Association between susceptibility to rheumatoid arthritis and <Emphasis Type="Italic">PADI4</Emphasis> polymorphisms: a meta-analysis

The objective of the study was to determine by meta-analysis whether polymorphisms of the gene encoding peptidylarginine deiminase 4 (PADI4) are associated with susceptibility to rheumatoid arthritis (RA). A literature review was conducted to identify data sets that described analyses of genetic association between PADI4 polymorphisms and RA. Data sets were collated and a meta-analysis was performed, with a specific focus on associations within Caucasian and Asian populations. A total of 15,947 RA cases and 22,696 controls that were taken from 28 studies in 24 papers were included in this study. Meta-analysis showed a significant association between allele 2 of the PADI4_94 polymorphism and RA in the overall population (odds ratio [OR]?=?1.155, 95 % confidence interval [CI]?=?1.069–1.249, p?=?2.7?×?10^?5). Stratification by ethnicity revealed an association between PADI4_94 allele 2 and RA in Asians (OR?=?1.273, 95 % CI?=?1.193–1.359, p?<?1.0?×?10^?9), but not in Caucasians (OR?=?1.024, 95 % CI?=?0.973–1.078, p?=?0.358). However, meta-analysis using homozygote contrast showed an association between PADI4_94 allele 2 and RA in both Asians (OR?=?2.311, 95 % CI?=?1.1.858–2.875, p?<?1.0?×?10^?9) and Caucasians (OR?=?1.523, 95 % CI?=?1.157–2.004, p?=?0.008). Meta-analysis also revealed an association between allele 2 of the PADI4_104 polymorphism and RA in both Asians (OR?=?1.547, 95 % CI?=?1.247–1.919, p?=?7.1?×?10^?6) and Caucasians (OR?=?1.096, 95 % CI?=?1.025–1.172, p?=?0.008). Finally, meta-analysis showed an association between allele 2 of the PADI4_92 polymorphism and RA in Asians (OR?=?1.263, 95 % CI?=?1.153–1.384, p?=?5.8?×?10^?8), but not in Caucasians (OR?=?1.123, 95 % CI?=?0.980–1.287, p?=?0.095). Meta-analysis indicated no association between allele 2 of either the PADI4_90 or PADI4_89 polymorphisms and RA in Asians. This meta-analysis revealed that the PADI4_94 and PADI_104 polymorphisms are associated with susceptibility to RA in Asians and Caucasians, and that the PADI4_92 polymorphism is associated with susceptibility to RA in Asians, but not in Caucasians.     

Association study of ankylosing spondylitis and polymorphisms in ERAP1 gene in Zhejiang Han Chinese population

The susceptibility loci of ERAP1 polymorphisms have been found to be strongly associated with ankylosing spondylitis (AS). The researches in multiple ethnic cohorts suggested that the population attributable risk in ERAP1 polymorphisms is at a high significance level. This study was undertaken to estimate the prevalence and incidence of subsets of AS and investigate the specific variants of ERAP1 polymorphisms in AS susceptibility, in the Han ethnic Chinese population in Zhejiang Province. AS patients were selected, diagnosed, and confirmed by a qualified rheumatologist. The basal clinical and demographic characteristics were compared with all subjects. Genotypes for eight selected single nucleotide polymorphisms (SNPs) in ERAP1 gene (rs27038, rs27037, rs27434, rs27980, rs7711564, rs30187, rs10050860, and rs17482078) were determined by using the Sequenom MassARRAY iPLEX platform in Zhejiang Han Chinese population. Association analyses were performed on the whole genotyped data set in 707 unrelated ankylosing spondylitis cases and 837 ethnically matched controls. We observed the strongest association between AS and HLA-B27, which confers over 90 % of ankylosing spondylitis cases. Moreover, we found three loci of ERAP1 polymorphisms were at a high significance level (rs27037 P = 0.00451; rs27434 P = 0.00012; rs27980 P = 0.00682) with AS in Zhejiang population. We also confirmed polymorphism locus of ERAP1 previously reported association with AS (rs27434; P = 5.3 × 10^?12). Our results indicated a difference in the mechanism of susceptibility loci in subsets of Zhejiang Han Chinese population and provided further evidence that rs27434 is the key polymorphism associated with AS in ERAP1 gene.     

The JAK2 46/1 haplotype (GGCC) in myeloproliferative neoplasms and splanchnic vein thrombosis: a pooled analysis of 26 observational studies

Numbers of observational studies suggest that the JAK2 46/1 (GGCC) haplotype may increase the risk of myeloproliferative neoplasms (MPNs) and splanchnic vein thrombosis (SVT), but the results remain controversial. We aimed to examine the association between the JAK2 46/1 haplotype and risk of MPNs and SVT by conducting a meta-analysis. PubMed, EMBASE, Cochrane Library, CBM, and CNKI databases were searched to identify eligible studies without restrictions and by reviewing reference lists of obtained articles. Both fixed and random-effects models were used to calculate the summary risk estimates. We identified 26 observational studies of the JAK2 46/1 haplotype and risk of MPNs and SVT involving 8,561 cases and 7,434 participants. In the overall analysis, it was found that the JAK2 46/1 haplotype significantly elevated the risk of MPNs (rs10974944: C vs T: odds ratio (OR)?=?2.19, 95 % confidence interval (CI)?=?1.86–2.57, P?<?0.0001; CC vs TT: OR?=?4.63, 95 % CI?=?3.32–6.47, P?<?0.0001; CT vs TT: OR?=?2.49, 95 % CI?=?2.11–2.95, P?<?0.0001; (CC?+?CT) vs TT: OR?=?2.92, 95 % CI?=?2.51–3.39, P?<?0.0001; rs12343867: C vs T: OR?=?1.88, 95 % CI?=?1.59–2.22, P?<?0.0001; CC vs TT: OR?=?3.16, 95 %CI?=?2.14–4.65, P?<?0.0001; CT vs TT: OR?=?2.04, 95 % CI?=?1.51–2.74, P?<?0.0001; (CC?+?CT) vs TT: OR?=?2.25, 95 % CI?=?1.73–2.95, P?<?0.0001) and SVT (C vs T: OR?=?1.27, 95 % CI?=?1.06–1.52, P?=?0.011; CC vs TT: OR?=?2.33, 95 % CI?=?1.42–3.81, P?=?0.001; (CC?+?CT) vs TT: OR?=?1.25, 95 % CI?=?1.02–1.53, P?=?0.034). There was no evidence of a significant association between the rs12343867 and the risk of SVT in the genetic model (CT vs TT: OR?=?1.01, 95 % CI?=?0.80–1.29, P?=?0.906). This meta-analysis provides new evidence supporting the conclusion that the JAK2 46/1 haplotype enrichment is significantly associated with the development of MPNs and SVT in these patients.     

Association between the functional <Emphasis Type="Italic">MHC2TA</Emphasis> −168 A/G polymorphism and susceptibility to rheumatoid arthritis: a meta-analysis

The aim of this study was to determine whether the functional major histocompatibility complex II transactivator (MHC2TA) ?168 A/G polymorphism is associated with susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted to estimate the association between the MHC2TA?168 A/G polymorphism and RA. A total of 15 comparative studies, which included 14,158 patients and 13,642 controls, were included in the meta-analysis. Based on the meta-analysis, there was no association between RA and the MHC2TA ?168 G allele in the study subjects (OR?=?1.046, 95 % CI?=?0.987–1.108, p?=?0.130) or Caucasians (OR?=?1.027, 95 % CI?=?0.986–1.070, p?=?0.193). However, the country-specific meta-analysis revealed an association between the MHC2TA ?168 G allele and RA in the Swedish population (OR?=?1.131, 95 % CI?=?1.023–1.250, p?=?0.016). A direct comparison between rheumatoid factor (RF)-positive and RF-negative patients revealed that the frequency of the G allele was significantly lower in RF-positive patients (OR?=?0.783, 95 % CI?=?0.628–0.975, p?=?0.029) than in RF-negative patients. This meta-analysis demonstrated that the MHC2TA ?168 A/G polymorphism is not associated with susceptibility to RA in Caucasians.     

Interleukin 12B gene polymorphisms and susceptibility to rheumatoid arthritis: a data synthesis

The aim of this study was to investigate the association of two common interleukin 12B (IL-12B) polymorphisms (rs3212227 and rs6887695) with rheumatoid arthritis (RA) susceptibility through meta-analyses. A systematic literature search of PubMed, Web of Science, Cochrane Library, and Embase databases was conducted on articles published before 28 February 2016. Then odds ratio (OR) with 95 % confidence interval (CI) was used to quantify the strength of association for homozygote, heterozygote, dominant, and recessive genetic models. Nine articles with a total of 17 case–control studies (12 for IL-12B rs3212227 polymorphism and 5 for IL-12B rs6887695 polymorphism) met our inclusion criteria. The pooled results demonstrated that IL-12B rs3212227 (homozygote model: OR?=?0.96, 95 % CI?=?0.81–1.15; heterozygote model: OR?=?1.07, 95 % CI?=?0.93–1.23; dominant model: OR?=?1.05, 95 % CI?=?0.91–1.20; recessive model: OR?=?0.93, 95 % CI?=?0.79–1.10) and rs6887695 (homozygote model: OR?=?1.01, 95 % CI?=?0.84-1.21; heterozygote model: OR?=?1.14, 95 % CI?=?0.86–1.51; dominant model: OR?=?1.14, 95 % CI?=?0.87–1.48; recessive model: OR?=?1.01, 95 % CI?=?0.85–1.21) polymorphisms may not be associated with RA risk. Our meta-analyses demonstrated that IL-12B rs3212227 and rs6887695 polymorphisms do not confer susceptibility to RA.     

C-reactive protein (CRP) polymorphisms and haplotypes are associated with SLE susceptibility and activity but not with serum CRP levels in Mexican population

To evaluate the association of C-reactive protein (CRP) polymorphisms with risk of development SLE in a group of Mexican individuals. Five CRP polymorphisms (rs3093059, rs3093062, rs1800947, rs1130864, and rs1205) were determined by PCR-restriction fragment length polymorphism and SNP rs3093061 by refractory mutation system PCR assay in 126 SLE patients and 131 controls. Four of the polymorphisms showed differences between patients and controls. rs3093061 polymorphism was associated with a lower risk of developing lupus principally in the codominant 2 (OR?=?0.219, 95% CI 0.108–0.785, P =?0.015) model. rs1130864 was associated with decreased risk mainly under codominant 1 (OR?=?0.288, 95% CI 0.143–0.581, P =?0.001) model. rs1205 was associated under the over-dominant model (OR?=?0.504, 95% CI 0.270–0.942, P =?0.032). The rs3091244 polymorphism was associated with decreased risk of SLE mostly under additive (OR?=?0.605, 95% CI 0.393–0.931. P =?0.022) model. Our study establishes that rs3093061, rs1130864, rs1205, and rs3091244 polymorphisms are associated with decreased risk of developing SLE.     

Discordant association of the <Emphasis Type="Italic">CREBRF</Emphasis> rs373863828 A allele with increased BMI and protection from type 2 diabetes in Māori and Pacific (Polynesian) people living in Aotearoa/New Zealand

Aims/hypothesis

The A (minor) allele of CREBRF rs373863828 has been associated with increased BMI and reduced risk of type 2 diabetes in the Samoan populations of Samoa and American Samoa. Our aim was to test rs373863828 for associations with BMI and the odds of type 2 diabetes, gout and chronic kidney disease (CKD) in Māori and Pacific (Polynesian) people living in Aotearoa/New Zealand.

Methods

Linear and logistic regression models were used to analyse the association of the A allele of CREBRF rs373863828 with BMI, log-transformed BMI, waist circumference, type 2 diabetes, gout and CKD in 2286 adults. The primary analyses were adjusted for age, sex, the first four genome-wide principal components and (where appropriate) BMI, waist circumference and type 2 diabetes. The primary analysis was conducted in ancestrally defined groups and association effects were combined using meta-analysis.

Results

For the A allele of rs373863828, the effect size was 0.038 (95% CI 0.022, 0.055, p?=?4.8?×?10^?6) for log-transformed BMI, with OR 0.59 (95% CI 0.47, 0.73, p?=?1.9?×?10^?6) for type 2 diabetes. There was no evidence for an association of genotype with variance in BMI (p?=?0.13), and nor was there evidence for associations with serum urate (β?=?0.012 mmol/l, p_corrected?=?0.10), gout (OR 1.00, p?=?0.98) or CKD (OR 0.91, p?=?0.59).

Conclusions/interpretation

Our results in New Zealand Polynesian adults replicate, with very similar effect sizes, the association of the A allele of rs373863828 with higher BMI but lower odds of type 2 diabetes among Samoan adults living in Samoa and American Samoa.

     

Association of HSD11B1 rs12086634 and HSD11B1 rs846910 gene polymorphisms with polycystic ovary syndrome in South Indian women

The 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme generates cortisol from cortisone for local glucocorticoid action in hepatocytes and adipocytes. Functional polymorphisms within 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) gene have shown an association with various factors including insulin resistance, diabetes, and obesity. In this study, we have assessed a candidate gene association study in order to examine the association of HSD11B1 gene polymorphisms with polycystic ovary syndrome (PCOS). A total of 200 women were investigated in this case-control study. DNA samples from PCOS women (n?=?100) and the age-matched control women (n?=?100) were analyzed. Genotyping of HSD11B1 rs12086634 and rs846910 variants was performed using tetra-primer amplification refractory mutation system (TETRA-ARMS) PCR. Odds ratio and 95% confidence interval were calculated to determine the association of HSD11B1 gene polymorphisms with polycystic ovary syndrome. The association analysis indicate that HSD11B1 rs12086634 showed positive association with polycystic ovary syndrome (OR?=?1.95; 95%CI?=?1.11–3.44, p?=?0.0195) and women with HSD11B1 rs12086634 TG genotype had significantly higher body mass index (28.05 kg/mt², p?=?0.001), higher waist circumference (89.68 cms, p?=?0.019), higher triglycerides (120.37 mg/dl, p?=?0.049), and lower HDL levels (45.56 mg/dl, p?=?0.004) compared to the women with HSD11B1 TT genotype. HSD11B1 rs846910 did not show any association with PCOS (OR?=?0.57; 95%CI?=?0.311–1.051, p?=?0.072). Our results suggest that HSD11B1 rs12086634 polymorphism is associated with PCOS and HSD11B1 rs846910 gene polymorphism is not associated with PCOS in South Indian women.     

Association of MCP-1-2518A/G polymorphism with susceptibility to autoimmune diseases: a meta-analysis

We performed a meta-analysis to estimate whether combined evidence shows the association between the MCP-1-2518A/G polymorphism and susceptibility to autoimmune diseases. Relevant articles dated to July 2014 were acquired from the PubMed, EMBASE, ISI, and CNKI databases. The number of the genotypes and/or alleles for the MCP-1-2518A/G in cases and control subjects was extracted, and statistical analysis was conducted using STATA 11.2 software. Summary odds ratios (ORs) with their 95 % confidence intervals (95 % CIs) were used to calculate the risk of autoimmune diseases with the MCP-1-2518A/G. Significant increased risk of autoimmune diseases could be found for A allele vs. G allele (OR?=?1.616, 95 % CI 1.027–2.542, P?=?0.038) and AA?+?AG vs. GG (OR?=?1.616, 95 % CI 1.027–2.542, P?=?0.038) in Asian patients with rheumatoid arthritis (RA), and for A allele vs. G allele (OR?=?1.383, 95 % CI 1.142–1.676, P?=?0.022) and AA vs. AG?+?GG (OR?=?1.575, 95 % CI 1.361–1.823, P?<?0.001) in European patients with Crohn’s disease (CD). In addition, when comparison of European patients with lupus nephritis (LN) and without LN, significant association between patients with LN and without LN also could be found for AA vs. AG?+?GG (OR?=?0.713, 95 % CI 0.545–0.933, P?=?0.014). This meta-analysis showed that the MCP-1-2518-A allele confers susceptibility to Asian patients with RA and European patients with CD.     

The search for putative unifying genetic factors for components of the metabolic syndrome

Aims/hypothesis

The metabolic syndrome is a cluster of factors contributing to increased risk of cardiovascular disease and type 2 diabetes but unifying mechanisms have not been identified. Our aim was to study whether common variations in 17 genes previously associated with type 2 diabetes or components of the metabolic syndrome and variants in nine genes with inconsistent association with at least two components of the metabolic syndrome would also predict future development of components of the metabolic syndrome, individually or in combination.

Methods

Genetic variants were studied in a large prospective study of 16,143 non-diabetic individuals (mean follow-up time 23 years) from the Malmö Preventive Project. In this study, development of at least three of obesity (BMI?≥?30 kg/m²), dyslipidaemia (triacylglycerol?≥?1.7 mmol/l and/or lipid-lowering treatment), hypertension (blood pressure?≥?140/90 mmHg and/or antihypertensive medication) and hyperglycaemia (fasting plasma glucose?≥?5.6 mmol/l and/or known diabetes) was defined as development of the metabolic syndrome. The risk of developing at least three components of the metabolic syndrome or the individual components was calculated by logistic regression adjusted for age at baseline, follow-up time and sex.

Results

Polymorphisms in TCF7L2 (rs7903146, OR 1.10, 95% CI 1.04–1.17, p?=?0.00097), FTO (rs9939609, OR 1.08, 95% CI 1.02–1.14, p?=?0.0065), WFS1 (rs10010131, OR 1.07, 95% CI 1.02–1.13, p?=?0.0078) and IGF2BP2 (rs4402960, OR 1.07, 95% CI 1.01–1.13, p?=?0.021) predicted the development of at least three components of the metabolic syndrome in both univariate and multivariate analysis; in the case of TCF7L2, WFS1 and IGF2BP this was due to their association with hyperglycaemia (p?p?=?0.0033 and p?=?0.027, respectively) and for FTO it was due to its association with obesity (p?=?0.004). A polymorphism in the GCKR gene predicted dyslipidaemia (rs1260326, OR 1.15, 95% CI 1.09–1.22, p?p?p?p?

Conclusions/interpretation

Polymorphisms in susceptibility genes for type 2 diabetes (TCF7L2, WFS1, IGF2BP2) and obesity (FTO) predispose to the metabolic syndrome by increasing the risk of one specific component of the metabolic syndrome. The findings argue against a unifying genetic component for the metabolic syndrome.

     

TLR9 polymorphisms and systemic lupus erythematosus risk: an update meta-analysis study

It has been reported that the Toll-like receptor 9 (TLR9) gene polymorphisms may be associated with systemic lupus erythematosus (SLE) risk. However, some studies yielded conflicting results. Therefore, a comprehensive meta-analysis was performed to assess the precise association between TLR9 polymorphisms and SLE susceptibility. We performed a systematic search in PubMed, Embase (Ovid), China National Knowledge Internet, and Wanfang databases up to July 15, 2015. Odds ratio (OR) and 95 % confidence interval (CI) were used to pool the effect size. Statistical analyses were performed with STATA 11.0 software. In total, 21 studies from nineteen articles with 10,273 subjects were included in this meta-analysis. The overall results suggested that there was a statistically significant association between TLR9 rs187084 polymorphism and SLE risk observed in recessive model (TT vs. TC + CC: OR 1.17, 95 % CI 1.05–1.30, P = 0.005), codominant model (TT vs. CC: OR 1.22, 95 % CI 1.03–1.43, P = 0.019), and allele model (T vs. C: OR 1.15, 95 % CI 1.02–1.30, P = 0.020) in Asians. However, we found that there may be no significant association between the other three TLR9 polymorphisms and SLE risk in either Asians or non-Asians. In conclusion, the meta-analysis results suggested that TLR9 rs187084 polymorphism may increase the risk of SLE in Asians. However, no significant association between TLR9 SNPs (rs352139, rs352140, and rs5743836) and SLE risk was identified.     

Non-driver mutations in patients with <Emphasis Type="Italic">JAK2</Emphasis>V617F-mutated polycythemia vera or essential thrombocythemia with long-term molecular follow-up

JAK2V617F monitoring and NGS of non-driver genes was performed in 100 patients with polycythemia vera (PV) or essential thrombocythemia (ET) with long molecular follow-up. Patients who did not progress to myelofibrosis (MF) or acute myeloid leukemia (AML) after more than 10 years (n?=?50) showed a low frequency of mutations at first sample (18%) and an incidence rate of 1.7 new mutations?×?100 person-years. Mutations were detected at first sample in 83% of PV/ET patients who later progressed to AML (n?=?12) with these patients having a rate of 25.6 mutations?×?100 person-years. Presence of mutations at diagnosis was the unique risk factor for acquiring a new genetic event (HR 2.7, 95% CI 1.1–6.8, p?=?0.03) after correction for age, PV diagnosis, and total duration of hydroxyurea (HU) exposure. Patients with additional mutation at first sample showed a higher probability of developing cytopenia under HU therapy and a higher risk of AML (HR 12.2, 95% CI 2.6–57.1, p?=?0.001) with mutations in ASXL1 (p?<?0.0001), TP53 (p?=?0.01), SRSF2 (p?<?0.0001), IDH1/2 (p?<?0.0001), and RUNX1 (p?<?0.0001) being associated with a higher probability of AML. Myelofibrotic transformation was more frequent in patients with additional mutations, especially in SF3B1 (p?=?0.02) and IDH1/2 (p?<?0.0001) although a persistently high or a progressive increase of the JAK2V617F allele burden while receiving cytoreduction was the strongest predictor of MF transformation (HR 10.8, 95% CI 2.4–49.1, p?=?0.002). In conclusion, NGS may be useful to identify a minority of PV and ET patients with high genetic instability and increased risk of AML transformation.     

Association study of copy number variants in <Emphasis Type="Italic">FCGR3A</Emphasis> and <Emphasis Type="Italic">FCGR3B</Emphasis> gene with risk of ankylosing spondylitis in a Chinese population

Ankylosing spondylitis (AS) is a common inherited autoimmune disease. Copy number variation (CNV) of DNA segments has been found to be an important part of genetic variation, and the FCGR3A and FCGR3B gene CNVs have been associated with various autoimmune disorders. The aim of the study was to determine whether CNVs of FCGR3A and FCGR3B were also associated with the susceptibility of AS. A total of 801 individuals including 402 AS patients and 399 healthy controls were enrolled in this study. The copy numbers of FCGR3 gene (two fragments, included FCGR3A and FCGR3B) were measured by AccuCopy? methods. Chi-square test and logistic regression model were used to evaluate association between FCGR3 gene CNVs and AS susceptibility. P values, odds ratio, and 95 % confidence intervals (CIs) were used to estimate the effects of risk. Significantly, difference in the frequencies of FCGR3A and FCGR3B gene CNVs was founded between the patients with AS and controls. For the FCGR3A gene, a low (≤3) copy number was significantly associated with AS [for ≤3 copies versus 4 copies, (OR 2.17, 95 % CI (1.41, 3.34), P < 0.001, adjusted OR 2.22, 95 % CI (1.44, 3.43), P < 0.001)]. A low FCGR3B copy number was also significantly associated with increasing risk of AS [for ≤3 copies versus 4 copies, (OR 1.87, 95 % CI (1.25, 2.79), P = 0.002, adjusted OR 1.94, 95 % CI (1.29, 2.91), P = 0.001)]; however, both the high FCGR3A and FCGR3B copy numbers (≥5) were not significantly associated with the risk of AS (≥5 copies versus 4 copies). The lower copy numbers (≤3) of FCGR3A and FCGR3B genes confer a risk factor for AS susceptibility.     

Associations between interleukin-10 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis and meta-regression

This study aimed to explore whether interleukin-10 polymorphisms are associated with susceptibility to rheumatoid arthritis (RA). Studies that have analyzed the associations of the interleukin-10-1082G>A, -592C>A, and -819C>T polymorphisms with RA were searched for in PubMed and EMBASE. Sensitivity and cumulative analyses were conducted to measure the robustness of our findings. Egger’s linear regression and Begg’s funnel plots were performed to analyze publication bias. The source of heterogeneity was analyzed by subgroup analysis and meta-regression. This meta-analysis involved 2661 RA patients and 3249 controls in 16 studies. There were significant associations with RA in the AG vs AA model (OR?=?0.79, 95% CI?=?0.67–0.93, P?<?0.01) and the AG + GG vs AA model (OR?=?0.80, 95% CI?=?0.69–0.93, P?<?0.01) for the interleukin-10-1082G>A polymorphism, in the TC vs TT model (OR?=?0.61, 95% CI?=?0.44–0.84, P?<?0.01) and the CC vs TT model (OR?=?0.64, 95% CI?=?0.46–0.89, P?<?0.01) for the interleukin-10-819C>T polymorphism, and in the AC vs AA model (OR?=?0.73, 95% CI?=?0.56–0.96, P?=?0.03) and the AC + CC vs AA model (OR?=?0.68, 95% CI?=?0.47–0.98, P?=?0.04) for the interleukin-10-592C>A polymorphism. Meta-regression revealed that the genotyping method was a major cause of heterogeneity in the AC vs AA model and the AC + CC vs AA model for the interleukin-10-592C>A polymorphism. This meta-analysis showed the interleukin-10-1082G>A, -592C>A, and -819C>T polymorphisms are correlated with the susceptibility to RA. Meta-regression indicated that the genotyping method is a major driver of heterogeneity in the relationship between the interleukin-10-592C>A polymorphism and RA.     

Association between primary Sjögren’s syndrome and pregnancy complications: a systematic review and meta-analysis

Systemic autoimmune disorders may interfere with normal reproductive function resulting in negative outcome of pregnancy. Primary Sjögren’s syndrome (pSS) is a common rheumatic disease that mostly affects females. There are many reports that this condition may increase risk of pregnancy complications and fetal loss. However, data regarding these adverse outcomes are scarce and inconclusive. We performed a systematic review and meta-analysis of available articles that assess the association between pSS and adverse pregnancy outcome. We comprehensively searched the databases of MEDLINE and EMBASE from their dates of inception to March 2016 and reviewed papers with validity criteria. A random-effects model was used to evaluate pregnancy complications in patients with pSS and healthy controls. From 20 full-text articles, 7 studies involving 544 patients and 1586 pregnancies were included in the meta-analysis. Fetal complications included spontaneous abortion, stillbirth, neonatal deaths, and intrauterine growth retardation. Compared with healthy pregnancy, patients with pSS had significantly higher chance of neonatal deaths (pooled odds ratio (OR)?=?1.77, 95 % confidence interval (CI) 1.28 to 1.46, p?=?0.01). However, there were no significant associations between pSS and premature birth (OR?=?2.10, 95 % CI 0.59–7.46, p?=?0.25), spontaneous abortion (OR?=?1.46, 95 % CI 0.72–2.93, p?=?0.29), artificial abortion (OR?=?1.12, 95 % CI 0.52–2.61, p?=?0.71), or stillbirth (OR?=?1.05, 95 % CI 0.38–2.97, p?=?0.92). There is an increased risk of fetal loss in pregnant patients with pSS. The presented evidence further supports multidisciplinary care for these patients to prevent complications during pregnancy.     

Influence of <Emphasis Type="Italic">MX1</Emphasis> promoter rs2071430 G/T polymorphism on susceptibility to systemic lupus erythematosus

The expression of interferon inducible genes are reported to be heightened in systemic lupus erythematosus (SLE); nevertheless, not much is known regarding the genetic variants underlying these genes and their role in the pathogenesis of disease. Herein, we aim to explore the potential association and contribution of polymorphisms in MX1 gene (i) promoter with part of exon 1 (ii) intron 6, and (iii) their resulting haplotypes, with susceptibility to SLE. A total of 306 subjects, 152 SLE and 154 healthy controls (HC), were screened by direct sequencing method. Statistical analysis was carried out using appropriate software. The screening region of interest in MX1 revealed the existence of promoter (?123C/A, ?88G/T, ?20 A/C) and intron 6 (+9862G/A, +10190G/A, +9901C/G, +9920C/A, +9959C/T, +10047A/G) variants in SLE and HC. A significant association was observed between MX1 ?88G/T SNP and susceptibility to SLE (χ ²?=?4.18, p?=?0.04, OR?=?1.89, 95 % CI 1.03–3.5). Haplotype analysis also revealed increased risk of SLE among individuals carrying CTA haplotype (?123 C, ?88 T, ?20 A) (χ ²?=?5.74, p?=?0.017, OR?=?4.28, 95 % CI 1.30–14.06). None of the other tested variants showed any significant association with SLE. The present study is the first to reveal the influence of genetic variation in MX1 gene in susceptibility to SLE.     

Interactive role of endothelial nitric oxide synthase gene polymorphisms in T2D with CAD and CAD patients of Punjab (North-West India)

Dysregulation of endothelial nitric oxide synthase (eNOS) activity causes the reduction in the production of nitric oxide (NO) which is an early indicator of type 2 diabetes (T2D) and cardiovascular complications. The present study evaluates the association of ?786 T?>?C, 894 G?>?T, and 4a/b polymorphisms of eNOS gene in total of 1223 individuals enrolling 307 coronary artery disease (CAD) cases, 486 T2D cases with (n?=?170) and without (n?=?316) CAD as the secondary macrovascular complication, and 430 healthy controls from Punjab (North-West India). Genotyping of ?786 T?>?C and 894 G?>?T polymorphisms was done with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the genotyping of 4a/b insertion/deletion polymorphism was done by PCR. The minor allele frequency (MAF) of ?786 T?>?C polymorphism was higher in CAD (21.8 %), T2D + CAD (22.4 %), and T2D cases (18.4 %) as compared to healthy controls (17.6 %). However, in single-locus analysis, no significant results were obtained for eNOS polymorphisms in any of the studied groups. Significant association of C-b-G haplotype with the risk of both CAD [P?=?0.003, odds ratio (OR)?=?1.89 (1.04–3.45)] and T2D [P?=?0.019, OR?=?1.69 (0.92–3.13)] was observed. Diplotype analysis showed that TbG/CbG haplotype combination conferred risk towards CAD and T2D [P?=?0.01, OR?=?2.04 (1.18–3.57); P?=?0.006, OR?=?2.13 (1.22–3.57), respectively]. Furthermore, phenotypic parameters like waist circumference, high-density lipoprotein, and waist to height ratio are significantly associated with 894 G?>?T genotypes among CAD patients. In conclusion, the eNOS polymorphisms did not provide any conclusive result individually; however, their interactive effect gives some insights towards eNOS role in the population of Punjab.     

Ankylosing spondylitis diagnosis in US patients with back pain: identifying providers involved and factors associated with rheumatology referral delay

This study aimed to identify providers involved in diagnosing ankylosing spondylitis (AS) following back pain diagnosis in the USA and to identify factors leading to the delay in rheumatology referrals. The Truven Health MarketScan® US Commercial Database was searched for patients aged 18–64 years with back pain diagnosis in a non-rheumatology setting followed by AS diagnosis in any setting during January 2000–December 2012. Patients with a rheumatologist visit on or before AS diagnosis were considered referred. Cox regression was used to determine factors associated with referral time after adjusting for age, sex, comorbidities, physician specialty, drug therapy, and imaging procedures. Of 3336 patients included, 1244 (37 %) were referred to and diagnosed by rheumatologists; the others were diagnosed in primary care (25.7 %), chiropractic/physical therapy (7 %), orthopedic surgery (3.8 %), pain clinic (3.6 %), acute care (3.4 %), and other (19.2 %) settings. Median time from back pain diagnosis to rheumatology referral was 307 days and from first rheumatologist visit to AS diagnosis was 28 days. Referred patients were more likely to be younger (hazard ratio [HR]?=?0.986; p?<?0.0001), male (HR?=?1.15; p?=?0.0163), diagnosed with uveitis (HR?=?1.49; p?=?0.0050), referred by primary care physicians (HR?=?1.96; p?<?0.0001), prescribed non-steroidal anti-inflammatory drugs (HR?=?1.55; p?<?0.0001), disease-modifying antirheumatic drugs (HR?=?1.33; p?<?0.0001), and tumor necrosis factor inhibitors (HR?=?1.40; p?=?0.0036), and to have had spinal/pelvic X-ray prior to referral (HR?=?1.28; p?=?0.0003). During 2000–2012, most patients with AS were diagnosed outside of rheumatology practices. The delay before referral to rheumatology was 10 months; AS diagnosis generally followed within a month. Earlier referral of patients with AS signs and symptoms may lead to more timely diagnosis and appropriate treatment.