Regulatory Single Nucleotide Polymorphism rs368698783 (G>A): a Genetic Modifier of Hb F Production Only under Erythropoietic Stress Characteristic for β-Globin Chain Deficiency?

A regulatory single nucleotide polymorphism (rSNP), the ^Aγ (+25?G>A) (rs368698783) (NG_000007.3: g47783G>A) located in the HBG1 proximal promoter, is a significant predictor of clinical severity by elevating Hb F levels in β-thalassemia (β-thal). In this study, the presence of the ^Aγ (+25?G>A) and ^Aγ (+25?A>A) genotypes was investigated in four subgroups from a total of 611 subjects, including 88 α-thalassemia (α-thal) carriers (group A), 162 β-thal carriers of point mutations (group B), 57 carriers of β-thal deletions (group C) and 152 non thalassemic individuals (group D). The result is that the genotypes G>A and A>A exhibit significantly high levels of Hb F compared with the genotype G>G in both groups B and C, while no significant difference was observed in both groups A and D. We assume that the effect of ^Aγ (+25?G>A) polymorphism on Hb F production is only under erythropoietic stress characteristic for β-globin chain deficiency.     

男性高尿酸血症与MTHFR基因C677T、β3-AR基因T190C、ACE基因I/D和AGT基因T704C多态性关系的研究

目的研究MTHFR基因C677T、β3-AR基因T190C、ACE基因I/D和AGT基因T704C多态性与高尿酸血症的关系。方法91例男性高尿酸血症患者和正常男性对照81人,分别检测生化指标,测量一般身体指标,用基因芯片法检测MTHFR、β3-AR、ACE和AGT基因的基因型。结果MTHFR基因的T等位基因的分布频率明显高于对照组(χ2>3.84,P<0.05),ACE、AGT及β3-AR基因各基因型总体频率分布无差异(χ2<3.84,P>0.05),MTHFR基因型中,T/T型较C/C型BM I、尿酸和甘油三酯水平明显升高,其差异有统计学意义(t<1.96,P>0.05)。结论男性MTHFR基因C677T突变可能与高尿酸血症有关。     

Assessment of tumor necrosis factor superfamily member 10 (TNFSF10) gene variants in systemic lupus erythematosus patients

Aim of the workTo investigate the association between tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) 1525 G > A (TNF supefamily member 10; TNFSF10, rs1131568) and 1595 C > T (TNFSF10 rs1131580) genetic variants and systemic lupus erythematosus (SLE) susceptibility in Egyptian patients and their relationship with clinical and laboratory outcomes of the disease.Patients and methodsA total of 123 SLE patients and 110 age- and sex-matched healthy control subjects were tested for TRAIL 1525 G > A and 1595 C > T genotyping by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), followed by confirmation of random samples from each genotype by direct sequencing technique. Disease activity was determined using the SLE Disease Activity Index (SLEDAI).ResultsThe patients were 107 females and 16 males with mean age 32.87 ± 9.6 years. The median value of SLEDAI of the patients was 18 (12–27). The two genetic variants of TRAIL, 1525 G > A and 1595 C > T, were in complete linkage disequilibrium. There was a significant increase in the frequencies of combined genotypes (GA + AA)/(CT + TT) and A/T alleles of TRAIL 1525/1595 variants among SLE cases when compared with the control group (OR = 1.7, 95 % CI = 1.0 – 2.98, p = 0.048; OR = 1.7, 95 % CI = 1.1 – 2.8, p = 0.02, respectively). Additionally, the A/T variants of TRAIL 1525/1595 were associated with higher risks of developing lupus nephritis (OR = 2.6, 95 % CI = 1.2 – 5.7, p = 0.015) and higher disease activity (OR = 3.8, 95 % CI = 1.3 – 10.9, p = 0.010).ConclusionTRAIL 1525 G > A and 1595 C > T gene variants confer susceptibility to SLE, which is significantly related to the clinical phenotypes of SLE and associated with higher disease activity.     

Differential lipid metabolism outcomes associated with ADRB2 gene polymorphisms in response to two dietary interventions in overweight/obese subjects

Background and aims

A precise nutrigenetic management of hypercholesterolemia involves the understanding of the interactions between the individual's genotype and dietary intake. The aim of this study was to analyze the response to two dietary energy-restricted interventions on cholesterol changes in carriers of two ADRB2 polymorphisms.

Resistance to activated protein C is a risk factor for pregnancy-related venous thrombosis in the absence of the F5 rs6025 (factor V Leiden) polymorphism

Resistance to activated protein C (aPC) is most commonly due to the F5 rs6025 (factor V Leiden) polymorphism, which increases the risk of venous thrombosis. In the present population-based study of 313 cases and 353 controls, we investigated whether reduced sensitivity to aPC was associated with a history of pregnancy-related venous thrombosis. Calibrated automated thrombography was used to determine the sensitivity to aPC, and normalized aPC sensitivity ratio (n-aPC-sr) was calculated. Pregnant women and women using oral contraceptives and/or anticoagulants were excluded due to the effect on the n-aPC-sr. In women without the F5 rs6025 polymorphism, free tissue factor pathway inhibitor (TFPI), free protein S and protein C activity were associated with n-aPC-sr. Unadjusted odds ratio for venous thrombosis for women with n-aPC-sr in the 4th quartile as compared with n-aPC-sr below the 4th quartile was 2·4 (95% confidence interval 1·7-3·6). Adjusting for free protein S, free TFPI and age did not influence the odds ratios. Also in carriers of the F5 rs6025 polymorphism the risk for venous thrombosis was increased for women with higher n-aPC-sr. Our findings substantiate the importance of the aPC resistant phenotype as a risk factor for pregnancy-related venous thrombosis.     

Association of IL-13 rs20541 and rs1295686 variants with symptomatic asthma in a Saudi Arabian population

Objective: Interleukin 13 (IL-13) plays a critical pro-inflammatory role in asthma. Several single nucleotide polymorphisms (SNPs) are associated with asthma susceptibility in specific populations; however, further replicative studies in other ethnic groups are mandatory. Methods: The association between IL-13 SNPs rs762534, rs20541, rs1295686, and rs1800925 (risk alleles A, A, T, and A, respectively) and asthma predisposition in a Saudi Arabian cohort was examined via a case–control cross-sectional study. Results: The frequencies of alleles between asthmatics and control populations were significantly different for rs20541 and rs1295686 SNPs (p < 0.001), whereas the frequencies of genotypes between asthmatics and controls were significantly different only for rs20541. The association of the risk (minor) alleles with asthma was examined using the dominant genetic model. Individuals with at least one copy of the risk alleles A (for rs20541) and T (for rs1295686) had significantly greater odds of being asthmatic (OR = 2.13, 95% CI = 1.39–3.26, p < 0.0001; OR = 1.69, 95% CI = 1.12–2.54, p = 0.008) relative to their most common homozygous genotypes. On the other hand, the minor A alleles for rs762534 and rs1800925 were not significantly associated with asthma risk. Regarding haplotype association analysis, individuals with at least one copy of the minor “risk” allele for both rs20541 and rs1295686 (CATG and CATA, respectively) had greater odds of being asthmatic relative to CGCG haplotype; however, this trend was not statistically significant (p > 0.3). Conclusions: IL-13 minor T and A alleles for rs1295686 and rs20541, respectively, were associated with significantly higher risk of asthma in the Saudi Arabian population.     

IFNL3 (IL28B) polymorphism does not predict long‐term response to interferon therapy in HBeAg‐positive chronic hepatitis B patients

The impact of IFNL3 (IL28B) polymorphism on response to interferon (IFN) treatment in patients infected with hepatitis B virus (HBV) is controversial. We aimed to investigate whether IFNL3 polymorphism (rs12979860) influences the long‐term response of chronic hepatitis B (CHB) treatment to conventional IFN. Design: Ninety‐seven HBeAg‐positive patients treated with IFN were evaluated in this study. Associations were investigated between IFNL3 genotypes and (i) HBeAg seroconversion at the end of treatment (EOT), (ii) sustained virological response (SVR) and (iii) HBsAg seroconversion through long‐term follow‐up (LTFU). Patients were followed for a median of 14 years. The majority of patients were infected with HBV genotype A (69.6%) and were Caucasian (77.9%). Ninety‐five patients were genotyped at rs12979860. Similar IFNL3 distribution was observed among the different ethnicities (P = 0.62) or across HBV genotypes A through G (P = 0.70). Thirty‐six patients experienced HBeAg seroconversion at EOT; HBeAg seroconversion rates were 37.0 and 35.5% in patients with CC and CT/TT genotypes, respectively (P = 0.82). Among the 44 patients (45%) who achieved a SVR, SVR rates were 48.9 and 39.6% in patients with CC and CT/TT IL28B genotypes, respectively (P = 0.80). HBsAg seroconversion occurred through LTFU in 28 patients. HBsAg seroconversion rates were 25.5 and 31.2% in patients with CC and CT/TT genotypes, respectively (P = 0.51). No significant relationship between IFNL3 rs12979860 and fibrosis stage was observed (P = 0.85). IFNL3 genotype was neither associated with SVR, nor with HBeAg seroconversion and long‐term HBsAg seroconversion in HBeAg‐positive CHB patients responding to IFN therapy.     

Alcohol-metabolizing enzyme gene polymorphisms in the Basque Country, Morocco, and Ecuador

Background: Genes ADH1B and ADH1C have certain functional SNPs that are related to alcoholism. The frequencies of these polymorphisms vary between populations, so studying them in populations made up of groups with different phylogeographic origins requires an individualized analysis of each group. In the Basque Country, various recently arrived foreign groups live side by side with the original Southern European population, particularly North Africans from Morocco and Hispanics from Ecuador. This study sets out to examine the distribution of the frequencies of alleles that encode alcohol dehydrogenase with different metabolization rates, as higher rates make for greater susceptibility to alcoholism. Methods: Four SNPs: rs1229984, rs2066702, rs698, and rs1693482 using Taqman technology with a Rt‐PCR were studied in a sample of 114 European individuals originating from the Basque Country, 100 North Africans from Morocco, and 109 Hispanics from Ecuador. The allele and genotype frequencies were calculated using Genepop v4.0. The most frequent haplotypes were estimated using the ELB algorithm with Arlequin v3.01. A breakdown of the complete disequilibrium commonly observed between the 2 missense polymorphisms that distinguish the common ADH1C alleles rs698 and rs1693482 was observed and confirmed by sequencing in 2 individuals from the Basque Country. Results: A higher frequency of protective allele ADH1C*1 was found in the North African population group. Haplotype combinations are also studied, and the rare association of alleles ADH1B*2–ADH1C*2 was observed in the Southern European group in the Basque Country, along with an allele not hitherto described in the ADH1C locus. Conclusions: This study provides the first data published on the allele and genotype frequencies of the ADH1C locus in the Moroccan population and on the ADH1B and ADH1C loci in the Ecuadorian population. The study shows differences in the distribution of the frequency of allele ADH1C*1 between the Basque Country and Moroccan populations, and a new allele not described to date.     

Hb F Levels in Indian Sickle Cell Patients and Association with the HBB Locus Variant rs10128556 (C>T), and the HBG XmnI (Arab-Indian) Variant

The prevalence of sickle cell disease in India is very high. Hb F is one of the most powerful modulators of disease severity in sickle cell disease patients. It was traditionally thought that the disease is milder in Indian sickle cell disease patients predominantly due to the Arab-Indian haplotype characterized by the HBG XmnI [rs7482144 (G>A)] variant, which is associated with increased Hb F levels. In the current study, we investigated the Hb F levels in individuals with the rs10128556 (C>T) variant and also determined its linkage with the HBG XmnI variant. The present study was conducted on a cohort of 275 individuals, which consisted of 221 patients with sickle cell disease and 54 patients with sickle cell trait. Analysis of hemoglobin (Hb) fractions and variants was done on the high performance liquid chromatography (HPLC) system. Genotyping for rs10128556 was done by direct sequencing of the products. Mean Hb F levels in the sickle cell disease patients was 19.36?±?6.79. The genotypic frequencies for rs10128556 were 82.0% (TT), 16.7% (CT) and 1.3% (CC) for sickle cell disease patients. The minor C allele resulted in 52.0% decrease in Hb F levels when homozygous and 7.0% decrease when heterozygous. The rs10128556 single nucleotide polymorphism (SNP) was in strong but not complete linkage with the HBG XmnI variant. In conclusion, the study determined for the first time the frequency and association of rs10128556 in Indian sickle cell disease patients with Hb F. It also established that it was not in complete linkage with the HBG XmnI variant in this high risk population.     

MicroRNA4293基因多态性与女性肝癌易感性相关

目的研究microRNA-4293的SNP(rs12220909)与原发性肝癌易感性的关系。方法收集人体血液样本1788份,样本取自健康对照者884名,原发性肝癌患者904例。抽提血液样本中基因组DNA,应用MassARRAY法对microRNA-4293的SNP(rs12220909)位点进行基因分型;应用二元逻辑回归法分析microRNA-4293的SNP(rs12220909)位点与肝癌易感性之间的关系。结果女性肝癌患者microRNA-4293的SNP(rs12220909)中CC基因型较健康对照组显著增加(P=0.04),在HBV相关肝癌中显著性进一步增加(P=0.02),提示CC基因可能增加女性肝癌尤其是HBV相关肝癌的易感性。而在男性患者中,microRNA-4293的SNP(rs12220909)与肝癌易感性并不相关(P=0.33)。结论microRNA-4293的SNP(rs12220909)与女性肝癌易感性相关。     

High Risk for Essential Hypertension in Males Conferred by g.15241A>G Polymorphism in Intron 3 of AGT Gene

A total of 180 hypertensive and 188 normotensive subjects were studied for demographic features and for variations in exon 4 including exon–intron boundary of AGT gene using single-strand conformation polymorphism analysis. Sequencing of the samples showing mobility shift revealed a single-nucleotide polymorphism variant g.15241A>G in intron 3 of the gene. The polymorphism was consistent with Hardy–Weinberg equilibrium in both the cases and the controls. Although the genotype distribution and allele frequencies did not differ significantly in general, high risk was observed for males with G allele (OR = 2.08; 95% CI = 1.02–4.21; P = .04). Similar results were obtained when the genotypes were tested in dominant model wherein G allele carriers were found to be at twofold risk for developing essential hypertension (OR = 2.09; 95% CI = 0.99–4.41; P = 0.05). This report is the first one in the literature showing association of g.15241A>G polymorphism with a clinical condition.     

Interleukin-21 gene polymorphisms and chronic hepatitis B infection in a Chinese population

AIM: To investigate the relationship between inter-leukin-21(IL21) gene polymorphisms and chronic hepatitis B virus(HBV) infection in a Chinese population. METHODS: In this case-control study, 366 Chinese HBV-infected patients were recruited and divided into hepatocellular carcinoma(HCC; n = 94) and non-HCC(n = 272) groups at The First Affiliated Hospital of Sun Yat-Sen University, from April 2009 to December 2012. In the non-HCC group, the patients were classified into three clinical subsets, 76 patients had chronic hepatitis B, 101 were HBV carriers and 95 patients had HBV-related cirrhosis. Two hundred eight unrelated healthy controls were also included. Genomic DNA was extracted from peripheral blood. Single nucleotide polymorphisms(SNPs) rs13143866, rs2221903, and rs907715 were subsequently genotyped using the SNaP shot SNP technique.RESULTS: There were no significant differences in allele and genotype frequencies of SNPs rs13143866, rs2221903, and rs907715 between chronic HBVinfected patients and control subjects. Furthermore, no significant differences were found in the frequencies of all alleles and genotypes between the HCC group and the non-HCC group. However, in the subgroup analysis, IL21 rs13143866 genotype AA frequency in the HBV carrier group was higher than in controls(OR = 6.280, 95%CI: 1.238-31.854; P = 0.019), and the effect of the recessive model(AA vs GG + GA, OR = 6.505, 95%CI: 1.289-32.828) was observed in the HBV carrier group. IL21 rs2221903 genotype TC frequency in the HBV carrier group was higher than in controls(OR = 1.809, 95%CI: 1.043-3.139; P = 0.035). In the haplotype analysis, the ATA haplotype(rs13143866, rs2221903, and rs907715) of IL21 was more frequent in the HCC group than in the non-HCC group(0.165 vs 0.104, P = 0.044; OR = 1.700, 95%CI: 1.010-2.863).CONCLUSION: Genotypes rs13143866 AA and rs2221903 TC are risk factors for carrying HBV; ATA haplotype increases the risk of HBV-related HCC onsetin a Chinese population.     

Influence of genetic variants of opioid-related genes on opioid-induced adverse effects in patients with lung cancer: A STROBE-compliant observational study

Despite the dramatic advancement of cancer chemotherapy and immunotherapy, the insufficient progress has been made in basic or translational research on personalization of opioid therapy. Predicting the effectiveness of opioid analgesic therapy and the risk of adverse effects prior to therapy are expected to enable safer and more appropriate opioid therapy for cancer patients. In this study, we compared the incidence of opioid-induced adverse effects between patients with different variants of the genes related to responsiveness to opioid analgesics.Participants were 88 patients with lung cancer who provided general consent for exome sequencing and were treated with morphine or oxycodone at Shizuoka Cancer Center Hospital between April 2014 and August 2018. Incidence rates for 6 adverse effects of opioid therapy (somnolence, nausea, constipation, delirium, urinary retention, and pruritus) were determined and the influence of single nucleotide polymorphisms in coding regions of the opioid μ receptor 1 (OPRM1) (rs1799971), opioid δ receptor 1 (rs2234918), opioid κ receptor 1 (rs1051660), catechol-O-methyltransferase (COMT) (rs4680), dopamine receptor D2 (rs6275), adenosine triphosphate binding cassette B1 (rs1045642), G-protein regulated inward rectifier potassium channel 2 (rs2070995), and fatty acid amide hydrolase (rs324420) genes on those adverse effects were analyzed.Analysis of OPRM1 gene variant status (Asn133Asp A > G) showed that G/G homozygotes were at significantly lower risk of somnolence compared with A allele carriers (0% vs 28.4%; Fisher exact test, P = .005; OR, 0; 95% CI, 0–0.6), and analysis of COMT gene variant status (Val158Met, G > A) showed that G/G homozygotes were at significantly higher risk of somnolence compared with A allele carriers (35.0% vs 10.4%; Fisher exact test, P = .008; OR, 4.5; 95% CI, 1.4–18.1). No relationship between variant status and adverse effects was found for the other genes.These findings demonstrate that OPRM1 and COMT gene variants influence the risk of somnolence as an adverse effect of opioid analgesic therapy.