Susceptibility of TSPAN5 polymorphisms to Kawasaki disease and immunoglobulin therapy resistance in southern Chinese children.

Kawasaki disease (KD) is a condition characterized by acute multi-system vasculitis and high fever in infants and children. Intravenous immunoglobulin (IVIG) is the established therapeutic approach of KD,foralleviating inflammation and mitigate the risk of arterial wall dilation and the development of coronary artery aneurysms (CAA). But almost 20% of the patients developed resistance to IVIG and displayed persistent fever after standard primary treatment. TSPAN5, belonging to the Tetraspanin family, has been demonstrated to modulate innate immunity in a range of human diseases. It accomplishes this by engaging with integrins and actively participating in the process of infection recognition. However, its relevance to susceptibility and IVIG therapy response of KD was unexposed. In the present study, our Integrative analysis of KD transcriptomic data and GTEx data revealed that the eQTL rs12504972 might modify the downregulation of TSPAN5 in KD patients. Moreover, our findings suggest a potential association between TSPAN5/rs12504972 and an elevated susceptibility as well as IVIG resistance among patients with Kawasaki disease in southern China. The results provided a new insight that TSPAN5 triggered KD susceptibility and resistance of IVIG therapy on the genomic level.

LncRNA FIRRE regulated endometrial cancer radiotherapy sensitivity via the miR-199b-5p/SIRT1/BECN1 axis-mediated autophagy.

BACKGROUND: Endometrial cancer (EC) poses a serious threat to women's health. Radiotherapy has been widely used for EC treatment. However, the mechanism of FIRRE in EC development and radioresistance remains unknown. METHODS: MTT and colony formation assays determined cell proliferation. The degree of autophagy was tested by the measurement of autophagy-related genes and immunofluorescence staining of LC3. Molecular interactions were demonstrated via luciferase reporter assay, RIP, and Co-IP. The FIRRE role's was analyzed by in vivo xenograft tumor model. RESULTS: FIRRE and SIRT1 were upregulated in EC tumor tissues, whereas miR-199b-5p was reduced. FIRRE knockdown increased EC cell radiotherapy sensitivity by sponging miR-199b-5p and inhibiting autophagy. SIRT1 was targeted and negatively regulated by miR-199b-5p. SIRT1 could otherwise deacetylate BECN1 protein and participate in FIRRE-mediated autophagy. Silencing FIRRE increased sensitivity of EC radiotherapy in vivo. CONCLUSION: FIRRE reduced EC cell radiotherapy sensitivity by stimulating autophagy via miR-199b-5p/SIRT1/BECN1 axis.

Association of living environmental and occupational factors with semen quality in chinese men: a cross-sectional study.

Sperm quality can be easily influenced by living environmental and occupational factors. This study aimed to discover potential semen quality related living environmental and occupational factors, expand knowledge of risk factors for semen quality, strengthen men's awareness of protecting their own fertility and assist the clinicians to judge the patient's fertility. 465 men without obese or underweight (18.5 < BMI < 28.5 kg/m2), long-term medical history and history of drug use, were recruited between June 2020 to July 2021, they are in reproductive age (25 < age < 45 years). We have collected their semen analysis results and clinical information. Logistic regression was applied to evaluate the association of semen quality with different factors. We found that living environment close to high voltage line (283.4 × 106/ml vs 219.8 × 106/ml, Cohen d = 0.116, P = 0.030) and substation (309.1 × 106/ml vs 222.4 × 106/ml, Cohen d = 0.085, P = 0.015) will influence sperm count. Experienced decoration in the past 6 months was a significant factor to sperm count (194.2 × 106/ml vs 261.0 × 106/ml, Cohen d = 0.120, P = 0.025). Living close to chemical plant will affect semen PH (7.5 vs 7.2, Cohen d = 0.181, P = 0.001). Domicile close to a power distribution room will affect progressive sperm motility (37.0% vs 34.0%, F = 4.773, Cohen d = 0.033, P = 0.030). Using computers will affect both progressive motility sperm (36.0% vs 28.1%, t = 2.762, Cohen d = 0.033, P = 0.006) and sperm total motility (57.0% vs 41.0%, Cohen d = 0.178, P = 0.009). After adjust for potential confounding factors (age and BMI), our regression model reveals that living close to high voltage line is a risk factor for sperm concentration (Adjusted OR 4.03, 95% CI 1.15-14.18, R2 = 0.048, P = 0.030), living close to Chemical plants is a protective factor for sperm concentration (Adjusted OR 0.15, 95% CI 0.05-0.46, R2 = 0.048, P = 0.001) and total sperm count (Adjusted OR 0.36, 95% CI 0.13-0.99, R2 = 0.026, P = 0.049). Time spends on computer will affect sperm total motility (Adjusted OR 2.29, 95% CI 1.11-4.73, R2 = 0.041, P = 0.025). Sum up, our results suggested that computer using, living and working surroundings (voltage line, substation and chemical plants, transformer room), and housing decoration may association with low semen quality. Suggesting that some easily ignored factors may affect male reproductive ability. Couples trying to become pregnant should try to avoid exposure to associated risk factors. The specific mechanism of risk factors affecting male reproductive ability remains to be elucidated.

Whole-Exome Sequencing for Identification of Potential Sex-Biased Variants in Kawasaki Disease Patients.

Kawasaki disease (KD) is an autoimmune disease of unknown etiology and has become a main cause of childhood acquired heart disease. KD is more prevalent in males than in females. The reason for this sex bias is unknown. Here, we used whole-exome sequencing (WES) to identify significantly different variants between male and female KD patients. From WES result, a total of 19,500 shared genetic variants in 8421 genes were captured via a series of filters. Further comparisons based on sex were performed to obtain 34 potential sex-biased variants in 34 genes for GO and Reactome Gene Sets enrichment analyses. Moreover, we selected 6 variants associated with immune, cells adhesion, platelet function, homeostasis, and ion channel signaling and expanded the sample size (1247 KD patients containing 713 males and 534 females, 803 healthy population containing 481 males and 322 females) for genotyping validation. From the results, USH2A/rs148135241, LMO7/rs142687160, CEMIP/rs12441101, and EFCC1/rs142391828 presented significant differences of alleles/genotypes frequency distributions between male and female only in KD patients (which were consistent with the result of WES analysis) but not in healthy population. In addition, the result also found that only EFCC1/rs142391828 polymorphism was associated with KD susceptibility. This result suggested that those four variants might play critical roles in sex bias in KD. The study would be in favor of a sex-specific genome atlas establishing and novel sex-specific precision therapies development for KD.

Thymic stromal lymphopoietin induces platelet mitophagy and promotes thrombosis in Kawasaki disease.

Kawasaki disease (KD) is an acute systemic vasculitis primarily affecting infants and children. Activated platelets predispose patients to coronary artery structural lesions that may lead to thrombotic cardiovascular events. To discover potential proteins underlying platelet activation in KD, we conducted a protein chip assay of 34 cytokines and discovered thymic stromal lymphopoietin (TSLP) was aberrantly expressed, which remained elevated after intravenous immunoglobulin G (IVIG) treatment and during convalescence in KD patients in comparison to healthy controls. Enzyme-linked immunosorbent assay (ELISA) corroborated the upregulation of TSLP in KD patients, which was exacerbated in convalescent patients complicated with thrombosis. TSLP receptors on platelets were also significantly upregulated in KD patients complicated with thrombosis. Platelet activation, apoptosis, and mitochondrial autophagy (mitophagy) were increased in convalescence KD patients complicated with thrombosis. In vitro, TSLP induced platelet activation and platelet mitophagy in healthy blood donors, as observed in KD patients. TSLP, similar to mitophagy agonist carbonyl cyanide 3-chlorophenyl hydrazone (CCCP), promoted thrombosis, which was attenuated by the mitophagy inhibitor Mdivi-1. Co-immunoprecipitation in TSLP-treated platelets revealed TSLP receptor (TSLPR) bound to mitophagy regulators, Parkin and Voltage Dependent Anion Channel Protein 1 (VDAC1).Thus, our results demonstrated that TSLP induced platelet mitophagy via a novel TSLPR/Parkin/VDAC1 pathway that promoted thrombosis in KD. These results suggest TSLP as a novel therapeutic target against KD-associated thrombosis.

The PTGS1 (rs1330344) CC Genotype Contributes to Susceptibility to Kawasaki Disease in Southern Chinese Children.

Kawasaki disease (KD) is an acute systemic vascular disease complicated by coronary artery injury. Although polymorphisms in prostaglandin-endoperoxide synthase 1 (PTGS1) are being increasingly explored in cardiovascular diseases, little is known regarding the connection between PTGS1 polymorphisms and KD risk. We evaluated 834 KD patients and 1474 healthy controls to explore the relationship between PTGS1 polymorphisms (rs1330344 and rs5788) and KD risk. Our results showed that the rs1330344 CC genotype was significantly associated with KD risk and coronary artery injury in children with KD. In combined analysis, individuals with 1-2 unfavorable genotypes had an increased risk of KD, compared with those with no risk genotype. Stratified analysis indicated that the rs1330344 CC genotype is strongly associated with increased risk of KD in children aged ≤60 months and females. Moreover, carrying 1-2 of these SNP genotypes had a higher risk of KD than those who harbored none of them in children ≤60 months of age and females; the risk of coronary artery dilatations/small aneurysms and medium/giant aneurysms was also significantly increased in KD patients. In summary, the PTGS1 rs1330344 CC genotype is associated with increased susceptibility to KD, which may contribute to KD pathogenesis and serve as a genetic biomarker.

LNC-ZNF33B-2:1 gene rs579501 polymorphism is associated with organ dysfunction and death risk in pediatric sepsis.

Background: Sepsis is a severe systemic reaction disease induced by bacteria and virus invading the bloodstream and subsequently causing multiple systemic organ dysfunctions. For example, the kidney may stop producing urine, or the lungs may stop taking in oxygen. Recent studies have shown that long non-coding RNAs (lncRNAs) are related to the dysfunction of organs in sepsis. This study aims to screen and validate the sepsis-associated lncRNAs and their functional single nucleotide polymorphisms (SNPs). Result: Unconditional multiple logistic regression based on the recessive model (adjusted odds ratio = 2.026, 95% CI = 1.156-3.551, p = 0.0136) showed that patients with the CC genotype of rs579501 had increased risk of sepsis. Stratification analysis by age and gender indicated that patients with the rs579501 CC genotype had higher risk of sepsis among children aged <12 months (adjusted odds ratio = 2.638, 95% CI = 1.167-5.960, p = 0.0197) and in male patients (adjusted odds ratio = 2.232, 95% CI = 1.127-4.421, p = 0.0213). We also found a significant relationship between rs579501 and severe sepsis risk (CC versus AA/AC: adjusted odds ratio = 2.466, 95% CI = 1.346-4.517, p = 0.0035). Stratification analysis for prognosis and number of organ dysfunctions demonstrated that the rs579501 CC genotype increased non-survivors' risk (adjusted odds ratio = 2.827, 95% CI = 1.159-6.898, p = 0.0224) and one to two organs with dysfunction risk (adjusted odds ratio = 2.253, 95% CI = 1.011-5.926, p = 0.0472). Conclusion: Our findings showed that the lnc-ZNF33B-2:1 rs579501 CC genotype increases the susceptibility to sepsis. From the medical perspective, the lnc-ZNF33B-2:1 rs579501 CC genotype could be serving as a biochemical marker for sepsis.

Association between Rab31/rs9965664 polymorphism and immunoglobulin therapy resistance in patients with Kawasaki disease.

Background: Kawasaki disease (KD) is an acute febrile systemic vasculitis affecting infants and young children. A high dose of intravenous immunoglobulin (IVIG) is the first-line strategy for patients with KD to reduce persistent inflammation and the risk of coronary artery aneurysm (CAA) formation. Unfortunately, 10-20% of the patients showed no response to the treatment and were defined as resistant to IVIG. Rab31 has been reported to regulate innate immunity in several human diseases. However, whether single nucleotide polymorphism (SNP) in Rab31 gene could predispose to IVIG therapy response in KD was uncovered. Methods: Rab31/rs9965664 polymorphism was genotyped in 1,024 Chinese patients with KD through TaqMan assay. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association between Rab31/rs9965664 polymorphism and IVIG therapeutic effects. Results: Our results showed that Rab31/rs9965664 AA/GA genotype was significantly associated with an increased risk of IVIG resistance compared to GG genotype (GA vs. GG: p = 0.0249; AA vs. GG: p = 0.0016; AA/GA vs. GG: p = 0.0039; and AA vs. GG/GA: p = 0.0072). Moreover, the KD individuals carrying the rs9965664 A allele displayed lower Rab31 protein levels, and the expression level of Rab31 in the IVIG-resistant group was decreased significantly when compared to that observed in the response group. A mechanical study demonstrated that Rab31 modulated IVIG response through NLRP3 and p38 pathways. Conclusion: These results suggested that Rab31/rs9965664 polymorphism might be associated with an increased risk of IVIG resistance in southern Chinese patients with KD. The possible mechanism is that Rab31 regulates the NLRP3 pathway negatively to inhibit IVIG response.

The Associated of the Risk of IVIG Resistance in Kawasaki Disease with ZNF112 Gene and ZNF180 Gene in a Southern Chinese Population.

Background: Kawasaki disease (KD) was one of the most common primary vasculitis. IVIG resistance was associated with an increased risk of coronary artery aneurysm. Accumulating evidences demonstrated that inflammatory gene polymorphisms might play important roles in IVIG resistance, and zinc finger proteins were closely related to immune inflammation regulation, but the effect of ZNF112/rs8113807 and ZNF180/rs2571051 on IVIG resistance in KD patients has not been reported. Methods: A total of 996 KD patients were recruited, and the assay of TaqMan-real-time polymerase chain reaction was used for ZNF112/rs8113807 and ZNF180/rs2571051 genotyping. Odds ratio (OR) and 95% confidence interval (CI) were calculated for estimating the relationship between the polymorphisms of the both SNPs (ZNF112/rs8113807 and ZNF180/rs2571051) and the risk of IVIG resistance. Results: Both of the ZNF112/rs8113807 CC/TC genotype and the ZNF180/rs2571051 TT/CT genotype increased the risk of IVIG resistance in KD (rs8113807: CC vs TT: adjusted OR = 1.83, 95% CI = 1.06-3.16, p = 0.0293; CC/TC vs TT adjusted: OR = 1.49, 95% CI = 1.10-2.02, p = 0.0094. rs2571051: TT vs CC adjusted: OR = 2.64, 95% CI = 1.62-4.29, p < 0.0001; TT/CT vs CC adjusted: OR = 2.14, 95% CI = 1.37-3.37, p = 0.0009; TT vs CC/CT adjusted: OR = 1.66, 95% CI = 1.22-2.27, p = 0.0014). Furthermore, the combinative analysis of risk genotypes in ZNF112/rs8113807 and ZNF180/rs2571051 showed that patients with two unfavorable genotypes were more likely to increase risk of IVIG resistance than those who carried with zero or one unfavorable genotypes (adjusted: OR = 1.68, 95% CI = 1.24-2.27, p = 0.0008). Conclusion: Our findings enriched the genetic background of IVIG resistance risk in the KD development and suggested that the ZNF112/rs8113807 C-carrier and the ZNF180/rs2571051 T-carrier were associated with increased risk of IVIG resistance in KD patients in Chinese southern population.

The rs8506 TT Genotype in lincRNA-NR_024015 Contributes to the Risk of Sepsis in a Southern Chinese Child Population.

Background: Sepsis is a highly life-threatening heterogeneous syndrome and a global health burden. Studies have shown that many genetic variants could influence the risk of sepsis. Long non-coding RNA lincRNA-NR_024015 may participate in functional alteration of endothelial cell via vascular endothelial growth factor (VEGF) signaling, whereas its relevance between the lincRNA-NR_024015 polymorphism and sepsis susceptibility is still unclear. Methods: 474 sepsis patients and 678 healthy controls were enrolled from a southern Chinese child population in the present study. The polymorphism of rs8506 in lincRNA-NR_024015 was determined using Taqman methodology. Results: Overall, a significant association was found between rs8506 polymorphism and the risk of sepsis disease (TT vs. CC/CT: adjusted OR = 1.751, 95%CI = 1.024-2.993, P = 0.0406). In the stratified analysis, the results suggested that the carriers of TT genotypes had a significantly increased sepsis risk among the children aged 12-60 months, females, early-stage sepsis and survivors (TT vs. CC/CT: ORage = 2.413; ORfemale = 2.868; ORsepsis = 2.533; ORsurvivor = 1.822; adjusted for age and gender, P < 0.05, respectively). Conclusion: Our study indicated that lincRNA-NR_024015 rs8506 TT genotype might contribute to the risk of sepsis in a southern Chinese child population. Future research is required to elucidate the possible immunoregulatory mechanisms of this association and advance the development of novel biomarkers in sepsis.

The EIF2AK4/rs4594236 AG/GG Genotype Is a Hazard Factor of Immunoglobulin Therapy Resistance in Southern Chinese Kawasaki Disease Patients.

Background: Kawasaki disease (KD) is an acute, self-limited vasculitis disorder of unknown etiology in children. Immunologic abnormalities were detected during the acute phase of KD, which reflected that the effect cells of the activated immune system markedly increased cytokine production. High-dose intravenous immunoglobulin (IVIG) therapy is effective in resolving inflammation from KD and reducing occurrence of coronary artery abnormalities. However, 10%-20% of KD patients have no response to IVIG therapy, who were defined as IVIG resistance. Furthermore, these patients have persistent inflammation and increased risk of developing coronary artery aneurysm (CAA). EIF2AK4 is a stress sensor gene and can be activated by pathogen infection. In addition, the polymorphisms of EIF2AK4 were associated with various blood vessel disorders. However, it remains unclear whether the EIF2AK4 gene polymorphisms were related to IVIG therapy outcome in KD patients. Methods: EIF2AK4/rs4594236 polymorphism was genotyped in 795 IVIG response KD patients and 234 IVIG resistant KD patients through TaqMan, a real-time polymerase chain reaction. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association between EIF2AK4/rs4594236 polymorphism and IVIG therapeutic effects. Results: Our results showed that the EIF2AK4/rs4594236 AG/GG genotype was significantly associated with increased risk to IVIG resistance compared to the AA genotype (AG vs. AA: adjusted ORs = 1.71, 95% CIs = 1.17-2.51, and p = 0.0061; GG vs. AA: adjusted ORs = 2.09, 95% CIs = 1.36-3.23, and p = 0.0009; AG/GG vs. AA: adjusted ORs = 1.82, 95% CIs = 1.27-2.63, and p = 0.0013; and GG vs. AA/AG: adjusted ORs = 1.45, 95% CI = 1.04-2.02, and p = 0.0306). Furthermore, the stratified analysis of age and gender in the KD cohort indicated that male patients carrying the rs4594236 AG/GG genotype tends to be more resistant to IVIG therapy than female patients. Conclusion: These results suggested that EIF2AK4/rs4594236 polymorphism might be associated with increased risk of IVIG resistance in southern Chinese KD patients.

The rs7404339 AA Genotype in CDH5 Contributes to Increased Risks of Kawasaki Disease and Coronary Artery Lesions in a Southern Chinese Child Population.

Background: Kawasaki disease (KD) is an acute, self-limited febrile illness of unknown cause. And it predominantly affects children <5 years and the main complication is coronary artery lesion (CAL). Studies demonstrated that vascular endothelial cells (VECs) played a very important role in the CAL of KD. VE-cad encoded by CDH5 may exert a relevant role in endothelial cell biology through controlling the cohesion of the intercellular junctions. The pathogenesis of KD remains unclear and genetic factors may increase susceptibility of KD. However, the relationship between CDH5 polymorphisms and KD susceptibility has not been reported before. The present study is aimed at investigating whether the rs7404339 polymorphism in CDH5 is associated with KD susceptibility and CAL in a southern Chinese child population. Methods and Results: We recruited 1,335 patients with KD and 1,669 healthy children. Each participant had supplied 2 mL of fresh blood in the clinical biologic bank at our hospital for other studies. Multiplex PCR is used to assess the genotypes of rs7404339 polymorphism in CDH5. According to the results, we found significant correlated relationship between rs7404339 polymorphism in CDH5 and KD susceptibility [AA vs. GG: adjusted odds ratio (OR) = 1.43, 95% confidence interval (CI) = 1.00-2.05; p = 0.0493; recessive model: adjusted OR = 1.44, 95% CI = 1.01-2.06, P = 0.0431]. In further stratified analysis, we found that children younger than 60 months (adjusted OR = 1.46, 95% CI = 1.01-2.10; p = 0.0424) and male (adjusted OR = 1.70, 95% CI = 1.09-2.65; p = 0.0203) with the rs7404339 AA genotype in CDH5 had a higher risk of KD than carriers of the GA/GG genotype. Furthermore, stratification analysis revealed that patients with the rs7404339 AA genotype exhibited the significantly higher onset risk for CAL than carriers of the GA/GG genotype (adjusted age and gender odds ratio = 1.56, 95% CI = 1.01-2.41; P = 0.0433). Conclusion: Our results showed that rs7404339 AA genotype in CDH5 is significant associated with KD susceptibility. And children younger than 60 months and male with the rs7404339 AA genotype had a higher risk of KD than carriers with the GA/GG genotype. Furthermore, patients with the rs7404339 AA genotype exhibited a significantly higher risk of CAL complication than carriers of the GA/GG genotype.

Association between the rs3802201 polymorphism of the lncRNA MIR2052HG gene and the risk of recurrent miscarriage in a Southern Chinese population.

BACKGROUND: Plenty of studies have indicated that some genetic polymorphisms of the breast cancer which associated with its susceptibility may also be related to the susceptibility of abortion. MIR2052HG plays an important role in the onset and progression of breast cancer by maintaining the level of ERα, but to the best of our knowledge, the correlation between risk of recurrent abortion and MIR2052HG rs3802201 C>G polymorphism is still unclear. Therefore, we conducted this case-control study to investigate whether MIR2052HG rs3802201 C>G polymorphism is associated with susceptibility of recurrent miscarriage (RM). METHODS: We recruited 392 healthy controls and 248 patients with RM to process this research, the participants were all from southern China, and genotyping was performed by TaqMan method. RESULTS: Our results showed that there was no evidence indicates the MIR2052HG rs3802201 C>G is related to RM (CG and CC: adjusted OR = 0.970, 95% CI = 0.694-1.355, p = 0.8577; GG and CC: adjusted OR = 0.743, 95% CI = 0.416-1.330, p = 0.3174; dominant model: adjusted OR = 0.925, 95% CI = 0.672-1.272, p = 0.6298; recessive model: adjusted OR = 0.751, 95% CI = 0.430-1.321, p = 0.3233). CONCLUSION: We verified that the MIR2052HG rs3802201 C>G allele might be uncorrelated to the RM risk, but these findings require further validation in multicenter studies with larger sample size and different ethnicities.

Association study of miR-149, miR-196a2, and miR-499a polymorphisms with coronary artery aneurysm of Kawasaki disease in southern Chinese population.

BACKGROUND: Accumulating evidence suggests that several microRNA (miRNA) polymorphisms are closely associated with disease susceptibility or progression, such as in Kawasaki disease (KD). Our previous studies revealed the association of miR-149 rs2292832 T>C and miR-196a2 rs11614913 C>T polymorphisms with KD susceptibility. The present study further focused on the relationship between three miRNA polymorphisms (miR-149 rs2292832 T>C, miR-196a2 rs11614913 C>T and miR-499a rs3746444 A>G) and the risk of coronary artery aneurysm (CAA) in southern Chinese KD patients. METHODS: We evaluated 318 KD patients with CAAs and 784 patients without CAAs. TaqMan assays were used to estimate genotyping and analyze the relationship between miRNA polymorphisms (miR-149 rs2292832 T>C, miR-196a2 rs11614913 C>T and miR-499a rs3746444 A>G) and risk associations of CAA by odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We found that the miR-149 rs2292832 TC/CC genotype increased the CAA risk (adjusted OR = 1.53, 95% CI = 1.15-2.03, p = 0.003 for TC, adjusted OR = 1.63, 95% CI = 1.08-2.47, p = 0.021 for CC), whereas the miR-499a rs3746444 AG genotype decreased the CAA risk in KD patients (adjusted OR = 0.33, 95% CI = 0.25-0.45 p ≤ 0.001). Moreover, patients carrying two or three of these single nucleotide polymorphism (SNP) genotypes (rs2292832 TC/CC and rs11614913 TT and rs3746444 AA) had a higher risk for CAA than those who harbored only zero or one of these SNP genotypes. CONCLUSIONS: Our results demonstrated that the miR-149 rs2292832 T>C polymorphism increased the risk of CAA in KD patients and that the miR-499a rs3746444 A>G polymorphism decreased the risk of CAA in KD patients. Further studies with larger sample sizes and different centers are needed to confirm the findings of the present study.

Protective Effect of TNFRSF11A rs7239667 G > C Gene Polymorphism on Coronary Outcome of Kawasaki Disease in Southern Chinese Population.

BACKGROUND: The main symptoms of Kawasaki disease (KD) are inflammatory vasculitis characterized by fever lasting 1-2 weeks, failure to respond to antibiotic treatment, conjunctivitis, redness of the lips and mouth, strawberry tongue, and painless enlargement of the neck lymph nodes. Studies have been shown that tumor necrosis factor (TNF) and TNF receptor family members are abnormally expressed in the acute phase of Kawasaki disease, also revealing that these two play a significant role in the pathogenesis of KD. The purpose of our study is to determine the relationship between TNFRSF11A rs7239667 and the pathogenesis of KD and Coronary artery lesions in KD. METHODS AND RESULTS: In this study, TNFRSF11A (rs7239667) genotyping was performed in 1396 patients with KD and 1673 healthy controls. Our results showed that G > C polymorphism of TNFRSF11A (rs7239667) was not associated with KD susceptibility. In addition, the patients with KD were divided into CAA and NCAA groups according to whether they had coronary artery aneurysm (CAA) or not, and the TNFRSF11A rs7239667 genotyping was performed in the two groups. After gender and age calibration, We found that genotype CC of TNFRSF11A may be a protective factor in KD coronary artery damage (adjusted OR = 0.69 95% CI = 0.49-0.99 P = 0.0429) and is more significant in children with KD ≤ 60 months (adjusted OR = 0.49 95% CI = 0.49-0.93 P = 0.0173). CONCLUSION: Our study suggests that TNFRSF11A rs7239667 G > C polymorphism maybe play a protective gene role for the severity of KD coronary artery injury and is related to age, which has not been previously revealed.

The lncRNA ANRIL Gene rs2151280 GG Genotype is Associated with Increased Susceptibility to Recurrent Miscarriage in a Southern Chinese Population.

BACKGROUND: Genetic factors may play an important role in susceptibility to recurrent miscarriage. Some cardiovascular disease-related candidate genes have been shown to be associated with recurrent miscarriage. Long noncoding RNA ANRIL has been confirmed to be associated with susceptibility to various diseases, such as cardiovascular disease. However, it remains unclear whether the ANRIL gene polymorphism is related to recurrent miscarriage susceptibility. METHODS: Three ANRIL gene polymorphisms (rs2151280, rs1063192 and rs564398) were genotyped in 819 controls and 610 recurrent miscarriage patients through TaqMan real-time polymerase chain reaction. The odds ratios and 95% confidence intervals (CIs) were used to assess the strength of each association. RESULTS: Our results showed that the ANRIL rs2151280 GG genotype was associated with increased susceptibility to recurrent miscarriage (GG vs AA: adjusted OR=1.527, 95% CI=1.051-2.218, p=0.0262; GG vs AG/AA adjusted OR=1.460, 95% CI=1.021-2.089, p=0.0381). By combining the analysis of the risk genotypes in the three SNPs, we found that individuals with 2-3 risk genotypes had a significantly increased risk of recurrent miscarriage compared with those with a 0-1 risk genotype (adjusted OR=1.728, 95% CI=1.112-2.683, p=0.0149). This risk was more significant in subgroups of women less than 35-40 years of age and women with 2-3 miscarriages. CONCLUSION: These results suggested that a specific SNP in the ANRIL gene may be associated with increased susceptibility to recurrent miscarriage in a southern Chinese population.

FNDC1 Polymorphism (rs3003174 C > T) Increased the Incidence of Coronary Artery Aneurysm in Patients with Kawasaki Disease in a Southern Chinese Population.

BACKGROUND: A large number of studies demonstrated that the key to the occurrence and development of Kawasaki disease (KD) is the over-activation of immune cells and the generation of various inflammatory factors, leading to the imbalance of the immune system. Recently, mutations in the FNDC1 gene have been shown to be associated with inflammatory responses. However, there have been no reports on the relationship between FNDC1 gene and KD so far. METHODS: We enrolled 1611 controls and 1459 patients with KD, including 372 patients with coronary artery aneurysm (CAA) and 179 patients with coronary artery lesion (CAL). The relationship between FNDC1 rs3003174 polymorphism and KD with CAA or without CAA was investigated. RESULTS: This study showed no evidence that the association between FNDC1 rs3003174 C>T polymorphism and KD susceptibility was statistically significant (CT versus CC: adjusted odds ratio (OR) =0.897, 95% confidence interval (CI) =0.769-1.045, P=0.162; TT versus CC: adjusted OR=0.995, 95% CI=0.786-1.260, P=0.968; dominant model: adjusted OR=0.916, 95% CI=0.792-1.059, P=0.235; and recessive model: adjusted OR=1.055, 95% CI=0.845-1.316, P=0.638). However, our further stratified analysis in the control and KD group bore out that the incidence of TT genotype of FNDC1 rs3003174 C > T polymorphism was higher than that of CC/CT genotype in KD patients stratified by CAA (adjusted OR=1.437, 95% CI=1.034-1.996, P=0.031). Moreover, a stratified analysis of age and gender in KD patients indicated that the rs3003174 TT genotype increased the risk of CAA formation in aged ≦60 months (CC/CT vs TT: adjusted OR=1.580, 95% CI=1.106-2.259, P=0.012) and male (CC/CT vs TT: adjusted OR=1.653, 95% CI=1.101-2.481, P=0.015) KD patients. CONCLUSION: The results of this study demonstrated that the FNDC1 rs3003174 C>T polymorphism may be a hazard factor in the formation of CAA in KD patients that was not disclosed before.

The SERPINA4 rs2070777 AA Genotype is Associated with an Increased Risk of Recurrent Miscarriage in a Southern Chinese Population.

BACKGROUND: Many inflammation-related gene polymorphisms are associated with susceptibility to recurrent miscarriage. SERPINA4 is involved in inflammation and is associated with susceptibility to a variety of diseases, but its relevance in recurrent miscarriage is unclear. Therefore, this study aimed to investigate the relationship between SERPINA4 gene polymorphisms and susceptibility to recurrent spontaneous abortion. METHODS: Two SERPINA4 polymorphisms were genotyped in 631 patients with recurrent miscarriage and 771 controls by TaqMan real-time polymerase chain reaction, and the strength of each association was evaluated through 95% confidence intervals (CIs) and odds ratios (ORs). RESULTS: The results showed that SERPINA4 rs2070777 AA genotypes were associated with an increased risk of recurrent miscarriage (AA vs AT/TT adjusted OR=1.409, 95% CI=1.032-1.924, P=0.0309), and we also found a significant association between the rs910352 T allele in the SERPINA4 gene and susceptibility to recurrent miscarriage (CT vs CC adjusted OR=1.579, 95% CI=1.252-1.992, P=0.0001; TT vs CC adjusted OR=1.524, 95% CI=1.134-2.049, P=0.0052). The combined analysis of two SNPs of the SERPINA4 gene revealed that carriers with one to two unfavorable genotypes were associated with a higher risk for recurrent miscarriage compared with individuals with no unfavorable genotypes (adjusted OR=1.257, 95% CI=1.019-1.550). Moreover, our study indicates that having one to two unfavorable genotypes is associated with an increased risk of recurrent miscarriage in women 35-40 years of age. CONCLUSION: Our study suggests that SERPINA4 rs2070777AA genotypes might contribute to an increased risk of recurrent miscarriage in a southern Chinese population.

LncRNA SOX2OT rs9839776 Polymorphism Reduces Sepsis Susceptibility in Southern Chinese Children.

BACKGROUND: Sepsis in children is one of the main causes of death in pediatric intensive care units (PICUs); however, the pathogenesis of sepsis is not fully clear. Previous studies revealed that many genetic variations were related to sepsis susceptibility. A long non-coding RNA SOX2 overlapping transcript (SOX2OT) may play a role in mitochondrial homeostasis and antioxidative activity, but the relationship between the lncRNA SOX2OT polymorphism and sepsis susceptibility has not been reported. METHODS: In this study, 474 pediatric sepsis patients and 678 healthy controls were recruited from southern China. After genotyping, the strength of the associations was evaluated through odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The SOX2OT rs9839776 T allele was associated with decreased susceptibility to sepsis in southern Chinese children (TT/CT vs CC adjusted OR = 0.778, 95% CI = 0.610-0.992; P = 0.0431). Moreover, the difference in susceptibility was greater in children of age >60 months (adjusted OR = 0.458, 95% CI = 0.234-0.896; P = 0.0225), survivors (adjusted OR = 0.758, 95% CI = 0.585-0.972; P = 0.0358), males (adjusted OR = 0.655, 95% CI = 0.479-0.894; P = 0.0077) and the sepsis subgroup (adjusted OR = 0.548, 95% CI = 0.343-0.876; P = 0.0120). CONCLUSION: The rs9839776 T allele may contribute to decreased sepsis risk in Chinese children. Future studies with a larger sample size are needed to verify these results.

The rs1051931 G>A Polymorphism in the PLA2G7 Gene Confers Resistance to Immunoglobulin Therapy in Kawasaki Disease in a Southern Chinese Population.

Background: Kawasaki disease (KD) is a common cardiovascular disease in infants and young children, with fever, rash, and conjunctivitis as the main clinical manifestations, which can lead to the occurrence of coronary aneurysms. Intravenous immunoglobulin (IVIG) is the preferred treatment for KD patients, but 10-20% of patients are resistant to IVIG. Lipoprotein-associated phospholipase A 2 (Lp-PLA2) is a potential therapeutic target for coronary atherosclerotic heart disease, and the polymorphism of Phospholipase A2 Group VII (PLA2G7) is closely related to the activity of Lp-PLA2, of which rs1051931 is the strongest. Therefore, the rs1051931 polymorphism may be a predictor of IVIG resistance in KD patients. Methods: A total of 760 KD cases, including 148 IVIG-resistant patients and 612 IVIG-responsive patients, were genotyped for rs1051931 in PLA2G7, we compared the effects of rs1051931 on IVIG treatment in KD patients by odds ratios (OR) and 95% confidence interval (CI). Results: The homozygous mutation AA may be a protective factor for IVIG resistance in KD patients (adjusted OR = 3.47, 95% CI = 1.14-10.57, P = 0.0284) and is more evident in patients with KD aged <60 months (adjusted OR = 3.68, 95% CI = 1.10-12.28, P = 0.0399). Conclusions: The PLA2G7 rs1051931 G>A polymorphism may be suitable as a biomarker for the diagnosis or prognosis of IVIG resistance in KD in a southern Chinese population.