics of patients.

Conclusion

We provide for the first time an association between the risk of developing idiopathic achalasia and IL-33 variant, underling the role of cytokines and inflammatory mediators on the pathogenesis of the disease.     

Association of the (TAAAA)n repeat polymorphism of SHBG gene with the age at menopause in Greek postmenopausal women

Objective

To assess the potential association of the pentanucleotide (TAAAA)n repeat polymorphism in the promoter of SHBG gene with the age at menopause in a Greek female population.

Study design

Cross-sectional study. Two hundred and ten postmenopausal women aged 46–63 years were enrolled. The age at the last menstrual period and anthropometric parameters were recorded in all participants. Blood sampling for genotyping of the (TAAAA)n polymorphism of SHBG gene was performed.

Main outcome measure(s)

Frequency and association of the (TAAAA)_n alleles with age at menopause.

Results

The alleles with seven and eight TAAAA repeats were associated with the age at menopause. The age at menopause was higher in carriers than in non-carriers of the (TAAAA)₇ allele (50.2 ± 3.1 years vs. 48.0 ± 4.8 years, p = 0.026). Furthermore, the age at menopause was lower in women carrying the (TAAAA)₈ allele (47.5 ± 4.8 years) than in women not carrying this allele (48.8 ± 4.4 years, p = 0.048).

Conclusions

The (TAAAA)₇ and (TAAAA)₈ alleles of the SHBG (TAAAA)_n polymorphism may contribute to variation in the timing of natural menopause in postmenopausal women of Northwestern Greece.     

Increased serum levels of quinolinic acid indicate enhanced severity of hepatic dysfunction in patients with liver cirrhosis

Background

The Model for End-Stage Liver Disease (MELD) score is a tool for assessment of the degree of hepatic insufficiency/failure. Quinolinic acid (QuinA) is a tryptophan metabolite produced by activated macrophages. Here we investigate whether the degree of systemic inflammation (QuinA, neopterin, CRP and IL-6) correlates with clinical liver dysfunction according to the MELD Score.

Method

Ninety-four patients with liver cirrhosis were categorized into 2 groups according to baseline MELD score (group I, MELD <20, n = 61, and group II, MELD ?20, n = 33).

Results

Serum levels of QuinA, neopterin, CRP, and IL-6 significantly correlated with MELD score (r = 0.77, 0.75, 0.57, and 0.50; p < 0.0001, respectively). Patients of group II had significantly higher serum levels of QuinA, neopterin, CRP, and IL-6 than group I (p ? 0.0001). ROC curve analysis showed that QuinA and neopterin are more sensitive markers for severity of liver disease than established markers of inflammation such as CRP and IL-6 (sensitivity = 86% and 79%, respectively) (AUC = 0.89 and 0.89, respectively). QuinA provided the most sensitive index with regard to the identification of patients with hepatic encephalopathy.

Conclusion

Serum levels of QuinA reflect the degree of liver dysfunction. Moreover, high levels of QuinA may serve as a sensitive indicator of hepatic encephalopathy.     

Association between DPP6 polymorphism and the risk of progressive multiple sclerosis in Northern and Southern Europeans

Background

In this study, we investigated the role of the dipeptidyl-peptidase-6 (DPP6) gene in the etiopathogenesis of progressive forms of multiple sclerosis (PrMS).This gene emerged as a candidate gene in a genome-wide association study (GWAS) performed in an Italian sample of PrMS and controls in which two SNPs located in the gene (rs6956703 and rs11767658) showed evidence of association (nominal p-value < 10⁻⁴) (Martinelli-Boneschi et al.) [18]. Moreover, the gene is highly expressed in the central nervous system, and it has been found to be associated with sporadic cases of amyotrophic lateral sclerosis which shares some feature with PrMS.

Methods

We genotyped 19 SNPs selected using a direct and tagging approach in 244 Italian PrMS and 225 controls, and we measured the expression levels of the gene in 13 PrMS cases and 25 controls.

Results

Five out of 19 SNPs were found to be associated with the disease (adjusted p < 0.05), and they have been tested in an independent sample of 179 primary progressive MS and 198 controls from Northern Europe. None of the SNPs was replicated, but combined analysis confirmed the presence of association for rs2046748 (p = 2.5 × 10⁻³,OR = 1.82, 95%CI = 1.24–2.69).

Conclusions

These results, inflated by the limited sample size determined by the rarity of this condition, suggest a possible role of this gene in the susceptibility to PrMS, at least in Southern Europeans. Moreover, DPP6 was over-expressed in PrMS patients compared to controls.     

FoxP3 rs3761548 polymorphism predicts autoimmune disease susceptibility: A meta-analysis

Background and aims

Autoimmune diseases (ADs) are associated with loss of self-tolerance leading to immune-mediated destruction of host tissues and organs. FoxP3 polymorphism (−3279 A/C, rs3761548) was shown to associate with AD susceptibility, but the results were inconsistent. This study performed a meta-analysis to investigate the FoxP3 −3279 A/C polymorphism for AD susceptibility.

Methods

A total of eight published case-control studies, including 1844 cases and 1857 controls were retrieved from the PubMed database for the meta-analysis. Heterogeneity was assessed with a standard Q-statistic test and I² test. Crude pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the FoxP3 polymorphism and AD risk according to the random-effective model and fixed-effective model.

Results

A significant relationship between FoxP3 −3279 A/C gene polymorphism and ADs was found under the allelic (OR: 1.477, 95% CI: 1.326–1.645, P = 0.000), homozygous (OR: 2.094, 95% CI: 1.390–3.153, P = 0.000), recessive (OR: 1.804, 95% CI: 1.083–3.008, P = 0.024), dominant (OR: 1.323, 95% CI: 1.154–1.516, P = 0.000), and additive (OR: 1.516, 95% CI: 1.360–1.689, P = 0.000) genetic models. However, there was no significant association between FoxP3 −3279 A/C polymorphism and ADs under the heterozygous genetic model (OR: 1.202, 95% CI: 0.899–1.606, P = 0.215).

Conclusion

FoxP3 −3279 A/C polymorphism may influence AD risk, especially, the A allele variant carriers of FoxP3 −3279 A/C polymorphism definitively associated with AD susceptibility.     

Genetic factors and multiple sclerosis in the Moroccan population: A role for HLA class II

Background and objective

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system that mainly affects young adults. The association between susceptibility to MS and HLA class II genes, in particular the DRB1*15 allele, has been reported in diverse ethnic groups. The aim of our study was to investigate the distribution of HLA-DRB1* and -DQB1* alleles in Moroccan population and their implication in the susceptibility to the disease.

Methods

Fifty-seven MS patients were compared to 172 healthy controls unrelated to one another and matched by age, sex and ethnic origin. HLA class II (DRB1* and DQB1*) typing was performed by PCR-SSP and/or Luminex (PCR-SSO). Allelic and haplotypic frequencies, P-values, odds ratio (OR) and 95% confidence interval (CI) were calculated using the software SPSS.

Results

A significant increase of DRB1*15 allele frequency (17.6% vs 8.4%, OR = 2.67, 95% CI = 1.36–5.23, P = 0.004) and HLA-DRB1*15-DQB1*06 haplotype (8.8% vs 4.08%, OR = 2.78, 95% CI = 1.41–5.48, P = 0.002) were observed in Moroccan MS patients. No association of the DR15 allele with sex or age at onset was appreciated. Concerning HLA-DQB1* alleles, no significant difference between patients and controls was found.

Conclusions

Our results reveal a role for HLA-DRB1*15 allele molecules in the predisposition of Moroccan patients to MS. Although this study should be confirmed on a larger sample size, it analyzes for the first time the possible role of a genetic marker for susceptibility to MS in Moroccan population.     

Does health coaching change patients’ trust in their primary care provider?

Objective

To assess the impact of health coaching on patients’ in their primary care provider.

Methods

Randomized controlled trial comparing health coaching with usual care.

Participants

Low-income English or Spanish speaking patients age 18–75 with poorly controlled type 2 diabetes, hypertension and/or hyperlipidemia.

Main outcome measure

Patient trust in their primary care provider measured by the 11-item Trust in Physician Scale, converted to a 0–100 scale.

Analysis

Linear mixed modeling.

Results

A total of 441 patients were randomized to receive 12 months of health coaching (n = 224) vs. usual care (n = 217). At baseline, the two groups were similar to those in the usual care group with respect to demographic characteristics and levels of trust in their provider. After 12 months, the mean trust level had increased more in patients receiving health coaching (3.9 vs. 1.5, p = 0.47), this difference remained significant after adjustment for number of visits to primary care providers (adjusted p = .03).

Conclusions

Health coaching appears to increase patients trust in their primary care providers.

Practice Implications

Primary care providers should consider adding health coaches to their team as a way to enhance their relationship with their patients.