Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

BackgroundPathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study.MethodsInformation was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age.ResultsAt time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5–3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1–2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1–3.5), with trends up to 2–4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3–0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4–0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2.ConclusionThe PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants.     

Alleles and genotypes of polymorphisms of IL-18, TNF-α and IFN-γ are associated with a higher risk and severity of hepatocellular carcinoma (HCC) in Brazil

Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver. We evaluated the association of alleles and genotypes of polymorphisms of IL-18 (-607C/A and -137G/C), IFN-γ (+874T/A) and TNF-α (-238G/A and -308G/A) with the risk and severity of HCC. One-hundred-and-twelve patients with HCC and 202 healthy controls were studied. Single nucleotide polymorphisms (SNPs) were amplified by PCR with specific primers and the products were submitted to polyacrylamide gel electrophoresis and stained with silver. We evaluated tumor presentation, tumor size and presence of metastasis. Significant higher risk of HCC was associated with: alleles IL-18 -607^∗A (P = 0.0235; OR = 1.48; 95%CI = 1.06–2.08); TNF-α -238^∗A (P = 0.0025; OR = 2.12; 95%CI = 1.32–3.40) and TNF-α -308^∗A (P = 0.0351; OR = 1.82; 95%CI = 1.07–3.08); and genotypes IL-18–607AA (P = 0.0048; OR = 3.03; 95%CI = 1.40–6.55); TNF-α -238GA (P = 0.0011; OR = 2.44; 95%CI = 1.45–4.12); and TNF-α -308GA (P = 0.0031; OR = 2.51; 95%CI = 1.39–4.51). Significant association was found between multinodular HCC and IL-18 -607^∗C allele (P = 0.029; OR = 2.40, 95%CI: 1.09–5.28), and IL-18 -607CC genotype (P = 0.028; OR = 3.5, 95%CI: 1.24–9.86). Diffuse HCC was significantly associated with IFN-γ +874TA genotype (P = 0.044; OR = 3.6, 95%CI: 1.03–12.47). The IL-18 -137^∗C allele showed a significant association with the presence of metastasis. Thus, IL-18 -607^∗A and TNF-α (-238^∗A and -308^∗A) alleles may confer susceptibility to HCC, while IL-18 -607^∗C and -137^∗C alleles more severe disease.     

Association of PTPN22 rs2476601 and EGFR rs17337023 Gene polymorphisms and rheumatoid arthritis in Zahedan,Southeast Iran

In this study we aimed to evaluate the possible association of PTPN22 rs2476601 as well as epidermal growth factor receptor (EGFR) rs17337023 gene polymorphism and rheumatoid arthritis (RA) in a sample of Iranian population. This case‐control study was performed on 120 patients with RA and 120 healthy subjects. Genomic DNA was extracted from whole blood and PTPN22 rs2476601 and EGFR rs17337023 polymorphisms were determined using tetra amplification refractory mutation system–polymerase chain reaction (T‐ARMS‐PCR). The results showed that PTPN22 rs2476601 CT genotype as well as rs2476601 T allele was a risk factor for susceptibility to RA (OR=5.89 95%CI = 1.78–19.48, P = 0.004 and OR = 4.78, 95%CI = 1.59–14.35, P = 0.003, respectively). We also found that EGFR rs17337023 AT and rs17337023 TT genotypes were risk factor for susceptibility to RA (OR = 9.94 95%CI = 3.65–26.73, P < 0.001 and OR = 3.66, 95%CI = 1.46–9.15, P = 0.005, respectively). In addition the EGFR rs17337023 T allele was a risk for predisposition to RA (OR = 1.56, 95%CI=1.06‐2.30, P = 0.030). In conclusion, we found an association between PTPN22 rs2476601 and EGFR rs17337023 polymorphisms and the risk of RA in a sample of Iranian population.     

Meta-analysis of the relationship between 14bp insertion/deletion polymorphism of HLA-G gene and susceptibility to systemic lupus erythematosus

We performed a meta-analysis to examine the relationship between the human leukocyte antigen-G (HLA-G) 14 base pairs sequence (14bp) insertion (ins)/deletion (del) polymorphism to systemic lupus erythematosus (SLE). Eligible studies were extracted in PubMed, Embase, Cochrane Library and CNKI (Chinese) up to March 31, 2014. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated to evaluate the strength of the association. Finally, 7 studies with 1864 cases and 2259 controls were involved in this meta-analysis. Overall, the HLA-G 14bp ins/del polymorphism was significantly associated with SLE susceptibility (ins vs. del: OR = 1.179, 95%CI = 1.037–1.341, P = 0.012; ins/ins vs. del/del: OR = 1.394, 95%CI = 1.153–1.684, P = 0.001; ins/del vs. del/del: OR = 1.199, 95%CI = 1.041–1.382, P = 0.012; ins/ins + ins/del vs. del/del: OR = 1.252, 95%CI = 1.097–1.430, P = 0.001). When stratified by ethnicity, significance was found in Asians (ins/ins vs. del/del: OR = 1.326, 95%CI = 1.001–1.756, P = 0.049) and Caucasians (ins/ins vs. del/del: OR = 1.454, 95%CI = 1.126–1.878, P = 0.004; ins/del vs. del/del: OR = 1.288, 95%CI = 1.051–1.579, P = 0.015; ins/ins + ins/del vs. del/del: OR = 1.340, 95%CI = 1.106–1.623, P = 0.003). Our results suggest that the HLA-G 14bp insertion allele might act as an increased risk against SLE. Besides, this is the first meta-analysis to report an association between the HLA-G 14bp ins/del polymorphism and SLE. Larger and well-designed studies are needed to further confirm these findings.     

Meta-analysis of FKBP5 gene polymorphisms association with treatment response in patients with mood disorders

The aim of our study was to assess the association between FKBP5 gene polymorphisms and treatment response in patients with mood disorders using a meta-analysis. Eight separate studies that included data from 2199 subjects were identified. Meta-analysis was performed for three FKBP5 gene polymorphisms (rs1360780, rs3800373, and rs4713916). A significant association of FKBP5 gene rs4713916 polymorphism and response rate was found in patients with mood disorders (Overall: A versus G: OR = 1.28, 95%CI = 1.06–1.53, P = 0.01; GA + AA versus GG: OR = 1.32, 95%CI = 1.05–1.67, P = 0.02. Caucasian: A versus G: OR = 1.28, 95%CI = 1.06–1.55, P = 0.01; GA + AA versus GG: OR = 1.33, 95%CI = 1.04–1.70, P = 0.02). However, we did not detect the association between FKBP5 gene rs1360780 and rs3800373 polymorphisms and treatment response in patients with mood disorders (P > 0.05). This meta-analysis demonstrates that treatment response in patients with mood disorders is associated with FKBP5 gene rs4713916 polymorphism, but not rs1360780 and rs3800373.     

Toll-like receptor 6 gene polymorphisms increase the risk of bovine tuberculosis in Chinese Holstein cattle

Our present study aimed to investigate the effect of four SNPs (G1793A, C1859A, A1980G, G1934A) in toll-like receptor 6 (TLR6) on bovine tuberculosis (bTB) resistance in a case–control study. A total of 603 Chinese Holstein cattle (264 from a dairy farm of Henan province, 339 from Hubei province) were selected to analyze the genotype of TLR6 gene by PCR-RFLP. Genotype frequencies of C1859A and A1980G site differed significantly between bTB-infected and non-infected cows (χ² = 6.062, P = 0.048 and χ² = 6.749, P = 0.034, respectively). Relative risk of tuberculosis incidence result showed that genotypes of AA or CA had greater relative risk (OR = 2.730, 95%CI = 0.869–8.573; OR = 1.547, 95CI% = 0.803–2.982, respectively) than those with genotype CC at C1859A site between bTB-infected and non-infected animals. Genotypes of GG or GA had greater relative risk (OR = 2.986, 95%CI = 1.245–7.165; OR = 1.582, 95%CI = 0.734–3.409, respectively) than those with genotype AA at A1980G site. No significant association can be inferred from G1793A and G1934A polymorphism site. The present study suggests that variants in the TLR6 gene are associated with susceptibility to bTB and the TLR6 gene may be considered as a candidate gene for bTB resistance.     

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

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

Role of the early short-course corticosteroids treatment in ARDS caused by COVID-19: A single-center,retrospective analysis

PurposeSevere coronavirus disease 2019 (COVID-19) is strongly related to interstitial pneumonia with frequent development of acute respiratory distress syndrome (ARDS). The role of corticosteroids (CS) treatment in these patients is still controversial. Some studies evidenced a possible role of an early short-term course of CS treatment in the treatment of severe pneumonia.Patients and methodsThis is a single-center, retrospective study considering the patients with confirmed COVID-19 pneumonia admitted to our hospital between 9th March and 15^th June 2020. Two groups were considered: early high-dose of methyl-prednisolone (eHDM; n ​= ​31) and the control group (n ​= ​52). Patients in the eHDM group received the dose of 5-8 ​mg/kg/day of methyl-prednisolone for 2 consecutive days. Primary outcome was the mortality evaluation; secondary outcomes were clinical improvement, side-effects and laboratory/radiographic changes.ResultsSignificant differences between the two groups were: length of hospitalization (21.5 vs 28.4 days, p ​= ​0.026), length of non-invasive ventilation (NIV) or mechanical ventilation (11.5 vs 14.5 days, p ​= ​0.031), death (5 vs 12, p ​= ​0.006) and clinical improvement (16 vs 11, p=0.018). The following factors were related to in-hospital mortality in the multivariate analysis: comorbidities (OR ​= ​2.919; 95%CI ​= ​1.515-16.705; p<0.001), days from the onset of symptoms and the hospital admission (OR ​= ​1.404; 95%CI ​= ​1.069-12.492; p ​= ​0.011), PaO₂/FiO₂ (P/F) ratio (OR ​= ​3.111; 95%CI ​= ​2.334-16.991; p ​= ​0.009) and eHDM treatment (OR ​= ​0.741; 95%CI ​= ​0.129-0.917; p ​= ​0.007).ConclusionThe eHDM is an interesting and promising approach in the ARDS related to COVID-19 pneumonia, which reduces mortality, length of hospitalization and the need for mechanical ventilation.     

No association between IL-1RN VNTR and the risk of duodenal ulcer: A meta-analysis

The aim of this study was to perform a meta-analysis to investigate a more authentic association between interleukin-1 RN variable number of tandem repeats (IL-1RN VNTR) and duodenal ulcer (DU). Systematic searches of electronic databases Embase, PubMed and Web of Science were performed. Statistical analyses were conducted using software Stata 11.0. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were applied. Publication bias was tested by Begg’s funnel plot and Egger’s regression test. A total of 16 studies including 2115 cases and 3622 controls were included in our final meta-analysis. There was no evidence of significant association between IL-1RN VNTR and DU (allelic model: OR = 1.04, 95%CI = 0.87–1.26; additive model: OR = 0.85, 95%CI = 0.62–1.16; dominant model: OR = 1.06, 95%CI = 0.92–1.23; and recessive model: OR = 0.83, 95%CI = 0.61–1.12). Significant protective associations were found in additive model (OR = 0.51, 95%CI = 0.31–0.83) and recessive model (OR = 0.45, 95%CI = 0.28–0.73) in Caucasian subgroup. In conclusion, our meta-analysis suggests that there is no evidence of significant association between IL-1RN VNTR and DU with or without Helicobacter pylori infection in overall population, whereas significant association is found by subgroup analyses which showed protective effect of IL-1RN allele 2 against DU risk in Caucasian population.     

No association between IL-1β −31 C/T polymorphism and the risk of duodenal ulcer: A meta-analysis of 3793 subjects

The aim of this study was to perform a meta-analysis to investigate a more authentic association between IL-1β −31 C/T polymorphism and duodenal ulcer (DU). Systematic searches of electronic databases Embase, PubMed and Web of Science were performed. Study selection, data abstraction and study quality evaluation were independently conducted in duplicate. Statistical analyses were conducted using software Stata 11.0. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were applied. Publication bias was tested by Begg’s funnel plot and Egger’s regression test. A total of 12 studies including 1151 cases and 2642 controls were included in our final meta-analysis. There was no evidence of significant association between IL-1β −31 C/T polymorphism and DU (allelic model: OR = 0.96, 95%CI = 0.86–1.07; additive model: OR = 0.85, 95%CI = 0.67–1.07; dominant model: OR = 0.95, 95%CI = 0.81–1.13; and recessive model: OR = 0.95, 95%CI = 0.79–1.15). Significant association was found in additive model for PB subgroup (OR = 0.65, 95%CI = 0.44–0.96) and recessive model for non-Asian subgroup (OR = 0.72, 95%CI = 0.52–0.99). In conclusion, our meta-analysis suggested that there was no evidence of significant association between IL-1β −31 C/T polymorphism and DU with or without Helicobacter pylori infection in overall population, whereas significant association was found by subgroup analyses which showed protective effect of C/C genotype against DU risk.     

Genetic estrogen receptor alpha gene PvuII polymorphism in susceptibility to knee osteoarthritis in a Chinese Han population: A southern Jiangsu study

BackgroundKnee osteoarthritis (KOA) is the most prevalent type of arthritis and genetic factors play an important role in KOA pathogenesis. Some studies have reported the association of estrogen receptor alpha (ESRα) gene polymorphism and KOA susceptibility in different populations. This study was designed to verify whether ESRα gene polymorphism (rs2234693) was associated with primary KOA in a Chinese Han population living in the south of Jiangsu.MethodsA case–control association study on single nucleotide polymorphism (SNP) rs2234693 was performed, and a total of 1953 subjects (1033 OA cases and 920 controls) were genotyped. Allele and genotype frequencies were compared between KOA cases and control participants.ResultsSNP rs2234693 was significantly associated with KOA in the dominant genetic model (TT + TC vs. CC) in all the subjects (odds ratio (OR) = 1.30; 95% confidence interval (CI) = 1.02–1.66; P = .03), and T allele frequency was also higher compared with allele C (OR = 1.38; 95% CI = 1.06–1.80; P = .02). After stratification by gender, there was no evident difference between the two groups in female and male subjects (P > .05). With a stratification for KOA severity, the combined genotype (TT + TC) (OR = 1.47; 95% CI = 1.12–1.94; P < .01) and T allele (OR = 1.61; 95% CI = 1.19–2.19; P < .01) were evidently associated with mild KOA, but not with severe KOA.ConclusionsESRα gene is of considerable importance in the pathogenesis of early-stage KOA in a Chinese Han population living in southern Jiangsu.     

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

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

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

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

Association of HLA class II (-DRB1,-DQB1,-DPB1) alleles and haplotypes on susceptibility to aplastic anemia in northern Chinese Han

The Human Leukocyte Antigen (HLA) genes, playing key roles in mediating the immune response, especially HLA class II alleles were suggested to play a role in the activation of autoreactive T-cells in aplastic anemia (AA). Previous studies in different ethnic groups have indicated that some of HLA-A,-B,-DRB1 alleles had a protective or susceptive association with the prevalence, pathogenesis and development of AA. HLA class II genes, especially HLA-DQB1 and -DPB1 alleles or haplotypes at high-resolution level associated with AA have not been fully identified in northern Chinese Han populations. The aim of this study was to identify association of the variations in HLA class II region with AA in northern Chinese Han population. A recent case-control study, including 96 AA patients and 824 healthy controls was performed. The high-resolution HLA genotyping was conducted by PCR-SBT, -SSO and NGS-ION S5^TM platform. Based on genotypic data of the three loci, haplotype estimation was carried out. HLA-DRB1*15:01 (Pc = 2.87 × 10^-3; OR = 2.11, 95% CI = 1.45–3.07) and HLA-DQB1*06:02 (Pc = 1.86 × 10^-2; OR = 2.01, 95% CI = 1.32–3.06) were the risk and predisposition alleles to AA in northern Chinese Han after considering multiple testing. Moreover, the HLA-DRB1*15:01-DQB1*06:02 (Pc = 4.90 × 10^-3; OR = 2.09, 95% CI = 1.37–3.19) and HLA-DRB1*14:05-DQB1*05:03 (Pc = 2.65 × 10^-2; OR = 2.82, 95%CI = 1.45–5.50) haplotypes had direct strong relevance to AA and were the susceptible haplotypes. HLA-DPB1 alleles and 23 polymorphic amino acid residues spanning exon 2 ~ 4 of DPβ1 molecules have showed no statistically significant associations between AA and controls. The present findings establish a novel link between inherited HLA-DRB1,-DQB1,-DPB1 risk alleles and haplotypes in northern Chinese Han with AA, and open new avenues for development of targeted therapies to prevent or redirect immunopathology in AA.     

Association of ADIPOQ polymorphisms with obesity risk: A meta-analysis

Background

The association between ADIPOQ polymorphisms and the risk of obesity remains controversial. We perform a comprehensive meta-analysis to clarify the current understanding of this association.

Methods

We searched for relevant studies in PubMed, Embase and Cochrane library before February 2014. The strengths of the association between ADIPOQ polymorphisms and obesity risk were estimated by odds ratios (OR) with 95% confidence intervals (CI).

Results

Eighteen case–control studies analyzing four SNPs (rs17300539, rs266729, rs1501299 and rs2241766) of ADIPOQ gene were eligible for the present meta-analysis. The pooling results showed that rs17300539 (2GG+GA vs. 2AA+GA: OR = 0.78, 95%CI = 0.69–0.89) and rs1501299 (2GG+GA vs. 2AA+GA: OR = 0.89, 95%CI = 0.80–0.98) were associated with obesity risk in Caucasian ethnicity. The rs266729 were associated with obesity risk in Asian ethnicity (2CC+CG vs. 2GG+GCG: OR = 0.77, 95%CI = 0.65–0.92). However, there were no associations between rs2241766 and the obesity risk (P > 0.05). No publication bias was found among these studies (all P > 0.05).

Conclusions

This study suggests that ADIPOQ rs17300539 and rs1501299 are associated with risk of obesity in Caucasian ethnicity, and the rs266729 is associated with obesity risk in Asian ethnicity. However, there is no association between rs2241766 and obesity risk.     

Serum anti-inflammatory and inflammatory markers have no causal impact on telomere length: a Mendelian randomization study

IntroductionThe relationship between inflammatory and anti-inflammatory markers and telomere length (TL), a biological index of aging, is still poorly understood. By applying a 2-sample Mendelian randomization (MR), we investigated the causal associations between adiponectin, bilirubin, C-reactive protein (CRP), leptin, and serum uric acid (SUA) with TL.Material and methodsMR was implemented by using summary-level data from the largest ever genome-wide association studies (GWAS) conducted on our interested exposure and TL. Inverse variance weighted method (IVW), weighted median (WM)-based method, MR-Egger, MR-Robust Adjusted Profile Score (RAPS), and MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied. Sensitivity analysis was conducted using the leave-one-out method.ResultsWith regard to adiponectin, CRP, leptin, and SUA levels, we found no effect on TL for all 4 types of tests (all p > 0.108). Results of the MR-Egger (p = 0.892) and IVW (p = 0.124) showed that bilirubin had no effect on telomere maintenance, whereas the results of the WM (p = 0.030) and RAPS (p = 0.022) were negative, with higher bilirubin concentrations linked to shorter TL. There was a low likelihood of heterogeneity for all the estimations, except for bilirubin (IVW p = 0.026, MR Egger p = 0.018). MR-PRESSO highlighted no outlier. For all the estimations, we observed negligible intercepts that were indicative of low likelihood of the pleiotropy (all p > 0.161). The results of leave-one-out method demonstrated that the links are not driven because of single nucleotide polymorphisms (SNPs).ConclusionsOur results highlight that neither the anti-inflammatory nor pro-inflammatory markers tested have any significant causal effect on TL. The casual role of bilirubin on TL still needs to be investigated.     

Omega-6 fatty acids and the risk of cardiovascular disease: insights from a systematic review and meta-analysis of randomized controlled trials and a Mendelian randomization study

IntroductionOmega-6 polyunsaturated fatty acids (PUFAs) represent almost 15% of the total energy intake in Western countries. Their effects on the cardiovascular (CV) risk factors are still controversial. Thus, we performed a systematic review and meta-analysis of randomized control trials (RCTs) as well as a Mendelian randomization (MR) analysis to evaluate the links and possible causality between supplementation or serum levels of omega-6 PUFA, CV disease (CVD) and cardiometabolic risk factors.Material and methodsSelected databases were searched until September 2019 to identify prospective studies investigating the effects of omega-6 PUFA supplementation on CVD events/mortality. Random-effects model meta-analysis was performed for quantitative data synthesis. Trial sequential analysis (TSA) was used to evaluate the optimal sample size to detect a 20% reduction in outcomes after administration of omega-6 PUFAs. The inverse variance weighted (IVW) method, weighted median-based method, MR-Egger and MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied for MR.ResultsThe pooled estimate risk ratio (RR) of omega-6 PUFA supplementation was 0.94 for any CVD event (95% CI: 0.77–1.15, I² = 66.2%), 1.06 for CVD death (95% CI: 0.73–1.55, I² = 66.2%), 0.84 for coronary heart disease (CHD) events (95% CI: 0.61–1.16, I² = 79.4%), 0.87 for myocardial infarction (MI) (95% CI: 0.74–1.01, I² = 2.3%) and 1.36 for stroke (95% CI: 0.45–4.07, I² = 55.3%). In contrast, MR showed that individuals with higher serum omega-6 acid – adrenic acid (AA) levels had a greater risk for CHD events (IVW β = 0.526), MI (IVW β = 0.606) and large artery stroke (IVW β = 1.694), as well as increased levels of fasting blood glucose (FBG) (IVW β = 0.417), low-density lipoprotein cholesterol (LDL-C) (IVW β = 0.806), high-density lipoprotein cholesterol (HDL-C) (IVW β = 0.820), and lower levels of triglycerides (TG) (IVW β = –1.064) and total cholesterol (TC) (IVW β = –1.064).ConclusionsOmega-6 PUFA supplementation did not affect the risk for CVD morbidity and mortality. Additionally, based on MR analysis we found that higher AA levels might even significantly increase the risk of CHD, MI and large artery stroke, as well as the levels of FBG and LDL-C, whereas they were negatively associated with TC and TG. Since a considerable chance of heterogeneity was observed for some of the results, further research is needed to elucidate the effects of omega-6 PUFAs on cardiometabolic outcomes.     

Prenatal and perinatal factors associated with developing multiple sclerosis later in life: A systematic review and meta-analysis

ObjectiveBoth genetic and environmental factors play roles in Multiple Sclerosis (MS) etiopathogenesis. The relationship between prenatal/perinatal factors/exposures and future MS occurrence in the offspring remains controversial. Here, we aimed to review the available evidence on prenatal/perinatal factors associated with later MS occurrence.MethodWe performed systematic search of PubMed, Web of Science, and Scopus from inception to October 2020. We included original observational studies conducted on human participants addressing the association between prenatal/perinatal factors and MS occurrence. Data were extracted according to the PRISMA guideline. The adjusted odds ratio (OR) with 95% confidence interval (CI) was considered as the desired effect size. The heterogeneity was evaluated by Cochran's Q and I² and the publication bias was assessed. We excluded gestational/neonatal vitamin D level, season of birth, and latitude because of recently published systematic reviews/meta-analyses on these subjects.ResultsOverall, 2306 records were identified in the primary search. After excluding irrelevant studies, we evaluated 34 studies with contributing data on 100 prenatal/perinatal factors associated with an increased or decreased risk of MS occurrence. In the meta-analyses, we found no statistically significant associations between later MS occurrence in offspring and prenatal smoking exposure (OR = 1.01, 95% CI = 0.77–1.34), mode of delivery (OR = 0.90, 95% CI = 0.52–1.56), birth order (OR = 0.85, 95% CI = 0.72–1.00), and maternal age (OR = 1.34, 95% CI = 0.88–2.04). Paternal age and parents' marital status at the time of childbirth, maternal preeclampsia/ toxemia, forceps use, birth weight, plurality, and preterm birth were the other most studied factors, and none reported to affect MS risk.ConclusionWe found that prenatal smoking exposure, mode of delivery, birth order, and maternal age do not affect risk of future MS development. Moreover, most of the other investigated factors were reported not to affect MS risk in the offspring.     

Association of osteopontin polymorphisms with nasopharyngeal carcinoma risk

No previous study has reported the association of osteopontin polymorphisms with nasopharyngeal carcinoma (NPC) risk. We aimed to investigate the association in a Chinese population. Four variants of osteopontin, rs11730582, rs1126772, rs9138, and rs4754 polymorphisms, were assessed in a case-control study which consists of 108 NPC patients and 210 health controls, by using polymerase chain reaction – restriction fragment length polymorphism method. Serum osteopontin levels were measured by enzyme-linked immunosorbent assay. The serum osteopontin levels were significantly higher in NPC patients than those in controls (P < 0.01). Carriers of CC and CT genotype of rs11730582 presented lower serum osteopontin levels than those of TT genotype carriers (P < 0.05). Genotypes CT and CT + CC of rs11730582 were associated with the risk of NPC (CT:OR = 0.57, 95%CI = 0.34–0.94; CC + CT:OR = 0.54, 95%CI = 0.34–0.87). Haplotype analysis revealed that haplotype T-A-A-C of rs11730582, rs1126772, rs9138, and rs4754 was associated with NPC risk (OR = 0.49, 95%CI = 0.27–0.86). Stratification analysis showed that genotypes CT and CT + CC of rs11730582 were associated with tumor stage and lymph node metastasis (P < 0.05). No associations were found between rs1126772, rs9138, and rs4754 polymorphisms and NPC risk (P > 0.05). The variant rs11730582 of osteopontin is associated with NPC risk. It potentially serves as a genetic marker of NPC predisposition.     

Immune checkpoint inhibitors therapies in patients with cancer and preexisting autoimmune diseases: A meta-analysis of observational studies

IntroductionImmune checkpoints inhibitors (ICIs) are associated with frequent immune-related adverse events (irAEs), but patients with preexisting autoimmune disease (PAD) have been excluded from clinical trials, leaving serious gaps in knowledge.ObjectiveTo evaluate the safety and efficacy of ICIs in PAD patients and cancer and explore the impact of different PAD types and baseline receiving immunosuppressive therapy.MethodsSystematic searches were performed of PubMed, EMBASE, and the Cochrane library from inception through August 2019 for observational studies reporting safety and efficacy data among ICI-treated patients with cancer and PAD.Results619 ICI-treated patients with PAD in 14 publications were finally identified. In the random-effects meta-analysis, pooled incidence of PAD flares, de novo immune-related adverse events (irAEs) or both of any grade was 60% (95%CI = 52%–68%). Separately, there were 219 and 206 patients experiencing PAD exacerbation and de novo irAEs of any grade, yielding a pooled incidence of 35% (95%CI = 29%–41%) and 33% (95%CI = 24%–42%) respectively. Rheumatoid arthritis was associated with a trend toward higher flare occurrence compared with another individual PADs (RR = 1.25–1.88). A total of 136 patients showed complete or partial response, corresponding to a pooled response rates of 30% (95%CI = 22%–39%). There were no statistical differences between patients with and without immunosuppressive therapy at ICI start regarding flare (RR = 1.08, 95%CI = 0.72–1.62), but a trend toward lower response rates was observed in patients with baseline immunosuppressants (RR = 0.58, 95%CI = 0.26–1.33).ConclusionsImmune toxicities are frequent in ICI-treated patients with PAD but often mild and manageable without discontinuing therapy. ICI treatment are also effective in PAD patients, but close monitoring and multidisciplinary collaboration should be contemplated, especially for those concomitantly receiving immunosuppressant or having rheumatoid arthritis.