Coronary Artery Disease Risk Variant Dampens the Expression of CALCRL by Reducing HSF Binding to Shear Stress Responsive Enhancer in Endothelial Cells In Vitro.

BACKGROUND: CALCRL (calcitonin receptor-like) protein is an important mediator of the endothelial fluid shear stress response, which is associated with the genetic risk of coronary artery disease. In this study, we functionally characterized the noncoding regulatory elements carrying coronary artery disease that risks single-nucleotide polymorphisms and studied their role in the regulation of CALCRL expression in endothelial cells. METHODS: To functionally characterize the coronary artery disease single-nucleotide polymorphisms harbored around the gene CALCRL, we applied an integrative approach encompassing statistical, transcriptional (RNA-seq), and epigenetic (ATAC-seq [transposase-accessible chromatin with sequencing], chromatin immunoprecipitation assay-quantitative polymerase chain reaction, and electromobility shift assay) analyses, alongside luciferase reporter assays, and targeted gene and enhancer perturbations (siRNA and clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) in human aortic endothelial cells. RESULTS: We demonstrate that the regulatory element harboring rs880890 exhibits high enhancer activity and shows significant allelic bias. The A allele was favored over the G allele, particularly under shear stress conditions, mediated through alterations in the HSF1 (heat shock factor 1) motif and binding. CRISPR deletion of rs880890 enhancer resulted in downregulation of CALCRL expression, whereas HSF1 knockdown resulted in a significant decrease in rs880890-enhancer activity and CALCRL expression. A significant decrease in HSF1 binding to the enhancer region in endothelial cells was observed under disturbed flow compared with unidirectional flow. CALCRL knockdown and variant perturbation experiments indicated the role of CALCRL in mediating eNOS (endothelial nitric oxide synthase), APLN (apelin), angiopoietin, prostaglandins, and EDN1 (endothelin-1) signaling pathways leading to a decrease in cell proliferation, tube formation, and NO production. CONCLUSIONS: Overall, our results demonstrate the existence of an endothelial-specific HSF (heat shock factor)-regulated transcriptional enhancer that mediates CALCRL expression. A better understanding of CALCRL gene regulation and the role of single-nucleotide polymorphisms in the modulation of CALCRL expression could provide important steps toward understanding the genetic regulation of shear stress signaling responses.

A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage.

BACKGROUND: SH2B3 (SH2B adaptor protein 3) is an adaptor protein that negatively regulates cytokine signaling and cell proliferation. A common missense single nucleotide polymorphism in SH2B3 (rs3184504) results in substitution of tryptophan (Trp) for arginine (Arg) at amino acid 262 and is a top association signal for hypertension in human genome-wide association studies. Whether this variant is causal for hypertension, and if so, the mechanism by which it impacts pathogenesis is unknown. METHODS: We used CRISPR-Cas9 technology to create mice homozygous for the major (Arg/Arg) and minor (Trp/Trp) alleles of this SH2B3 polymorphism. Mice underwent angiotensin II (Ang II) infusion to evaluate differences in blood pressure (BP) elevation and end-organ damage including albuminuria and renal fibrosis. Cytokine production and Stat4 phosphorylation was also assessed in Arg/Arg and Trp/Trp T cells. RESULTS: Trp/Trp mice exhibit 10 mmHg higher systolic BP during chronic Ang II infusion compared to Arg/Arg controls. Renal injury and perivascular fibrosis are exacerbated in Trp/Trp mice compared to Arg/Arg controls following Ang II infusion. Renal and ex vivo stimulated splenic CD8+ T cells from Ang II-infused Trp/Trp mice produce significantly more interferon gamma (IFNg) compared to Arg/Arg controls. Interleukin-12 (IL-12)-induced IFNg production is greater in Trp/Trp compared to Arg/Arg CD8+ T cells. In addition, IL-12 enhances Stat4 phosphorylation to a greater degree in Trp/Trp compared to Arg/Arg CD8+ T cells, suggesting that Trp-encoding SH2B3 exhibits less negative regulation of IL-12 signaling to promote IFNg production. Finally, we demonstrated that a multi-SNP model genetically predicting increased SH2B3 expression in lymphocytes is inversely associated with hypertension and hypertensive chronic kidney disease in humans.. CONCLUSIONS: Taken together, these results suggest that the Trp encoding allele of rs3184504 is causal for BP elevation and renal dysfunction, in part through loss of SH2B3-mediated repression of T cell IL-12 signaling leading to enhanced IFNg production.

The role of adiposity, adipokines and polymorphisms of leptin and adiponectin in myelodysplastic syndromes.

The aim of the present study was to investigate the relationship between leptin and adiponectin gene polymorphisms, circulating levels of leptin and adiponectin, adiposity and clinical markers in patients with myelodysplastic syndrome (MDS). This cross-sectional study was conducted with 102 adults and elderly MDS patients and 102 age- and sex-matched controls. Clinical characteristics, co-morbidities, anthropometric data, laboratory evaluation and genetic analysis (polymorphisms -2548G > A/rs7799039 of the LEP gene and +276G > T/rs1501299 of the ADIPOQ gene) were investigated. Serum leptin was higher and adiponectin lower in MDS when compared with controls. There was a significant positive correlation between serum leptin levels and BMI (r = 0·264, P = 0·025), waist circumference (r = 0·235, P = 0·047), body fat percentage (BF %) (r = 0·373, P = 0·001) and the fat mass index (FMI) (r = 0·371, P < 0·001). A lower mean adiponectin was found among patients with high BF %, higher visceral adiposity index and metabolic syndrome. A significant association was found between the AA genotype (mutant) of the LEP polymorphism rs7799039 and male sex and blast excess (≥ 5 %). In addition, a significant association was observed between the TT genotype (mutant) of the ADIPOQ rs1501299 polymorphism and Fe overload. These results demonstrate the importance of a comprehensive and systematic evaluation in patients with MDS in order to identify and control negative factors not related to the disease at an early stage.

[－75 G/A Polymorphism of Apolipoprotein A1 Gene Promoter Region in Normal Pregnant Women and Patients With Gestational Diabetes Mellitus]. / æ­£å¸¸å­•å¦‡åŠå¦Šå¨ ç³–å°¿ç— æ‚£è€ apoA1åŸºå› å¯åŠ¨å­åŒºï¼75 G/Aå¤šæ€æ€§çš„ç ”ç©¶.

Objective: To investigate the －75 G/A single-nucleotide polymorphism in the promoter region of apolipoprotein A1 gene (apoA1) and its association with gestational diabetes mellitus (GDM) in pregnant women and to provide references for the exploration in the molecular genetic basis of GDM. Methods: A total of 626 GDM patients and 1022 normal pregnant women, ie, the controls, were included in the study. The genotyping of apoA1 －75 G/A polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glucose (Glu) were measured by enzymatic methods. Plasma insulin (INS) was measured by chemiluminescence immunoassay. The protein levels of apoA1 and apoB were measured by the turbidimetric immunoassay. Results: Allele frequencies of G and A were 0.718 and 0.282 in the GDM group and 0.713 and 0.287 in the control group, respectively. Distribution of the genotype frequencies was found to be in Hardy-Weinberg equilibrium in both the GDM and control groups. There was no significant difference in the frequencies of alleles G and A and the genotypes of apoA1 －75 G/A polymorphism between the GDM and the control group (P>0.05). In the GDM group, the carriers with the genotype AA were associated with significantly higher levels of TC, HDL-C, and apoA1 than those with genotypes GG and GA did (all P<0.05). After the GDM patients were divided into obese and non-obese subgroups, the genotype-related apoA1 variation was observed only in obese patients, while the genotype-related TC and HDL-C variations were evident in non-obese patients (P<0.05). In the control group, carriers of genotypes AA and GA had higher systolic blood pressure (SBP) and HDL-C than the carriers of genotype GG did (all P<0.05). Carriers of genotypes AA had significantly lower Glu levels than carriers of genotypes GG and GA did (P<0.05). The control subjects were further divided into subgroups according to their body mass index (BMI). Analysis of the subgroups showed that AA carriers were associated with higher SBP levels in the obese control women only, while lower Glu levels were evident in both obese and non-obese control women. Conclusion: These results suggest that －75 G/A polymorphism in the apoA1 gene is not associated with GDM. However, the genetic variation is closed associated with the plasma apoA1, HDL-C, and TC levels in GDM patients and plasma HDL-C, Glu, and SBP levels in the control subjects. The apoA1 variant-associated lipids and SBP variation is BMI dependent in both groups.

Causal Effect of the 25-Hydroxyvitamin D Concentration on Cerebral Small Vessel Disease: A Mendelian Randomization Study.

BACKGROUND: Previous observational studies reported that a lower serum 25-hydroxyvitamin D [25(OH)D] concentration is associated with a higher burden of cerebral small vessel disease (cSVD). The causality of this association is uncertain, but it would be clinically important, given that 25(OH)D can be a target for intervention. We tried to examine the causal effect of 25(OH)D concentration on cSVD-related phenotypes using a Mendelian randomization approach. METHODS: Genetic instruments for each serum 25(OH)D concentration and cSVD-related phenotypes (lacunar stroke, white matter hyperintensity, cerebral microbleeds, and perivascular spaces) were derived from large-scale genome-wide association studies. We performed 2-sample Mendelian randomization analyses with multiple post hoc sensitivity analyses. A bidirectional Mendelian randomization approach was also used to explore the possibility of reverse causation. RESULTS: We failed to find any significant causal effect of 25(OH)D concentration on cSVD-related phenotypes (odds ratio [95% CI], 1.00 [0.87-1.16], 1.01 [0.96-1.07], 1.06 [0.85-1.33], 1.00 [0.97-1.03], 1.02 [0.99-1.04], 1.01 [0.99-1.04] for lacunar stroke, white matter hyperintensity, cerebral microbleeds, and white matter, basal ganglia, hippocampal perivascular spaces, respectively). These results were reproduced in the sensitivity analyses accounting for genetic pleiotropy. Conversely, when we examined the effects of cSVD phenotypes on 25(OH)D concentration, cerebral microbleeds were negatively associated with 25(OH)D concentration (0.94 [0.92-0.96]). CONCLUSIONS: Given the adequate statistical power (>0.8) of the analyses, our findings suggest that the previously reported association between 25(OH)D concentration and cSVD phenotypes might not be causal and partly attributed to reverse causation.

Genetic variation in NFE2L2 is associated with outcome following aneurysmal subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: Nuclear factor erythroid 2-related factor 2 (NRF2; encoded by the NFE2L2 gene) has been implicated in outcome following aneurysmal subarachnoid haemorrhage (aSAH) through its activity as a regulator of inflammation, oxidative injury and blood breakdown product clearance. The aim of this study was to identify whether genetic variation in NFE2L2 is associated with clinical outcome following aSAH. METHODS: Ten tagging single nucleotide polymorphisms (SNPs) in NFE2L2 were genotyped and tested for association with dichotomized clinical outcome, assessed by the modified Rankin scale, in both a discovery and a validation cohort. In silico functional analysis was performed using a range of bioinformatic tools. RESULTS: One SNP, rs10183914, was significantly associated with outcome following aSAH in both the discovery (n = 1007) and validation cohorts (n = 466). The risk of poor outcome was estimated to be 1.33-fold (95% confidence interval 1.12-1.58) higher in individuals with the T allele of rs10183914 (pmeta-analysis  = 0.001). In silico functional analysis identified rs10183914 as a potentially regulatory variant with effects on transcription factor binding in addition to alternative splicing with the T allele, associated with a significant reduction in the NFE2L2 intron excision ratio (psQTL  = 1.3 × 10-7 ). CONCLUSIONS: The NFE2L2 SNP, rs10183914, is significantly associated with outcome following aSAH. This is consistent with a clinically relevant pathophysiological role for oxidative and inflammatory brain injury due to blood and its breakdown products in aSAH. Furthermore, our findings support NRF2 as a potential therapeutic target following aSAH and other forms of intracranial haemorrhage.

Genetic Testing for Hypertriglyceridemia in Academic Lipid Clinics: Implications for Precision Medicine-Brief Report.

BACKGROUND: Severe hypertriglyceridemia is often caused by variants in genes of triglyceride metabolism. These variants include rare, heterozygous pathogenic variants (PVs), or multiple common, small-effect single nucleotide polymorphisms that can be quantified using a polygenic risk score (PRS). The role of genetic testing to examine PVs and PRS in predicting risk for pancreatitis and severity of hypertriglyceridemia is unknown. METHODS: We examined the relationship of PVs and PRSs associated with hypertriglyceridemia with the highest recorded plasma triglyceride level and risk for acute pancreatitis in 363 patients from 3 academic lipid clinics who underwent genetic testing (GBinsight's Dyslipidemia Comprehensive Panel). Categories of hypertriglyceridemia included: normal triglyceride (<200 mg/dL), moderate (200-499 mg/dL), severe (500-999 mg/dL), or very severe (≥1000 mg/dL). RESULTS: PVs and high PRSs were identified in 37 (10%) and 59 (16%) individuals, respectively. Patients with both had increased risk for very severe hypertriglyceridemia compared with those with neither genetic risk factor. Risk for acute pancreatitis was also increased in individuals with both genetic risk factors (odds ratio, 5.1 [P=0.02] after controlling for age, race, sex, body mass index, and highest triglyceride level), but not in individuals with PV or high PRS alone. CONCLUSIONS: The presence of both PV and high PRS significantly increased risk for very severe hypertriglyceridemia and acute pancreatitis, whereas PV or PRS alone only modestly increased risk. Genetic testing may help identify patients with hypertriglyceridemia who have the greatest risk for developing pancreatitis and may derive the greatest benefit from novel triglyceride-lowering therapies.

Association between genetic variants in key vitamin-D-pathway genes and external apical root resorption linked to orthodontic treatment.

This study evaluated the association between single-nucleotide polymorphisms (SNPs) in vitamin-D-related genes and the amount of external apical root resorption linked to orthodontic treatment. One hundred and forty-three individuals were assessed. The amount of external apical root resorption of upper central incisors (EARRinc ) and lower first molars (EARRmol ) were evaluated in radiographs. Seven SNPs were genotyped across four genes including the vitamin D receptor [VDR], group-specific component [GC], cytochrome P450 family 27 subfamily B member 1 [CYP27B1], and cytochrome P450 family 24 subfamily A member 1 [CYP24A1]. Linear regressions were implemented to determine allele-effects on external apical root resorption. Individuals carrying the AA genotype in VDR rs2228570 had a 21% higher EARRmol than those having AG and GG genotypes (95% CI: 1.03,1.40). EARRmol in heterozygous rs2228570, was 12% lower than for homozygotes (95%CI: 0.78,0.99). Participants with the CCG haplotype (rs1544410-rs7975232-rs731236) in VDR had an EARRmol 16% lower than those who did not carry this haplotype. Regarding CYP27B1 rs4646536, EARRinc in participants who had at least one G allele was 42% lower than for homozygotes AA (95%CI: 0.37,0.93). Although these results did not remain significant after multiple testing adjustment, potential associations may still be suggested. Further replication studies are needed to confirm or refute these findings.

[Associations of genetic variations in pyroptosis related genes with acute adverse events in postoperative rectal cancer patients receiving concurrent chemoradiotherapy].

Objective: This study aims to investigate the associations between genetic variations of pyroptosis pathway related key genes and adverse events (AEs) of postoperative chemoradiotherapy (CRT) in patients with rectal cancer. Methods: DNA was extracted from the peripheral blood which was collected from 347 patients before CRT. Sequenom MassARRAY was used to detect the genotypes of 43 haplotype-tagging single nucleotide polymorphisms (htSNPs) in eight pyroptosis genes, including absent in melanoma 2 (AIM2), caspase-1 (CASP1), caspase-4(CASP4), caspase-5 (CASP5), caspase-11 (CASP11), gasdermin D (GSDMD), gasdermin E (GSDME) and NLR family pyrin domain containing 3 (NLRP3). The associations between 43 htSNPs and AEs were evaluated by the odd ratios (ORs) and 95% confidence intervals (CIs) by unconditional logistic regression models, adjusted for sex, age, clinical stage, tumor grade, Karnofsky performance status (KPS), surgical procedure, and tumor location. Results: Among the 347 patients with rectal cancer underwent concurrent CRT with capecitabine after surgery, a total of 101(29.1%) occurred grade ≥ 2 leukopenia. rs11226565 (OR=0.41, 95% CI: 0.21-0.79, P=0.008), rs579408(OR=1.54, 95% CI: 1.03-2.29, P=0.034) and rs543923 (OR=0.63, 95% CI: 0.41-0.98, P=0.040) were significantly associated with the occurrence of grade ≥ 2 leukopenia. One hundred and fifty-six (45.0%) had grade ≥ 2 diarrhea, two SNPs were significantly associated with the occurrence of grade ≥ diarrhea, including CASP11 rs10880868 (OR=0.55, 95% CI: 0.33-0.91, P=0.020) and GSDME rs2954558 (OR=1.52, 95% CI: 1.01-2.31, P=0.050). In addition, sixty-six cases (19.0%) developed grade ≥2 dermatitis, three SNPs that significantly associated with the risk of grade ≥2 dermatitis included GSDME rs2237314 (OR=0.36, 95% CI: 0.16-0.83, P=0.017), GSDME rs12540919 (OR=0.52, 95% CI: 0.27-0.99, P=0.045) and NLRP3 rs3806268 (OR=1.51, 95% CI: 1.03-2.22, P=0.037). There was no significant difference in the association between other genetic variations and AEs of rectal cancer patients (all P>0.05). Surgical procedure and tumor location had great impacts on the occurrence of grade ≥2 diarrhea and dermatitis (all P<0.01). Conclusion: The genetic variants of CASP4, CASP11, GSDME and NLRP3 are associated with the occurrence of AEs in patients with rectal cancer who received postoperative CRT, suggesting they may be potential genetic markers in predicting the grade of AEs to achieve individualized treatment of rectal cancer.

[Influence of rs2587552 polymorphism of DRD2 gene on the effect of a childhood obesity intervention: A prospective, parallel-group controlled trial].

OBJECTIVE: To explore the association between rs2587552 polymorphism (has a strong lin-kage disequilibrium with rs1800497 which had been found in many studies to be related to obesity, r2=0.85) of DRD2 gene and the effect of a childhood obesity intervention in Chinese population, and provide a scientific basis for future personalized childhood obesity intervention based on genetic background. METHODS: From a multi-center cluster randomized controlled trial studying the effect of a childhood obesity intervention, we enrolled 382 children from 8 primary schools (192 and 190 children from intervention and control groups, respectively) in Beijing as study subjects. Saliva was collected and DNA was extracted to detect the rs2587552 polymorphism of DRD2 gene, and the interactions between the gene and study arms on childhood obesity indicators [including body weight, body mass index (BMI), BMI Z-score, waist circumference, hip circumference, waist-to-hip ratio, waist-to-height ratio, and body fat percentage] were analyzed. RESULTS: No association was found between rs2587552 polymorphism and the changes in hip circumference or body fat percentage in the intervention group (P>0.05). However, in the control group, children carrying the A allele at DRD2 rs2587552 locus showed a greater increase in hip circumference and body fat percentage compared with those not carrying A allele (P < 0.001). There were interactions between rs2587552 polymorphism of DRD2 gene and study arms on the changes in hip circumference and body fat percentage (P=0.007 and 0.015, respectively). Compared with the control group, children in the intervention group carrying the A allele at DRD2 rs2587552 locus showed decrease in hip circumference by (-1.30 cm, 95%CI: -2.25 to -0.35, P=0.007) and decrease in body fat percentage by (-1.34%, 95%CI: -2.42 to -0.27, P=0.015) compared with those not carrying A allele. The results were consistent between the dominant model and the additive model (hip circumfe-rence: -0.66 cm, 95%CI: -1.28 to -0.03, P=0.041; body fat percentage: -0.69%, 95%CI: -1.40 to 0.02, P=0.056). No interaction was found between rs2587552 polymorphism and study arms on the changes in other childhood obesity-related indicators (P>0.05). CONCLUSION: Children carrying the A allele at rs2587552 polymorphism of DRD2 gene are more sensitive to intervention and showed more improvement in hip circumference and body fat percentage after the intervention, suggesting that future personalized childhood obesity lifestyle intervention can be carried out based on the rs2587552 polymorphism of DRD2 gene.

The KL genetic polymorphisms Associated with type 2 diabetes Mellitus.

Growing number of research studies have shown that an anti-ageing gene Klotho (KL) is closely associated with Type 2 Diabetes Mellitus (T2DM). In this study, the association is genetically analyzed with single nucleotide polymorphism (SNP) of KL found in T2DM case of an Asian cohort. KL SNP information was obtained from a big database of the Korean Association Resource (KARE) from which 20 KL SNPs were available. Statistical analyses were conducted based on the 3 genetic models, such as additive, dominant, and recessive. Of the 20 KL SNPs, 12 SNPs were found to be significantly associated with T2DM in both of additive and dominant models. Odds ratios of the KL SNPs indicate increased susceptibility to T2DM in additive and dominant models. Significant association of KL with T2DM was further analyzed using imputed KL SNPs from HapMap reference data of the Eastern population. The statistically significant KL SNPs including the imputed SNPs distributed evenly over the KL gene area. The results in this study suggest klotho is a major player in the development of T2DM and the KL SNPs found in the case could be a risk marker of T2DM in the cohort.

Genome-Wide Association Study and Identification of a Protective Missense Variant on Lipoprotein(a) Concentration: Protective Missense Variant on Lipoprotein(a) Concentration-Brief Report.

[Figure: see text].

15-Deoxy-Δ12,14-Prostaglandin J2 Reinforces the Anti-Inflammatory Capacity of Endothelial Cells With a Genetically Determined NO Deficit.

RATIONALE: Fluid shear stress (FSS) maintains NOS-3 (endothelial NO synthase) expression. Homozygosity for the C variant of the T-786C single-nucleotide polymorphism of the NOS3 gene, which solely exists in humans, renders the gene less sensitive to FSS, resulting in a reduced endothelial cell (EC) capacity to generate NO. Decreased bioavailability of NO in the arterial vessel wall facilitates atherosclerosis. Consequently, individuals homozygous for the C variant have an increased risk for coronary heart disease (CHD). OBJECTIVE: At least 2 compensatory mechanisms seem to minimize the deleterious effects of this single-nucleotide polymorphism in affected individuals, one of which is characterized herein. METHODS AND RESULTS: Human genotyped umbilical vein ECs and THP-1 monocytes were used to investigate the role of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) in vitro. Its concentration in plasma samples from genotyped patients with CHD and age-matched CHD-free controls was determined using quantitative ultraperformance LC-MS/MS. Exposure of human ECs to FSS effectively reduced monocyte transmigration particularly through monolayers of CC-genotype ECs. Primarily in CC-genotype ECs, FSS elicited a marked rise in COX (cyclooxygenase)-2 and L-PGDS (lipocalin-type prostaglandin D synthase) expression, which appeared to be NO sensitive, and provoked a significant release of 15d-PGJ2 over baseline. Exogenous 15d-PGJ2 significantly reduced monocyte transmigration and exerted a pronounced anti-inflammatory effect on the transmigrated monocytes by downregulating, for example, transcription of the IL (interleukin)-1ß gene (IL1B). Reporter gene analyses verified that this effect is due to binding of Nrf2 (nuclear factor [erythroid-derived 2]-like 2) to 2 AREs (antioxidant response elements) in the proximal IL1B promoter. In patients with CHD, 15d-PGJ2 plasma levels were significantly upregulated compared with age-matched CHD-free controls, suggesting that this powerful anti-inflammatory prostanoid is part of an endogenous defence mechanism to counteract CHD. CONCLUSIONS: Despite a reduced capacity to form NO, CC-genotype ECs maintain a robust anti-inflammatory phenotype through an enhanced FSS-dependent release of 15d-PGJ2.

Genetic host factors in Helicobacter pylori-induced carcinogenesis: Emerging new paradigms.

Helicobacter Pylori is a gram negative rod shaped microaerophilic bacterium that colonizes the stomach of approximately half the world's population. Infection with c may cause chronic gastritis which via a quite well described process known as Correas cascade can progress through sequential development of atrophic gastritis, intestinal metaplasia and dysplasia to gastric cancer. H. pylori is currently the only bacterium that is classified as a class 1 carcinogen by the WHO, although the exact mechanisms by which this bacterium contributes to gastric carcinogenesis are still poorly understood. Only a minority of H. pylori-infected patients will eventually develop gastric cancer, suggesting that host factors may be important in determining the outcome of H. pylori infection. This is supported by a growing body of evidence suggesting that the host genetic background contributes to risk of H. pylori infection and gastric carcinogenesis. In particular single nucleotide polymorphisms in genes that influence bacterial handling via pattern recognition receptors appear to be involved, further strengthening the link between host risk factors, H. pylori incidence and cancer. Many of these genes influence cellular pathways leading to inflammatory signaling, inflammasome formation and autophagy. In this review we summarize known carcinogenic effects of H. pylori, and discuss recent findings that implicate host genetic pattern recognition pathways in the development of gastric cancer and their relation with H. pylori.

Role of IL-9, IL-2RA, and IL-2RB genetic polymorphisms in coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) is one of the leading causes of disability and death worldwide. Inflammatory cytokines play an essential role in the pathogenesis of CHD. This study aimed to detect the potential association between interleukin (IL)-9, IL-2RA, and IL-2RB variants and CHD in a Han Chinese population. METHODS: This case-control study included 499 CHD patients and 496 healthy controls. Seven single-nucleotide polymorphisms (SNPs) were genotyped to investigate the possible association between the polymorphisms and CHD risk. Interactions between SNPs and CHD risk were analyzed via multifactor dimensionality reduction (MDR). RESULTS: We observed an association between IL­9 rs55692658 (OR = 1.72, p = 0.003) and increased CHD risk. Age-stratified analysis indicated that regardless of the participants' age, IL­9 rs55692658 and IL-2RB rs1573673 contributed significantly to CHD susceptibility (p < 0.05, respectively). Results showed an association between IL­9 rs55692658 and an increased risk for CHD (OR = 2.32, p = 0.003), while IL-2RA rs12722498 was correlated with decreased susceptibility to CHD (OR = 0.54, p = 0.033) in female patients. Furthermore, IL-2RA rs12569923 was related to diabetes risk in CHD patients (OR = 1.50, p = 0.028). The MDR analysis revealed a positive interaction between the SNPs. CONCLUSION: The present study demonstrated that IL­9 rs55692658, IL-2RA rs12569923, IL-2RA rs12722498, and IL-2RB rs3218264 polymorphisms might be related to CHD. The results require validation in larger studies.

Modulatory effect of single nucleotide polymorphism in Xmn1, BCL11A and HBS1L-MYB loci on foetal haemoglobin levels in ß-thalassemia major and Intermedia patients.

OBJECTIVE: To evaluate the influence of certain genetic modifiers on foetal haemoglobin levels in thalassemia major and thalassemia intermedia. METHODS: The cohort study was conducted from November 2018 to August 2019, at Department of Haematology, University of Health Sciences, Lahore and comprised beta thalassemia intermedia and thalassemia major patients who were referred by various healthcare facilities across Punjab, Pakistan. Foetal haemoglobin was quantified by high performance liquid chromatography. Primary mutation analysis and single nucleotide polymorphisms were done by amplification refractory mutation system-based polymerase chain reaction. Data was analysed using SPSS 20. RESULTS: Of the 116 patients, 52(45%) had beta thalassemia intermedia and 64(55%) had thalassemia major. Foetal haemoglobin levels were primarily influenced by alleles of the HBG2 (rs7482144) and BCL11A (rs766432) genes, but single nucleotide polymorphism of HBS1L-MYB (rs9399137) had no significant role (p>0.05). The rs7482144 single nucleotide polymorphism explained 8.3% of the variation in the foetal haemoglobin levels, while 5% of trait variation was explained by rs766432. CONCLUSIONS: There was found a clear association between foetal haemoglobin level and single nucleotide polymorphisms in HBG2 (rs7482144) and BCL11A (rs766432) genes. This correlation was additive and was seen both in thalassemia major and thalassemia intermedia cohorts.

Association of FSHR gene polymorphisms with endometriosis in women visiting tertiary-care hospitals of Lahore, Pakistan.

OBJECTIVE: The study aimed to explore the association of endometriosis risk factors with single nucleotide polymorphisms rs6166 and rs6165 (Asn680Ser and Ala307Thr) of follicle stimulating hormone receptor (FSHR) gene in Pakistani women. METHODS: This study was conducted from 2013 to 2016. The sampling and extraction of DNA was done in Department of Zoology GC University, Lahore, while the sequencing was performed at Yale University, USA. This case control study consisted of 364 subjects including 156 women diagnosed with endometriosis and 208 conveniently recruited controls. Subjects diagnosed at stage II-IV endometriosis with infertility were pooled for study. The women with adenomyosis, ovarian cancer and leiomyoma were excluded. The whole blood leukocytes were used for DNA extraction. Two important polymorphisms of exon 10 of FSHR gene were analyzed by direct DNA sequencing both in endometriosis and controls. RESULTS: Genetic variant SNP rs6166 in the affected endometriosis subjects exhibited high incidence of allele "A" (Asn/Asn) 68.3% as compared to controls 33.7% (OR= 4.240; P =0.001). Similarly, the allele "A" of SNP rs6165 (Thr/Thr) was more frequent in endometriosis 67.3% than in control subjects 37.5% (OR =3.430, P =0.001). The occurrence of haplotype AA (Asn/Thr) was 45.5% in endometriosis and 11 % in control subjects (P= 0.001). Remarkably, the incidence of haplotype GG (Ser/Ala) was contrary to previous observations, since only 9.9% occurred in endometriosis as opposed to 45.2% in controls (P= 0.001). CONCLUSIONS: Investigation of FSHR gene polymorphisms rs6165and rs6166 (Ala307Thr and Asn680Ser) in the current study showed that haplotype AA (680Asn/307Thr) was associated with endometriosis in Pakistani women.

[Correlation between PNPLA3 rs738409 and TM6SF2 rs58542926 gene polymorphism and primary liver cancer in the Han Population of China's Northeast region].

Objective: To investigate the correlation between patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 gene polymorphisms and the incidence of primary liver cancer in the Han population of China's Northeast region. Methods: A case-control study was used to enroll 521 patients with primary liver cancer as the case group and 164 healthy people as the control group. The case group was divided into groups with and without liver cirrhosis according to etiology. The polymerase chain reaction (PCR) method was used to detect the genetic polymorphisms of PNPLA3 rs738409 and TM6SF2 rs58542926, respectively. Results: Compared with the control group, the frequency distribution of PNPLA3 rs738409 G allele in the case group was significantly different (OR = 1.583, P = 0.001). Further grouping showed that there was no statistically significant difference between the control and hepatitis C-related liver cancer group (P = 0.161), but there were significant differences in other groups (P < 0.05). Compared with the control group, the frequency of TM6SF2 rs58542926 T allele in the case group was significantly higher than that in the control group (OR = 1.759, P = 0.048). After grouping, the frequency of CT/TT genotype in the liver cancer group combined with liver cirrhosis and the T allele frequency in the alcohol-related liver cancer group had statistically significant difference (P = 0.045 and 0.032, respectively) when compared with control group. The patients were divided into CG/GG group and CC group, and CT/TT group and CC group according to whether they carried PNPLA3 rs738409 G allele, and TM6SF2 rs58542926 T allele. Results showed that there were no statistically significant differences in liver enzyme indexes, albumin (ALB), total bilirubin (TBIL), alpha-fetoprotein (AFP) and fasting blood glucose between CG/GG group and CC group, and CT/TT group and CC group. The patients with liver cirrhosis in the case group were divided into≥7 groups and < 7 groups according to the Child-Pugh score. Results showed that there were no statistically significant difference in the Child-Pugh score between PNPLA3 rs738409 CG/GG group and CC group patients and TM6SF2 rs58542926 CT/TT group and CC group patients (P > 0.05). Conclusion: PNPLA3 rs738409 and TM6SF2 rs58542926 gene polymorphisms are correlated with the occurrence of primary liver cancer in the Han population of China's Northeast region. PNPLA3 rs738409 and TM6SF2 rs58542926 gene polymorphisms have no effect on indexes' such as liver enzymes, ALB, TBIL, AFP and FBS in primary liver cancer..

[Association between polymorphism of CASP and NOX3 with risk of noise-induced hearing loss].

Objective: To explore the effect of gene polymorphism on workers suffering from noise induced hearing loss (NIHL) . Methods: In May 2019, a case-control study was conducted to select noise exposed workers in five factories in Zhejiang Province from 2017 to 2018. The average hearing threshold of binaural high frequency (3, 4, 6 kHz) was >25 dB (A) as the NIHL group, and the hearing threshold of any language frequency (0.5, 1, 2 kHz) was ≤25 dB (A) as the non NIHL group, with 307 people in each group. The general demographic data, occupational history, pure tone audiometry results and oral swab mucosal samples of noise exposed workers were collected, and the DNA of oral mucosal cells was extracted. The relationship between genetic risk score (GRS) and NIHL was analyzed, single nucleotide polymorphisms (SNP) were genotyped, the relationship between genotype and NIHL was analyzed by logistic regression, and the relationship between haplotype and NIHL was analyzed by R language. Results: After adjusting for gender, age, education and working years, the risk of NIHL among workers carrying cysteine-aspartic acid protease 3 gene (CASP3) rs1049216 recessive model GG genotype, rs6948 recessive model TT genotype, NADPH oxidase 3 gene (NOX3) rs12195525 additive model GT genotype and dominant model TT+GT genotype decreased (P<0.05) , the risk of disease was higher in workers with AA genotype carrying cysteine-aspartic acid protease 7 gene (CASP7) rs12415607 additive model (P<0.05) . There was a strong linkage disequilibrium (LD) relationship between rs1049216 and rs6948 (D'>0.8) . Haplotype AT and GG composed of rs1049216-rs6948 increased the risk of NIHL (P<0.05) . The risk of NIHL increased with the increase of GRS (OR=2.69, P<0.05) . Conclusion: Genotype polymorphisms at rs1049216 and rs6948 (CASP3) , rs12195525 (NOX3) , rs12415607 (CASP7) may be associated with susceptibility to NIHL.

Significant association between paraoxonase 1 rs662 polymorphism and coronary heart disease : A meta-analysis in the Chinese population.

BACKGROUND: A growing number of studies have suggested that the single nucleotide polymorphism (SNP) rs662 (G>A) in paraoxonase 1 (PON1) is significantly associated with susceptibility to coronary heart disease (CHD) in the Chinese population. To further evaluate the effects of the PON1 RS662 (G>A) polymorphism on the risk of CHD, we performed a meta-analysis in a Chinese population. METHODS: PubMed, Embase, Wanfang Data, Chinese National Knowledge Infrastructure (CNKI) were searched to identify eligible studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the associations between RS662 (G>A) and CHD. RESULT: In the meta-analysis, we identified 14 articles, including a total of 4835 CHD patients and 5111 controls in the Chinese population. Our result showed that overall rs662 (G>A) was significantly associated with susceptibility to CHD in the Chinese population when compared with healthy controls. Furthermore, a G allele suggested an elevated risk of CHD. In the subgroup analyses stratified by ethnicity and geographic areas, significant associations were found in Chinese Han and South China, but not in North China. CONCLUSION: The present meta-analysis suggests that rs662 (G>A) SNP in PON1 is associated with CHD risk; the G allele might be the risk allele for CHD susceptibility in the Chinese population. However, more research is required to make a definite conclusion.