AC Haplotype Research Articles

Genetic predisposition of suicidal behavior: variants in GRIN2B, GABRG2, and ODC1 genes in attempted and completed suicide in two Balkan populations

AbstractCompleted suicide accounts for over 700,000 deaths worldwide annually, while attempted suicide is 20 times more frequent. Genetic background is an important factor contributing to suicidal behavior, including candidate genes in glutamate, γ-aminobutyric acid (GABA), and polyamine systems. Our aim was to differentiate genetic predispositions underlying different types of suicidal behavior, attempted and completed suicide, in two Balkan populations. Analysis of variants in the genes GRIN2B (rs2268115 and rs220557), GABRG2 (rs424740), and ODC1 (rs1049500 and rs2302614) was performed on a study sample including 173 suicide attempters with comorbid psychiatric disorders, 216 non-suicidal psychiatric patients and 172 healthy controls from Serbia, and 333 suicide completers and 356 non-suicidal autopsy controls from Slovenia. CA genotype of rs220557 in GRIN2B gene increased the risk for completed suicide (P = 0.021), and violent suicide (P = 0.037), compared to controls. In ODC1 gene, CA genotype of rs2302614 decreased the risk for completed suicide compared to suicide attempt (P = 0.012). Marginally, AC haplotype for variants rs1049500-rs2302614 in ODC1 gene decreased the risk for completed suicide compared to suicide attempt (P = 0.052). Specific genetic variants of glutamate and polyamine systems are differently distributed among diverse suicidal phenotypes, providing further information on the implication of these systems in suicidality.

Association between Toll-like receptor 2 rs4696483 and rs1898830 polymorphisms and the risk of triple-negative breast cancer

PurposeBreast cancer (BC) is heterogeneous in clinical manifestation, of which the triple-negative (TNBC) subtype is the most aggressive. This study examines the associations between Toll-Like Receptor (TLR)-2 polymorphisms and the susceptibility to BC and TNBC. MethodsGenotyping of TLR-2 rs1898830 and rs4696483 polymorphisms was done by real-time PCR in 488 women with BC (130 TNBC, 358 non-TNBC) and 476 cancer-free control women. ResultsThe minor allele frequency (MAF) of rs4696483 was significantly lower in BC cases compared to controls, and significantly lower frequencies of rs4696483 C/T and higher frequencies of rs1898830 G/G genotypes were seen in BC cases. Significantly higher MAF of rs4696483 and higher C/T and T/T rs4696483 genotypes frequencies were seen in TNBC than in non-TNBC cases. Considering the prevalent AC haplotype as a reference, 2-locus TLR-2 haplotype analysis did not identify any 2-locus TLR-2 haplotype associated with an altered risk of BC or TNBC. Positive associations of rs1898830 and rs4966483 were seen with the histological type in TNBC and negatively with distant metastasis and HR status in TNBC and non-TNBC rs1898830 carriers. In addition, rs4696483 was positively correlated with hormonotherapy and surgery in non-TNBC cases, while rs1898830 was negatively associated with hormonotherapy. Furthermore, rs1898830 was negatively and positively correlated with BMI in TNBC and TNBC cases, respectively, but positively with Ki-67 status. ConclusionsOur study highlights the association between TLR-2 genetic polymorphisms and BC and TNBC susceptibility, suggesting these variants' diagnostic/prognostic capacity in BC patients and patient subgroups.

Correlations of IL-1 and IL-6 Gene polymorphisms with hypertrophic cardiomyopathy.

The purpose of this study was to explore the correlations of interleukin-1 (IL-1) and IL-6 gene polymorphisms with hypertrophic cardiomyopathy (HCM). A total of 200 patients with HCM were enrolled as disease group, and 200 healthy individuals were included as control group. Peripheral blood was collected from all subjects in both disease and control groups. Gene polymorphisms and serum expression levels of IL-1 and IL-6 were detected, and conjoint analysis was performed based on results of cardiac color Doppler ultrasound examination. The allele distribution of IL-1 rs1878320 showed a difference between disease and control groups (P=0.000). The frequency of the allele T was lower in disease group. The genotype distribution of IL-1 rs1878320 (P=0.001) and IL-6 rs1474347 (P=0.000) in disease group was different from that in control. The frequency of TC genotype of IL-1 rs1878320 was lower in disease group, and that of CA genotype of IL-6 rs1474347 was higher in disease group. There was a difference in the distribution of the dominant model of IL-6 rs1474347 between disease and control groups (P=0.021), and the frequency of CC + CA in the dominant model was 171 (0.855). The frequency of AC haplotype of IL-1 gene was overtly higher in disease group (P=0.000), while the frequency of AT haplotype was lower in disease group (P=0.000). The IL-1 rs1516792 polymorphism had an association with serum IL-1 level (P<0.05), the IL-1 level was notably increased in the patients with the genotype AA, and it was higher in disease group. The polymorphism of rs1878320 locus in IL-1 gene was correlated with interventricular septal (IVS) (P=0.047), and IVS was reduced in the patients with TC genotype. The polymorphism of rs1516792 locus in IL-1 gene was distinctly related to left ventricular outflow tract (LVOT) (P=0.041), and LVOT was lowered in the patients with GG genotype. The IL-6 rs2069831 polymorphism was associated with left ventricular ejection fraction (LVEF) (P=0.035), and LVEF declined in the patients with TT genotype. The IL-1 and IL-6 gene polymorphisms are correlated with the susceptibility and progression of HCM.

Three candidate SNPs show associations with thyroid-stimulating hormone in euthyroid subjects: Tehran thyroid study.

Previous studies have shown interindividual variation in free thyroxine (FT4) serum levels and thyroid stimulating hormone (TSH) in healthy persons. Genetic factors mainly determine this variation, and genome-wide association studies have increased the number of thyroid function-associated variants. The present study investigates the association of candidate variants with FT4 and TSH in a euthyroid Iranian population. A total of 2931 unrelated euthyroid subjects (FT4 10.29-21.88pmol/L; TSH 0.32-10 mIU/L, thyroid peroxidase antibody TPOAb < 33IU/mL in men and < 35IU/mL in women), with available genotypes were chosen from the Tehran Thyroid Study (TTS), to examine the impact of selected SNPs on thyroid hormone under the additive genetic model. In order to evaluate regional associations with FT4 and TSH levels, a haplotype analysis was done. We identified a strong association between the rs4338740-C allele and TSH in the adjusted model (β = -0.095, P-value = 0.0004). Also, findings indicated that rs4954192 ACMSD and rs4445669 CADM1 correlated with normal TSH levels (P-value = 0.011, P-value = 0.014, respectively). Haplotype analysis revealed that two haplotypes were significantly associated with TSH levels in euthyroid individuals. The ACGA and AC haplotypes on chromosomes 8 and 14 were significantly correlated with normal TSH levels, respectively (P-value = 0.014, P-value = 0.016). This is the first genetic association study with TSH and FT4 reference values in an Iranian population. Our findings indicate that a few gene variants associated with the reference values of TSH in other populations are also associated with the reference values of TSH in Iranians. The online version contains supplementary material available at 10.1007/s40200-023-01383-2.

Haplotype of the Lipoprotein(a) Gene Variants rs10455872 and rs3798220 Is Associated with Parameters of Coagulation, Fibrinolysis, and Inflammation in Patients after Myocardial Infarction and Highly Elevated Lipoprotein(a) Values.

Lipoprotein(a) (Lp(a)) is an independent risk factor for future coronary events. Variants rs10455872 and rs3798220 in the gene encoding Lp(a) are associated with an increased Lp(a) concentration and risk of coronary artery disease. We aimed to determine whether in high-risk coronary artery disease patients these two genetic variants and the kringle IV type 2 (KIV-2) repeats are associated with impairment of inflammatory and hemostatic parameters. Patients after myocardial infarction with elevated Lp(a) levels were included. Blood samples underwent biochemical and genetic analyses. In carriers of the AC haplotype, the concentrations of tumor necrosis factor (TNF)-α (4.46 vs. 3.91 ng/L, p = 0.046) and plasminogen activator inhibitor-1 (PAI-1) (p = 0.026) were significantly higher compared to non-carriers. The number of KIV-2 repeats was significantly associated with the concentration of high-sensitivity C-reactive protein (ρ = 0.251, p = 0.038) and overall fibrinolytic potential (r = -0.253, p = 0.038). In our patients, a direct association between the AC haplotype and both TNF-α and PAI-1 levels was observed. Our study shows that the number of KIV-2 repeats not only affects proatherosclerotic and proinflammatory effects of Lp(a) but is also associated with its antifibrinolytic properties.

Association of IL-18 gene polymorphisms with clinical aspects of hyperlipidemia in middle-aged and early people in the community.

Hyperlipidemia is notorious for causing coronary artery disease (CAD). IL-18 is a proinflammtory cytokine that contributes to the pathogenesis of CAD. Previous reports have revealed that genetic polymorphism of IL-18 is associated with its expression level as well as the susceptibility to CAD. In the present study, we aim to investigate the relationship between IL-18 single nucleotide polymorphisms (SNPs) and hyperlipidemia in the Han Chinese population in Taiwan. A total of 580 participants older than 30 were recruited from the community. We collected the demographics, self-reported disease histories, and lifestyles. We also assessed the levels of lipid profiles including total cholesterol (CHOL), triglyceride, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol. Two SNPs, rs3882891C/A (intron 5) and rs1946518A/C (promoter -607) of IL-18 were elucidated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Our results revealed that rs3882891 AA was associated with lower risk of hypercholesterolemia, higher CHOL and LDL-C in subjects (p=0.003, p=0.000 and p=0.005 separately), and rs1946518 CC was associated with hypercholesterolemia, higher CHOL and LDL-C as well (p=0.021, p=0.003 and p=0.001 separately) Furthermore, both SNPs were associated with IL-18 expression level, which was examined by Genotype-Tissue Expression (GTEx) Portal (p=0.042 and 0.016 separately). Finally, the haplotype of IL-18 was subsequently arranged in the order of rs3882891 and rs1946518. The result revealed that the AC haplotype of 2 IL-18 SNPs was also associated with lower risk of hypercholesterolemia, lower levels of CHOL and LDL-C (p=0.01, p=0.001 and 0.003). The current study is the first to report the association between IL-18 SNPs and hyperlipidemia in the Chinese Han population.

Assessment of the association of CYP1A1 gene polymorphisms with the susceptibility of cervical cancer: A case-control study and meta-analysis

BackgroundCervical cancer (CC) is the second most common type of female malignancy in Bangladesh. Polymorphisms in the CYP1A1 gene have been reported to be associated with CC in different populations. This case-control study with meta-analysis was undertaken to assess the relation of CYP1A1 rs4646903 and rs1048943 polymorphisms with the susceptibility of CC. MethodsA total of 185 CC patients and 220 controls were recruited, and the PCR-RFLP (Polymerase chain reaction-restriction fragment length polymorphism) technique was applied for genotyping. Again, 42 eligible studies (24 with rs4646903 and 18 with rs1048943) were included for meta-analysis, and RevMan 5.3 and the MetaGenyo web-based tool were used. ResultsThe rs4646903 polymorphism was significantly linked with CC in all association models, namely, additive 1, additive 2, dominant, recessive, overdominant, and allele models (OR = 2.41, 4.75, 2.67, 3.61, 2.13, and 2.44 with corresponding 95% CI = 1.55–3.76, 1.81–12.45, 1.75–4.07, 1.39–9.35, 1.38–3.30, and 1.71–3.48, respectively). On the contrary, rs1048943 showed no association (p > 0.05) with CC. Haplotype analysis revealed AT and AC haplotypes significantly decreased (OR = 0.45) and increased (OR = 4.86) CC risk, respectively, and SNPs are in strong linkage disequilibrium (D’ = 0.912, r2 = 0.448). Again, rs4646903 carriers with a contraception history and >5 years of taking contraceptives showed an enhanced risk of CC (OR = 2.39, OR = 3.05). Besides, rs1048943 carriers aged >40 years (OR = 0.44), conceived first child aged ≤18 years (OR = 3.45), and history of contraceptives (OR = 2.18) were significantly linked with CC. Our meta-analysis found that for CYP1A1 rs4646903 codominant 1 (COD 1), codominant 2 (COD 2), codominant 3 (COD 3), dominant model (DM), recessive model (RM), and allele model (AM) in Caucasians and overdominant model (OD) in the overall population are associated with an elevated risk of CC, whereas rs1048943 is also associated with CC in overall, Caucasians and Asians in some genetic models. ConclusionOur case-control study and meta-analysis summarize that CYP1A1 rs4646903 and rs1048943 polymorphisms may be correlated with cervical cancer.

Association Between CYP2C19 Genotypes With Clinical Phenotypes and Adipokine Levels Among Ischemic Stroke Patients: A Prospective Observational Study.

Background Cytochrome P450 system is implicated in vascular pathologies, including stroke. Besides its role as a drug metabolizer, it also plays an important role in the metabolism of several endogenous substances like fatty acids, arachidonic acid, etc., which have pro-inflammatory effects. On the other hand, leptin and adiponectin are two of the most common adipose tissue-derived cytokines (adipokines), which are pro-inflammatory andanti-inflammatory in nature,respectively. Both of them are implicated in the pathogenesis of stroke. Methods We prospectively recruited ischemic stroke patients (within three months of occurrence of an attack of stroke). The occurrence of composite outcome (recurrence of transient ischemic attack/ischemic stroke or death)was evaluated for association with genetic variants of CYP2C19 (allele *2, *17, *3, and *4, i.e., single nucleotide polymorphism (SNP) 1/2/3/4, identified using TaqMan assays and DNA sequencing). Adiponectin and leptin levels weredetermined usingan enzyme-linked immunosorbent assay. Comparisons were made betweenstroke vs. control patients and between CYP2C19 intermediate metabolizer (IM)/poor metabolizer (PM) vs. extensive metabolizer (EM)/ultra metabolizer (UM) (PM: *2/*2; IM: *1/*2vs. EM: *1/*1; UM: *1/*17). P < 0.05 was taken as the threshold for statistical significance. Results A total of 204 patients and 101 controls were recruited. With regardto the occurrence of stroke, SNP2 showed a significant positive association. Haplotypes (SNP1/SNP2) AC (OR = 1.75 (1.08-2.83), p= 0.024) and GT (OR = 3.33 (1.53-7.22), p = 0.0026) were strongly associated with the occurrence of ischemic stroke even after adjustment for age and sex (global haplotype association p-value: 0.0062). Haplotype phenotype gender interaction was evident. Among stroke patients, with regardto composite outcome, only SNP1 showed a positive association. The AC haplotype was significantly associated with the occurrence of composite outcome (OR = 2.27 (1.17-4.41), p = 0.016). Among stroke patients, a significant positive association was seen between death and SNP1 (OR = 2.35 (1.13-4.90), p = 0.021) and AC haplotype (OR = 2.73 (1.20-6.22), p = 0.018). However, none of the SNPs or haplotypes showed any association with recurrence. Significant higher leptin and lower adiponectin levels were observed among stroke patients compared to controls.Leptin levels were higher in IM/PM group. IM/PM phenotypes showed a higher incidence of occurrence of composite outcome (hazard ratio = 2.07 (0.96-4.47), p = 0.056). Conclusion CYP2C19 polymorphisms may play a significant role in the pathogenesis of stroke. Leptin could serve as a prominent biomarker of atherosclerosis and inflammation in the early post-stroke period; however, further study is warranted with a larger sample size.

LRP5-/6 gene polymorphisms and its association with risk of abnormal bone mass in postmenopausal women

ObjectivesTo assess LRP5-/6 gene polymorphisms and its association with risk of abnormal bone mass (ABM) in postmenopausal women.MethodsThe study recruited 166 patients with ABM (case group) and 106 patients with normal bone mass (control group) based on bone mineral density (BMD) results. Multi-factor dimensionality reduction (MDR) was used to analyze the interaction between the Low-density lipoprotein receptor-related protein 5 (LRP5) gene (rs41494349, rs2306862) and the Low-density lipoprotein receptor-related protein 6 (LRP6) gene (rs10743980, rs2302685) and the subjects’ clinical characteristics of age and menopausal years.Results(1) Logistic regression analysis showed that the subjects with the CT or TT genotype at rs2306862 had a higher risk of ABM than those with the CC genotype (OR = 2.353, 95%CI = 1.039–6.186; OR = 2.434, 95%CI = 1.071, 5.531; P < 0.05). The subjects with the TC genotype at rs2302685 had a higher risk of ABM than those with the TT genotype (OR = 2.951, 95%CI = 1.030–8.457, P < 0.05). (2) When taking the three Single-nucleotide polymorphisms (SNPs) together, the accuracy was the highest with the cross-validation consistency of 10/10 (OR = 1.504, 95%CI:1.092–2.073, P < 0.05), indicating that the LRP5 rs41494349 and LRP6 rs10743980, rs2302685 were interactively associated with the risk of ABM. (3) Linkage disequilibrium (LD) results revealed that the LRP5 (rs41494349,rs2306862) were in strong LD (D′ > 0.9, r2 > 0.3). AC and AT haplotypes were significantly more frequently distributed in the ABM group than in the control group, indicating that subjects carrying the AC and AT haplotypes were associated with an increased risk of ABM (P < 0.01). (4) MDR showed that rs41494349 & rs2302685 & rs10743980 & age were the best model for ABM prediction. The risk of ABM in “high-risk combination” was 1.00 times that of “low-risk combination”(OR = 1.005, 95%CI: 1.002–1.008, P < 0.05). (5) MDR showed that there was no significant association between any of the SNPs and menopausal years and ABM susceptibility.ConclusionThese findings indicate that LRP5-rs2306862 and LRP6-rs2302685 polymorphisms and gene–gene and gene–age interactions may increase the risk of ABM in postmenopausal women. There was no significant association between any of the SNPs and menopausal years and ABM susceptibility.

Interleukin 12B rs3212227 and rs6887695 single nucleotide polymorphisms are associated with the susceptibility to preeclampsia: Genetic, haplotype and bioinformatics analysis

It is well-known that functional single nucleotide polymorphisms (SNPs) in IL-12B gene might intensely change the protein expression level, or modify its functions, which might result in immune disorders. The association between common IL-12B SNPs with preeclampsia (PE) risk has remained unclear yet. In a case-control study, 253 PE patients and 250 healthy subjects were genotyped for SNPs in IL-12B rs3212227 by PCR-RFLP and in IL-12B rs6887695 by AS-PCR. Novel in-silico analysis were performed to predict the potential functions of these polymorphisms, as well. The rs3212227 variation in IL12B gene showed an association with susceptibility to PE. The AC and CC genotypes and also C allele of this SNP were more frequent in patients. Likewise, they were frequent in early onset and late onset PE. The G allele and GC and CC genotype of rs6887695 SNP correlated negatively with PE development and it shown protective effect on PE risk. In addition, the AG and CC haplotypes of IL-12B were more prevalent in PE patients. Then, IL12B AC haplotype was less frequent in PE compare to healthy pregnant women. In-silico analysis of IL-12B rs3212227 gene polymorphism might not have significant impact on the mRNA structure and transcription of IL-12B. The results of our study revealed a significant relationship between rs3212227A/C and rs6887695G/C polymorphisms in IL-12B gene and the risk of PE in the Iranian population.

Polymorphism of LYPLAL1 and TGFA Genes Associated With Progression of Knee Osteoarthritis in Residents Central Chernozem Region of Russia

Background. Кnee osteoarthritis (OA) is a multifactorial disease in which genetic factors play an important role. The share of the hereditary component in the development of OA, according to various literature sources, ranges from 40 to 65%. Кnee OA is a progressive disease that leads to a decrease in the quality of life and disability.&#x0D; The study aimed to evaluate the role of polymorphic markers of candidate genes rs2820436 and rs2820443 LYPLAL1, rs3771501 TGFA, rs11177 GNL3, rs6976 GLT8D1 in the progression of knee OA in the population of the Central Chernozem Region of Russia.&#x0D; Methods. The study was performed in a case-control design on a sample of 500 patients with knee OA. Case patients with III-IV stages of the disease according to KellgrenLawrence (n = 325), control (individuals who do not have the analyzed sign III-IV stages of the disease) patients with stage II (n = 175). Genotyping of five single nucleotide polymorphisms (SNPs) of candidate genes was performed using the polymerase chain reaction method for DNA synthesis. The study of the associations of the studied polymorphic loci, the calculation of haplotype frequencies and the analysis of their relationship with the progression of knee OA was carried out by the method of logistic regression in the program PLINK v 2.050.&#x0D; Results. Significant associations with the progression of OA of the knee were established for allelic variant A rs2820436 of LYPLAL1 gene according to allelic (OR = 1.48, p = 0.010, pperm = 0.012), additive (OR = 1.58, p = 0.009, pperm = 0.010), dominant (OR = 1.61, p = 0.024, pperm = 0.030) genetic models and A/A genotype of the same polymorphism (OR = 2.53, p = 0.041). The genotypes C/C rs2820436 LYPLAL1 (OR = 0.67, p = 0.043), A/G rs3771501 TGFA (OR = 0.67, p = 0.042) have a protective role in the progression of the disease. It was found that the frequency of the AC haplotype of haploblock rs2820436-rs2820443 in the group of patients with III-IV stages of the disease was significantly higher than in patients with stage II (OR = 1.83, p = 0.002, pperm = 0.002). The identified molecular genetic markers rs2820436 and rs2820443 of LYPLAL1 gene, rs3771501 of TGFA gene are associated both with the risk of developing OA according to previous genome-wide studies and, according to our data, are associated with the progression of knee OA.&#x0D; Conclusions. Genetic risk factors for the development of knee OA of III-IV radiological stages are allelic variant A and genotype A/A rs2820436 of LYPLAL1 gene, haplotype AC of haploblock rs2820436-rs2820443 in the population of the Central Chernozem Region of Russia. Genotypes C/C rs2820436 of LYPLAL1 gene and A/G rs3771501 of TGFA gene have a protective value in the progression of this disease.

Genetic variation in CSF2 (5q31.1) is associated with longitudinal susceptibility to pediatric malaria, severe malarial anemia, and all-cause mortality in a high-burden malaria and HIV region of Kenya

Plasmodium falciparum infections remain among the leading causes of morbidity and mortality in holoendemic transmission areas. Located within region 5q31.1, the colony-stimulating factor 2 gene (CSF2) encodes granulocyte–macrophage colony-stimulating factor (GM-CSF), a hematopoietic growth factor that mediates host immune responses. Since the effect of CSF2 variation on malaria pathogenesis remains unreported, we investigated the impact of two genetic variants in the 5q31.1 gene region flanking CSF2:g-7032 G > A (rs168681:G > A) and CSF2:g.64544T > C (rs246835:T > C) on the rate and timing of malaria and severe malarial anemia (SMA, Hb < 5.0 g/dL) episodes over 36 months of follow-up. Children (n = 1654, aged 2–70 months) were recruited from a holoendemic P. falciparum transmission area of western Kenya. Decreased incidence rate ratio (IRR) for malaria was conferred by inheritance of the CSF2:g.64544 TC genotype (P = 0.0277) and CSF2 AC/GC diplotype (P = 0.0015). Increased IRR for malaria was observed in carriers of the CSF2 AT/GC diplotype (P = 0.0237), while the inheritance of the CSF2 AT haplotype increased the IRR for SMA (P = 0.0166). A model estimating the longitudinal risk of malaria showed decreased hazard rates among CSF2 AC haplotype carriers (P = 0.0045). Investigation of all-cause mortality revealed that inheritance of the GA genotype at CSF2:g-7032 increased the risk of mortality (P = 0.0315). Higher risk of SMA and all-cause mortality were observed in younger children (P < 0.0001 and P = 0.0015), HIV-1(+) individuals (P < 0.0001 and P < 0.0001), and carriers of HbSS (P = 0.0342 and P = 0.0019). Results from this holoendemic P. falciparum area show that variation in gene region 5q31.1 influences susceptibility to malaria, SMA, and mortality, as does age, HIV-1 status, and inheritance of HbSS.

Multi-locus SNP analyses of interleukin 1 receptor associated kinases 2 gene polymorphisms with the susceptibility to rheumatoid arthritis.

BackgroundThe genetic polymorphisms (rs708035, rs3844283) of Interleukin-1 receptor associated kinases 2 (IRAK2) is involved in the NFκB regulatory pathway. The frequencies of IRAK2 gene are unknown in Pakistani population. Therefore, the study was designed to examine the association of targeted single nucleotide polymorphism(s) in IRAK2 gene of RA patients.MethodologyThe study participants were selected by ACR/EULAR 2010 standards. After ethical approval, the blood samples of patients and healthy controls were collected for the extraction of DNA followed by the amplification of targeted polymorphism(s) via Tetra-primer Amplification Refractory Mutation System (T-ARMS PCR). Desired products were observed via agarose gel electrophoresis.ResultsThe allele frequency of wild type A and C is frequent among patients and mutant T and G is frequent among controls. The rs708035 showed significant protective association while rs3844283 was found to be associated with risk of RA. Genetic model associations were applied to determine the role of genotypes. In combination analyses of alleles revealed AC haplotype was found to be associated with risk and TG provide protection against RA. Moreover, targeted SNPs were found to be in 61% Linkage Disequilibrium among the targeted population.ConclusionsCurrent study revealed the protective and risk association of targeted SNPs (rs708035, rs3844283). Study might be beneficial as it provides baseline data regarding targeted SNPs and their role in the disease progression. This could be served as potential biomarker for diagnostic purpose and effectively utilized in precision medicine approach.

GLUT4 gene rs5418 polymorphism is associated with increased coronary heart disease risk in a Uygur Chinese population

BackgroundTo explore possible associations between glucose transporter 4 (GLUT4) genetic polymorphisms in the patients with coronary heart disease (CHD) in Han and Uygur Chinese populations in Xinjiang, China.MethodsTwo GLUT4 polymorphisms (rs5418 and rs5435) were genotyped in 1262 Han (628 CHD patients and 634 healthy controls) and 896 Uyghur (397 CHD patients and 499 healthy controls) Chinese populations.ResultsIn the Han Chinese population, there were no significant differences in allelic or genotypic distribution of rs5418 and rs5435 between the CHD and control groups (all P > 0.05). However, in the Uygur population, there were significant differences in genotype and allele distributions for rs5418 between CHD and the control group (all P < 0.05). Binary Logistic regression analysis showed that carriers with the rs5418 A allele had a higher risk of CHD compared to carriers of the rs5418 G allele (OR = 1.33, 95% CI: 1.069–1.649, P = 0.01), after adjustment for gender, age, drinking and smoking behavior, hypertension and diabetes. Furthermore, haploid association analysis of the two SNP loci of the GLUT4 gene showed that the AC haplotype was associated with CHD in the Uygur population (P = 0.001598; OR = 1.36, 95% CI = 1.1228–1.6406).Conclusionsrs5418 GLUT4 gene variants are associated with CHD in the Uygur Chinese population.

Correlations of IL-18 and IL-6 gene polymorphisms and expression levels with onset of glioma.

The aim of this study was to explore the correlations of interleukin (IL)-18 and IL-6 gene polymorphisms and expression levels with the onset of glioma. The differences in the expression levels of IL-18 and IL-6 between glioma patients and normal people in the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were analyzed. A total of 200 glioma patients and 200 healthy people were taken as the research subjects. Peripheral blood was collected to extract deoxyribonucleic acids (DNAs). IL-18 and IL-6 gene polymorphisms were detected and analyzed combined with haplotype analysis and gene expression levels of IL-18 and IL-6, as well as their levels in serum. Both IL-18 and IL-6 were highly expressed in tumor tissues of glioma patients, whereas they were lowly expressed in normal cerebral tissues, with statistically significant differences (p<0.05). Statistically significant differences in the allele distributions of IL-18 gene polymorphisms rs371411440 (p=0.041) and rs371828055 (p=0.002) and IL-6 gene polymorphisms rs201211345 (p=0.000) and rs201439472 (p=0.003) were observed between disease group and control group (p<0.05). Genotype distributions of IL-18 gene polymorphism rs371828055 (p=0.005) and IL-6 gene polymorphisms rs201211345 (p=0.000) and rs201439472 (p=0.019) in disease group were significantly different from those in control group (p<0.05). Disease group exhibited significantly higher frequencies of genotype GG of IL-18 gene polymorphism rs371828055, genotype AA of IL-6 gene polymorphism rs201211345 and genotype TT of IL-6 gene polymorphism rs201439472 than control group (p<0.05). There were statistically significant differences in the distributions of the dominant model AA+AC of IL-6 gene polymorphism rs201211345 (p=0.016) and the recessive model GT+TT of IL-18 gene polymorphism rs371828055 (p=0.010) between the two groups (p<0.05). Differences in the distributions of haplotypes CC (p=0.001) and GT (p=0.027) of IL-18 gene polymorphisms rs371411440 and rs371828055 and haplotypes AC (p=0.009), AT (p=0.000) and CT (p=0.000) of IL-6 gene polymorphisms rs201211345 and rs201439472 were observed between disease group and control group (p<0.05). In addition, a high degree of linkage disequilibrium was detected between IL-6 gene polymorphisms rs201211345 and rs201439472 (D'=0.583). The genotypes of IL-18 gene polymorphism rs371828055 were evidently correlated with the gene expression of IL-18 (p=0.000). Meanwhile, patients with genotype GT had a distinctly lower expression level of IL-18 (p<0.05). The genotypes of IL-6 gene polymorphism rs201211345 were obviously associated with the expression of IL-6 (p=0.002). The expression of IL-6 was markedly down-regulated in patients carrying genotype AA (p<0.05). Consistent with the expression levels of IL-18 and IL-6, the genotypes of IL-18 gene polymorphism rs371828055 were associated with the content of serum IL-18 (p<0.05). Moreover, patients carrying genotype GT had distinctly lower content of serum IL-18 (p<0.05). Additionally, the genotypes of IL-6 gene polymorphism rs201211345 were evidently correlated with the content of serum IL-6 (p<0.05), and the content of serum IL-6 declined distinctly in patients with genotype AA (p<0.05). IL-18 and IL-6 gene polymorphisms and expression levels are significantly correlated with the onset of glioma.

Association of genetic variants of the vitamin D receptor gene with vitiligo in a tertiary care center in a Saudi population: a case-control study.

BACKGROUND: Vitiligo is a common cutaneous disorder of the skin and hair caused by a systemic depigmentation disorder that affects 1% of the population or less due to its onset in early adulthood. Meta-analyses have documented a linkage between vitiligo and the vitamin D receptor (VDR) gene.OBJECTIVE: Investigate the relationship between the ApaI, BsmI, FokI and TaqI genetic variants in the VDR gene with vitiligo in a Saudi population.DESIGN: Case-control.SETTING: Single tertiary care center.PATIENT AND METHODS: The case-control study was carried out between January 2015-December 2015 in Saudi vitiligo patients and healthy controls. VDR genetic variants or polymorphisms (ApaI, BsmI, FokI and TaqI) were genotyped by polymerase chain reaction-restriction fragment length analysis followed by 3% agarose gel electrophoresis. Applicable statistical methods were used to assess relationships between vitiligo cases and controls.MAIN OUTCOM MEASURE: Effect of genotype distribution among four single nucleotide polymorphisms.SAMPLE SIZE: 152 vitiligo (median [IQR] 23 [19] years) patients and 159 healthy controls (45 [28.5] years).RESULTS: We found an association of vitiligo with ApaI and BsmI polymorphisms (P<.05). However, a decreased risk was noted in vitiligo patients with FokI and TaqI polymorphisms and in the diplotype and haplotype analysis within males and females. A positive association with vitiligo was observed in ACAC and AC (adjusted by gender) haplotypes (P<.05). The strongest linkage disequilibrium was observed between rs79785232 (ApaI) and rs731236 (TaqI) polymorphisms (r2=.83), followed by rs2228570 (FokI) and rs1544410 (BsmI) polymorphisms (r2=.53).CONCLUSIONS: Our results confirm an association of vitiligo with ApaI and BsmI polymorphisms and fail to show an association in TaqI and FokI polymorphism with vitiligo. Additional studies need to be carried out in different Arab populations to determine whether the polymorphisms are present.LIMITATIONS: Controls not age matched, small sample size, lack of biochemical parameters.CONFLICT OF INTEREST: None.

HSP70 functional gene polymorphism and haplotype as a genetic factor for type 2 diabetes mellitus

Oxidative stress is a major cause underlying the development of Type 2 Diabetes Mellitus (T2DM). The heat shock protein 70 (HSP70) is a redox sensor for intracellular oxidative stress. The present study was aimed to understand the association of HSPA1L (HSP70-hom) rs2075800 and HSPA1B (HSP70-2) rs6457452 gene polymorphisms and haplotype with susceptibility to T2DM. In this case-control study, 200 T2DM patients and 200 healthy people were genotyped for HSPA1L rs2075800 and HSPA1B rs6457452 polymorphisms by Tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) method. The HSPA1B rs6457452 CT (OR = 0.52, 95%CI: 0.33–0.81, P = 0.004) and TT (OR = 0.05, 95%CI: 0.07–0.43, P = 0.005) genotypes were associated with decreased risk of T2DM. Moreover, the T allele was detected as a protective genetic factor against T2DM (OR = 0.43, 95%CI: 0.29–0.63, P < 0.001). We didn't find any significant differences in genotype and allele distributions between T2DM patients and controls for HSPA1L rs2075800 polymorphism. Haplotype analysis showed significant results for all haplotype windows except AC (rs6457452/rs2075800) haplotype. Haplotype GT (OR = 0.554; 95%CI = 0.332–0.924; p = 0.022) and AT (OR = 0.388; 95%CI = 0.230–0.654; p = 0.0002) showed highly significant association with decreased risk of T2DM. Increased risk was observed in haplotype GC (OR = 1.505; 95%CI = 1.132–1.999; p = 0.004). In conclusion, we conducted for the first time, that these polymorphism and haplotype are associated with T2DM in an Iranian population.

Transforming growth factor beta 1 (TGFβ1) plasmatic levels and haplotype structures in obesity: a role for TGFβ1 in steatosis development.

Obesity is considered a chronic inflammatory disease and transforming growth factor beta 1 (TGFβ1) might exert important roles in disease pathogenesis regulating adipocyte differentiation and immune-inflammatory environment. However, the role of this cytokine as a biomarker in obesity is poorly addressed. Therefore, the present study aimed to evaluate the impact of TGFB1 polymorphisms and TGFβ1 plasmatic levels in obesity METHODS AND RESULTS: TGFB1 promoter region polymorphisms (rs1800468, G-800A and rs1800469, C-509T) were evaluated in 75 obese patients and 45 eutrophic patients through PCR-RFLP and plasmatic TGFβ1 was quantified through ELISA from 37 of the obese patients, and correlations with clinical and biochemical parameters were tested. Despite no association was found between TGFB1 polymorphisms and obesity susceptibility, several correlations with clinical data were noted. Among others, AC haplotype negatively correlated with plasmatic TGFβ1, while plasmatic TGFβ1 negatively correlated with C-reactive protein and positively correlated with liver abnormalities on ultrasound and, specifically, with steatosis presence and degree. Conversely, GT haplotype, which associates with higher TGFβ1 production, was also positively correlated with the same parameters of liver abnormalities. Further, plasmatic vitamin D negatively correlated with TGFβ1, while positively correlated with AC haplotype. Overall, the results indicate that TGFβ1 might exert important roles in obesity pathophysiology and correlate with biochemical and clinical parameters both at systemic protein as well as at genetic level. Importantly, the consistent positive correlation at both levels with steatosis might suggest this cytokine as a biomarker for this hepatic abnormality in obese patients.

IL17F: A Possible Risk Marker for Spondyloarthritis in HLA-B*27 Negative Brazilian Patients.

HLA-B*27 is an important marker for spondyloarthritis (SpA), however, many SpA patients are HLA-B*27 negative. Thus, the aim of this study was to investigate the influence of IL17, TNF and VDR gene polymorphisms in SpA patients who were HLA-B*27 negative. This case-control study was conducted in 158 patients [102 patients with ankylosing spondylitis (AS) and 56 with psoriatic arthritis (PsA)] and 184 controls. HLA-B*27 genotyping was performed using PCR-SSP and IL17A (rs2275913), IL17F (rs763780), TNF-308 (rs1800629), TNF-238 (rs361525), FokI C>T (rs2228570), TaqI C>T (rs731236), ApaI A>C (rs7975232), and BsmI C>T (rs1544410) using PCR-RFLP. Statistical analyses were performed by Chi-square and logistic regression using OpenEpi and SNPStats software. The IL17F C allele frequency was higher in patients with SpA, AS and PsA compared to controls. The IL17F T/C genotype frequency was higher in SpA patients in an overdominant inheritance model and when men and women were separately analyzed. IL17A_IL17F AC haplotype was significantly associated to the risk for SpA patients. As for VDR, the ApaI a/a was a potential risk factor for SpA in men. In conclusion, IL17F C variant contributed to the risk of SpA in Brazilian patients who were HLA-B*27 negative and could be a potential marker for SpA.

Polymorphisms of the PRLR Gene and Their Association with Milk Production Traits in Egyptian Buffaloes

Simple SummaryThe two non-synonymous g.11685G>A and g.11773T>C SNPs of PRLR(L2) were significantly associated with milk yield, fat%, and protein%, and mRNA and protein levels of PRL and PRLR in milk somatic cells. GT-animals had the best milk performance; however, AC-animals had inferior milk production. Thus, the selection of buffaloes with GT haplotypes may enhance milk performance in Egyptian buffaloes.Prolactin (PRL) and its receptor (PRLR) were considered as potential genetic markers for milk production and quality traits in cattle. However, little information is available regarding PRLR genetic diversity and association studies with milk traits in Egyptian water buffaloes. Therefore, the present study was conducted to search for mutations in PRLR and determine their associations with milk performance in these animals. Exon3 (E3) and E10 of PRLR were screened for polymorphisms using single strand conformation polymorphism (SSCP) and sequencing in 400 buffaloes. The associations between haplotypes and milk production (fat%, protein%, lactose%, and solid%) traits as well as mRNA and protein levels of PRL and PRLR were studied. Two single nucleotide polymorphisms (SNPs) in E10 were detected: g.11685G>A (p.Ala494Thr) and g.11773T>C (p.Val523Aal). The G and T alleles were wild (ancestral) alleles, while the A and C alleles were mutant alleles. These SNPs resulted in four haplotypes; AC, AT, GC, and GT. Buffaloes with wild GT haplotypes showed significantly higher milk yield, fat% and protein%, mRNA and protein levels of PRL and PRLR in milk somatic cells than other animals. Animals carrying mutant AC haplotype had inferior milk traits and lowest levels of associated mRNAs and proteins. With these results, we could conclude that the selection of buffaloes with wild GT haplotypes for g.11685G>A and g.11773T>C SNPs of the PRLR gene might improve the milk production traits of Egyptian water buffaloes.