Significant Difference In Genotype Distribution Research Articles

Real-life glecaprevir/pibrentasvir in a large cohort of patients with hepatitis C virus infection: The MISTRAL study.

It is paramount to identify predictors of treatment failure with direct antiviral agents in 'field-practice' patients, including people who inject drugs (PWID). Data on the efficacy of glecaprevir/pibrentasvir (GLE/PIB) in a field-practice scenario are scant. The multicentre MISTRAL study enrolled 1177 patients, including PWID, to assess real-life efficacy and safety of GLE/PIB and to identify the predictive factors for this treatment. This was a prospective, longitudinal study. The outcome variable was the rate of sustained virological response (SVR) at week 12. A total of 123 patients (10%) were infected from hepatitis C virus (HCV) 3. METAVIR fibrosis score was F4 in 104 subjects (9%); 118 patients (10%) were PWID. Overall, 1163/1177 (99%) patients achieved SVR. The baseline clinical factors discriminating between treatment success and treatment failure were age at treatment (P=0.031) and creatinine level (P=0.034). SVR rates were not influenced by gender, substance abuse, previous treatment, treatment duration, fibrosis or chronic kidney disease stage. Compared with non-substance users, the 118 PWID exhibited a significantly different genotype pattern distribution (χ2 <0.001). A total of 40/118 (33.9%) of substance users were HCV3 compared to 83/1056 (7.9%) non-substance users. Only 6 patients (0.5%) reported a serious adverse event. The MISTRAL study provides evidence of GLE/PIB efficacy in a field-practice scenario in a highly epidemic HCV area in southern Italy; it unveiled significant differences in genotype distribution among the most underserved and difficult-to-treat patient subgroups including PWID.

Association study of apelin-APJ system genetic polymorphisms with incident metabolic syndrome in a Chinese population: a case-control study

Objectives: Apelin-APJ system has been implicated in the regulation of metabolic homeostasis. This study aimed to explore the genetic predisposition of the apelin-APJ system to metabolic syndrome. Materials And Methods: 1005 subjects were enrolled, including 448 metabolic syndrome patients and 557 controls. Seven single nucleotide polymorphisms, including rs909656, rs5975126, and rs3115757 of the apelin gene and rs7119375, rs10501367, rs9943582 and rs11544374 of the APJ gene, were genotyped. Results: For males, apelin-36 were higher in metabolic syndrome subjects compared with controls (p < 0.05). Apelin-36 were significantly lower in those with TT genotype of rs10501367 than those with CC and CT genotypes (p < 0.05), and fasting plasma glucose were higher in T allele carriers of rs10501367 and A allele carriers of rs7119375 compared with non-carriers (both p < 0.05). A significant difference in genotype distribution between diabetes mellitus patients and controls existed for both rs10501367 and rs7119375 (both p < 0.05). However, the association between apelin-APJ system genetic polymorphisms and metabolic syndrome was nonsignificant. For females, apelin-36 were higher in metabolic syndrome subjects compared with controls (p < 0.05). The association between apelin-APJ system genetic polymorphisms and apelin-36, fasting plasma glucose and diabetes mellitus was nonsignificant. However, carrying A allele in rs7119375 was associated with lower metabolic syndrome risk compared with non-carriers of A allele (odds ratio: 0.646, 95% confidence interval: 0.420–0.994, p = 0.043). Conclusions: The current findings revealed a gender-specific association of apelin-APJ system genetic polymorphisms with metabolic syndrome and glucose homeostasis disorders in a Han Chinese population.

Investigating the Contribution of NPSR1, IL-6 and BDNF Polymorphisms to Depressive and Anxiety Symptoms in Hemodialysis Patients

AimsPsychological symptoms are prevalent in hemodialysis (HD) patients. Previous investigations showed that brain-derived neurotrophic factor (BDNF) and interleukin-6 (IL-6) as well as the interaction with neuropeptide S receptor 1 (NPSR1) are linked to the development of psychological distress. This study examined the association of polymorphisms of genes encoding these proteins with depression and anxiety in a representative group of Jordanian HD patients. MethodsA total of 302 HD patients were involved in the study and categorized into three groups based on the Hospital Anxiety and Depression Scale, HADS-D or HADS-A scores as follows: normal (<7), mild (8–10) and moderate-severe (11-21). Single nucleotide polymorphism (SNP) of NPSR1 Asn107Ile (rs324981), IL-6 G174C (rs1800795), and BDNF Val66Met (rs6265) was genotyped using blood samples. ResultsThe frequency of Ile-allele of NPSR1 Asn107Ile was significantly higher in patients with moderate-severe HADS-A scores versus normal (53% vs. 40.8%, p = .035). Using ordinal regression analysis, Asn-allele of NPSR1 polymorphism was nominally significantly associated with a lower risk of anxiety (OR = 0.57, CI: 0.33–0.97, p = .038) after adjusting for other covariates. A marginally significant difference in genotype distribution of IL-6 G174C was observed among patients according to HADS-D scores (p = .05). Furthermore, carriers of IL-6174 CC genotype showed lower median IL-6 serum concentration versus carriers of GG genotype (5.2 vs. 1.35 pg/mL, p < .05). ConclusionsThe results support the genetic role of NPSR1 in the pathogenesis of anxiety and suggest that carriers of NPSR1 Ile-allele are at increased risk of anxiety in HD patients. Neither BDNF Val66Met nor IL-6 G174C were linked to psychological symptoms. Future studies among other ethnicities are necessary to verify the observations.

High Plasmodium infection and multiple insecticide resistance in a major malaria vector Anopheles coluzzii from Sahel of Niger Republic

BackgroundInformation on insecticide resistance and the mechanisms driving it in the major malaria vectors is grossly lacking in Niger Republic, thus hindering control efforts. To facilitate evidence-based malaria control, the role of Anopheles coluzzii population from southern Niger, in malaria transmission, its insecticides resistance profile and the molecular mechanisms driving the resistance were characterized.MethodsBlood fed female Anopheles gambiae sensu lato resting indoor were collected at Tessaoua, Niger. Source of blood was established using PCR and infection with Plasmodium determined using TaqMan assay. Resistance profile was established with the major public health insecticides, and resistance intensity determined with deltamethrin. Synergist assays were conducted with piperonyl butoxide and diethyl maleate. Presence of L1014F and L1014S knockdown resistance (kdr) mutations in the voltage-gated sodium channel (VGSC) was investigated using TaqMan genotyping, and strength of selection pressure acting on the Anopheles populations determined by assessing the genetic diversity of a fragment spanning exon-20 of the VGSC from alive and dead females.ResultsHigh human blood index (96%) and high Plasmodium falciparum infection (~ 13%) was observed in the An. coluzzii population. Also, a single mosquito was found infected with Plasmodium vivax. High pyrethroid and organochloride resistance was observed with mortalities of less than 20% for deltamethrin, permethrin, α-cypermethrin, and DDT. A high LD50 (156.65 min) was obtained for deltamethrin, with a resistance ratio of ~ 47.18 compared to the susceptible Ngoussou colony. Moderate carbamate resistance was observed, and a full susceptibility to organophosphates recorded. Synergist bioassays with piperonyl butoxide and diethyl maleate significantly recovered deltamethrin and DDT susceptibility, respectively implicating CYP450 s (mortality = 82%, χ2 = 84.51, p < 0.0001) and glutathione S-transferases (mortality = 58%, χ2 = 33.96, p < 0.001) in resistance. A high frequency of 1014F kdr mutation (82%) was established, with significant difference in genotype distribution associated with permethrin resistance [odds ratio = 7.71 (95% CI 2.43–14.53, χ2 = 13.67, p = 0.001]. Sequencing of intron-1 of the voltage-gated sodium channel (VGSC) revealed a low genetic diversity.ConclusionHigh pyrethroid resistance highlight the challenges to the effectiveness of the pyrethroids-based ITNs and indoor residual spraying (IRS) against An. coluzzii in Niger. The pyrethroids-synergists LLINs and organophosphate-based IRS maybe the alternatives for malaria control in southern Niger.

Temporal escalation of Pyrethroid Resistance in the major malaria vector Anopheles coluzzii from Sahelo-Sudanian Region of northern Nigeria

Despite the highest global burden of malaria, information on bionomics and insecticide resistance status of malaria vectors is grossly lacking in the densely populated Sahelo-Sudanian region of Nigeria. To support evidence-based vector control we characterised transmission and resistance profiles of Anopheles coluzzii populations from three sites in northern Nigeria. High sporozoite infection (~19.51%) was found in the An. coluzzii populations. A high pyrethroid resistance was observed with only 1% mortality against deltamethrin, a high LD50 (96.57 µg/ml), and a high LT50 (170.27 min, resistance ratio of ~51 compared with the fully susceptible Ngoussou colony). Moderate carbamate resistance was observed. Synergist bioassays significantly recovered deltamethrin susceptibility implicating CYP450s (mortality = 85%, χ2 = 134.04, p < 0.0001) and esterases (mortality = 56%, χ2 = 47.31, p < 0.0001). Reduced bed net efficacy was also observed, with mortalities on exposure to the roof of PermaNet3.0 (PBO + deltamethrin) more than 22 times compared to the side panel (deltamethrin). TaqMan genotyping revealed a high frequency of 1014F kdr mutation (82%) with significant difference in genotype distribution associated with permethrin resistance [OR = 4.69 (CI:1.53–14.35, χ2 = 8.22 p = 0.004]. Sequencing of exons 18–21 of the VGSC led to detection of two additional nonsynonymous mutations, Ile10148Asn and Ser1156Gly. These findings highlight the threats posed by the highly resistant An. coluzzii to malaria control in Nigeria.

Assessment of risk factor variants of LRRK2, MAPT, SNCA and TCEANC2 genes in Hungarian sporadic Parkinson’s disease patients

IntroductionParkinson’s disease is the second most common neurodegenerative disease. Lifestyle, environmental effects and several genetic factors have been proposed to contribute to its development. Though the majority of PD cases do not have a family history of disease, genetic alterations are proposed to be present in 60 percent of the more common sporadic cases. ObjectiveThe aim of this study is to evaluate the frequency of PD related specific risk variants of LRRK2, MAPT, SNCA and PARK10 genes in the Hungarian population. Out of the ten investigated polymorphisms three are proposed to have protective effect and seven are putative risk factors. MethodsFor genotyping, TaqMan allelic discrimination and restriction fragment length polymorphism method was used. LRRK2 mutations were investigated among 124 sporadic PD patients and 128 healthy controls. MAPT and SNCA variant frequencies were evaluated in a group of 123 patients and 122 controls, while PARK10 variant was studied in groups of 121 patients and 113 controls. ResultsNo significant difference could be detected in the frequencies of the investigated MAPT and PARK10 variants between the studied Hungarian PD cases and controls. The minor allele of the risk factor S1647T LRRK2 variant was found to be more frequent among healthy male individuals compared to patients. Moreover, in the frequency of one of the investigated SNCA variant a significant intergroup difference was detected. The minor allele (A) of rs356186 is proposed to be protective against developing the disease. In accord with data obtained in other populations, the AA genotype was significantly more frequent among Hungarian healthy controls compared to patients. Similarly, a significant difference in genotype distribution was also found in comparison of patients with late onset disease to healthy controls, which was due to the higher frequency of AG genotype among patients. ConclusionThe frequencies of different gene variants show great differences in populations. Assessment of the frequency of variants of PD related genes variants is important in order to uncover the pathomechanisms underlying the disease, and to identify potential therapeutic targets. This is the first comprehensive study focusing on these genetic variants in the population of East-Central European region. Our results extend the knowledge on the world wide occurrence of these polymorphisms by demonstrating the occurrence of specific alleles and absence of others in Hungarian PD patients.

Analysis on correlation between single nucleotide polymorphisms of vitamin D receptor gene with susceptibility to allergic rhinitis

Objective: To investigate the relationship between single nucleotide polymorphism(SNP) of vitamin D receptor(VDR) gene with susceptibility to allergic rhinitis(AR). Method: Two hundred and ten AR patients were selected as AR group, and 180 healthy volunteers from the same period were selected as control group. Fasting venous blood was collected from all subjects and blood DNA was extracted. Polymorphisms at ApaⅠ(rs7975232) and FokⅠ(rs2228570) loci of VDR gene were detected by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP), and the relationships between different genotypes with susceptibility to AR were comparatively analyzed. The Hardy-Weinberg's law of genetic balance verifies whether the two genotype frequencies were representative; Logistic multiple regression analysis was used to analyze the related factors affecting susceptibility of AR. Result: There were SNPs at rs7975232 locus of VDR gene, which were wild homozygote CC type, mutant heterozygote AC, and mutant homozygote AA. SNPs existed at rs2228570 locus, which were wild homozygote GG, mutant heterozygote GA, and mutant homozygote AA. The distributions of genotypes at rs7975232 and rs2228570 locus of VDR gene conformed to Hardy-Weinberg law. There was a significant difference in the distribution of rs7975232 genotype(P<0.05), and the frequency of C allele in the study group was significantly higher than that in the control group(P<0.05). There was no significant difference in genotype distribution of rs2228570 locus (P>0.05). Logistic analysis showed that CC genotype of ApaⅠwas a risk factor for AR susceptibility. Conclusion: The polymorphism of ApaⅠ(rs7975232) locus of VDR gene is correlated with AR susceptibility. CC genotype may be a susceptible factor for AR patients, but there is no significant correlation between FokⅠ polymorphism and AR. .

Association of opioid receptor gene polymorphisms with drinking severity and impulsivity related to alcohol use disorder in a Korean population.

AimsRecent evidence suggests that the opioid system is implicated in the pathophysiology of alcohol use disorder (AUD). We aimed to examine the genetic influence of opioid receptors on susceptibility to AUD and its clinical and psychological characteristics including harmful drinking behavior and various aspects of impulsivity in AUD patients.MethodsThree μ‐opioid receptor gene (OPRM1) variants and two κ‐opioid receptor gene (OPRK1) variants were examined in 314 male patients with AUD and 324 male controls. We applied the Alcohol Use Disorders Identification Test (AUDIT), Obsessive Compulsive Drinking Scale (OCDS), and Alcohol Dependence Scale. AUD patients also completed the stop‐signal task, delay discounting task, balloon analogue risk task, and the Barratt Impulsiveness Scale version 11 (BIS‐11).ResultsNo significant differences in genotype distributions or haplotype frequencies were found between AUD patients and controls. However, OPRK1 SNP rs6473797 was significantly related to the severity of alcohol‐related symptoms as measured by AUDIT and OCDS and a haplotype containing rs6473797 was also related to OCDS scores in AUD patients. For other psychological traits, OPRM1 SNP rs495491 was significantly associated with scores on the motor subfactor of the BIS‐11.ConclusionGenetic variations in opioid receptors may contribute to symptom severity and impulsivity in AUD patients.

Association between CYP3A4 gene rs4646437 polymorphism and the risk of hypertension in Chinese population: a case-control study.

Using a case–control design, we assessed the association between single nucleotide polymorphisms of CYP3A4 gene rs4646437 polymorphism and the risk of hypertension in Chinese population. We recruited 450 hypertension patients from The First Clinical College, Henan University of Chinese Medicine between June 2017 and May 2018. There was a significant difference in genotype distribution between case group and control group (χ2=18.169, P=0.000). The minor A allele was significantly higher in the case group than that in the control group (31.0 vs 24.8%, P=0.000, odds ratio [OR]=1.36, 95% confidence interval [95% CI]: 1.12–1.66). Significant differences were also observed in other gene models: the GA/AA genotype did not increase the risk of hypertension compared with GG genotype (OR=1.16, 95% CI: 0.90–1.49, P=0.259). Compared with GG/GA genotype, the AA genotype also increased the risk of hypertension (OR=2.34, 95% CI: 1.56–3.50, P=0.000). For additive model, the AA genotype was significantly associated with GG genotype (OR=2.25, 95% CI: 1.49–3.42, P=0.000). The same results were found for AA vs GA (OR=2.50, 95% CI: 1.60–3.89, P=0.000). For the allele genotype, the A allele frequency was significantly higher in the case group than that in the control group (31.0 vs 24.8%, P=0.002). The A allele of CYP3A4 rs4646437 was associated with an increased risk for hypertension (OR=1.36, 95% CI: 1.12–1.66, P=0.002). Our results revealed a possible genetic association between CYP3A4 gene rs4646437 and hypertension, and the AA genotype of rs4646437 increased the risk of hypertension in Chinese Han population, and this effect could be confirmed by multivariable analyses.

Interaction between GDF5 gene polymorphisms and environment factors increased the risk of knee osteoarthritis: a case-control study.

Using a case–control design, we assessed the association between single nucleotide polymorphisms (SNPs) of growth and differentiation factor 5 (GDF5)/rs143383 gene and interaction with environments and knee osteoarthritis (KOA). We recruited 288 KOA patients from the First Clinical College, Henan University of Chinese Medicine between June 2017 and May 2018. There was significant difference in genotype distribution between case group and control group (χ2 = 22.661, P=0.000). The minor C allele was significantly higher in the case group than that in the control group (20.5 vs 8.1%, P=0.000, odds ratio (OR) = 1.62, 95% confidence interval (CI): 1.29–2.03). Significant differences were also observed in other gene models. For age, all models show significant differences (P<0.05) for those whose age was more than 60 years, and no significant difference was observed for those under 60 years. For non-smoking group, there were significant differences between case group and control group, and for smoker, significance level was found in TT compared with CC and allele gene models. Patients with drinking and Bbody mass index (MI )≥ 24 also showed significant relationship between rs143383 and osteoarthritis (OA) under the following models: TT vs CC (P=0.000, P=0.018), TT/CT vs CC (P=0.043), TT vs CT/CC (P=0.000, P=0.009), and T vs C (P=0.024, P=0.000). Other gene models indicated no significance (P>0.05). Our results revealed a possible genetic association between GDF5 and KOA, and the TT genotype of rs143383 increased the risk of KOA in Chinese Han population. The interaction between GDF5 gene and drinking, smoking, and obesity further increased the risk of KOA.

Cytochrome P450 CYP2B6*6 distribution among Congolese individuals with HIV, Tuberculosis and Malaria infection

BackgroundThe cytochrome P450 CYP2B6*6 (CYP2B6 c.516G>T; rs3745274) is one of the genetic factors that alters the drug metabolism in antimalarial, antiretroviral and TB first-line drugs. In Central African populations, the distribution of the CYP2B6*6 variant is poorly documented. This study investigated the distribution of CYP2B6 c.516G>T variant among Congolese individuals. MethodsA total of 418 patients with HIV-1 mono-infection, HIV-1 and Tuberculosis coinfection and symptomatic P. falciparum malaria were genotyped for the CYP2B6 c.516G>T SNP using Restriction Fragment Length Polymorphism (RFLP). The allele frequencies and genotype distributions were determined. ResultsThe CYP2B6 c.516G>T was successfully analysed in 69% (288/418) of the study participants. Among the investigated individuals, the distribution of the major allele CYP2B6*G was 45% and the minor CYP2B6*T allele was 55%. Significant differences in genotype distribution were also observed among the studied individuals. The CYP2B6*GG (rapid metabolizer) genotype was observed in 17% (49/288) followed by CYP2B6*GT (intermediate metabolizer) 55% (159/288) and CYP2B6*TT (poor metabolizers) 28% (80/288). ConclusionThis study contributes to increasing understanding on population pharmacogenetics and may help policy makers regulate treatment guidelines in the Congolese population with a high burden of HIV, Malaria and TB.

Association and gene-gene interaction analyses for polymorphic variants in CTLA-4 and FOXP3 genes: role in susceptibility to autoimmune thyroid disease.

Polymorphic variants of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and forkhead box protein P3 (FOXP3) genes are implicated in dysregulated immune homeostasis and autoimmune disorders. We analyzed the association between CTLA-4 rs231775 and FOXP3 rs3761548, rs3761549 polymorphisms and predisposition to autoimmune thyroid disease (AITD), inclusive of Hashimoto's thyroiditis (HT) and Graves' disease (GD) in South-Indian population. A total of 355 AITD subjects (comprising 275 HT and 80 GD) and 285 randomly selected age- and sex-matched control subjects were genotyped for the aforementioned polymorphisms by PCR-RFLP method. The rs231775 "G" allele was preponderant in HT and GD subjects when compared with controls and exerted a dominant influence on the susceptibility to HT (p = 0.009) and GD (p = 0.02), respectively. There was no allelic association of rs3761548 and rs3761549 polymorphisms with AITD susceptibility, albeit a significant difference in genotype distribution with respect to rs3761549. Haplotype analysis revealed an increased frequency of rs3761548 "C"-rs3761549 "T" in HT and GD subjects, thereby associating it with disease predisposition (p = 0.03). Epistatic interaction analysis by multifactor dimensionality reduction approach revealed redundancy between CTLA-4 and FOXP3 genes in influencing the susceptibility to AITD. The genetic variation in CTLA-4 gene with reference to rs231775 polymorphism contributes to an increased predisposition to HT and GD. Also, in conjunction with FOXP3 gene variants it seems to influence the susceptibility to HT and GD respectively. The significance of these findings in combination with antithyroid antibody screening could plausibly contribute towards meticulous case-finding for effective treatment of HT and GD.

Association of rs6259 polymorphism with SHBG levels and Poly Cystic Ovary Syndrome in Indian population: a case control study.

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy of reproductive-aged women. PCOS reflects a number of possible etiologies but its pathophysiology is still unclear. The principal abnormality of the syndrome is hyperandrogenism (70-80%). The access of androgens to target tissues is regulated by sex hormone-binding globulin (SHBG), a transport protein secreted by liver i.e. specific for androgens. Present study was done to find the association of rs6259 polymorphism with SHBG levels and Poly Cystic Ovary Syndrome in Indian population. Present study was a case control study. 400 subjects were enrolled for the study and serum SHBG levels and D327N polymorphism were measured. The D327N polymorphism (wild-type and variant allele) was detected using PCR-RFLP method (restriction enzyme Bbs-I). PCOS group was found to have significantly lower SHBG levels than healthy controls. There was no significant difference in genotype distribution between PCOS and controls (χ2 = 1.0335, p = 0.59). Significant difference in SHBG levels of PCOS and control group highlights the potential of SHBG as a biomarker for PCOS. However, no significant difference in genotype distribution between PCOS and controls provided an insight that rs6259 polymorphism is not associated with the risk of PCOS and SHBG levels.

CRISPLD1 rs12115090 polymorphisms alters antiplatelet potency of clopidogrel in coronary artery disease patients in Chinese Han

BackgroundDual antiplatelet therapy (DAPT) with aspirin and clopidogrel is a recommended treatment for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI) to reduce the rate of ischemic events and stent thrombosis. However, high on-treatment platelet reactivity (HTPR) during clopidogrel therapy for some patients may lead to outcome failure and occurrence of cardiovascular events. Amounts of studies have proved that genetic factors may contribute to HTPR. In our study, we explored the predictive value of 10 single nucleotide polymorphisms (SNPs) in 8 genes indicated by exome sequencing with clopidogrel efficacy. MethodsTwo hundred and forty-one Han Chinese CAD patients (mean age: 61 ± 10 years) receiving dual antiplatelet therapy were recruited, among which 118 patients administered with 300 mg loading dose (LD) clopidogrel for 12–24 h and 123 subjects administered with 75 mg/day maintain dose (MD) clopidogrel for at least 5 days before discharge. The platelet reaction index (PRI) was determined to reflect clopidogrel response in the patients. Venous blood samples were drawn from all participants to extract genomic DNA. MassARRAY, Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to determine the genotypes of 10 SNPs. ResultsAllelic tests showed significant differences in genotype distribution between HTPR and normal on-treatment platelet reactivity (NTPR) patients for 3 SNPs including CYP2C19 rs4244285 (CYP2C19*2) (co-dominant model: p = 0.003, dominant model: p = 0.004, recessive model: p = 0.012), CRISPLD1 rs12115090 (co-dominant model: p = 0.011, dominant model: p = 0.004), and LTA4H rs11108379 (dominant model: p = 0.041). After adjusting for covariates including clinical characteristics of patients, concomitant medications and complications, we confirmed that carriers of the CYP2C19*2 showed significantly increased risk of HTPR (*2/*2 vs *1/*1: OR = 12.266, 95% CI: 1.336–112.592, p = 0.027; *1/*2 + *2/*2 vs *1/*1: OR = 2.202, 95% CI: 1.083–4.480, p = 0.029). Contrarily, carriers of the CRISPLD1 rs12115090 C allele showed significantly reduced risk of HTPR (CC vs AA: OR = 0.242, 95% CI: 0.078–0.752, p = 0.014; CA + CC vs AA: OR = 0.457, 95% CI: 0.232–0.904, p = 0.024) in Chinese CAD patients. In addition, carriers of the CYP2C19*2 allele showed significantly increased PRI (*1/*2 vs *1/*1: p = 0.008, 2/*2 vs 1/*1: p < 0.001, *2/*2 vs 1/*2: p = 0.011), while patients carrying the rs12115090 C allele showed significantly decreased PRI than the wild-type AA homozygotes (CA vs AA: p = 0.046, CA + CC vs AA: p = 0.023). ConclusionCYP2C19*2 reduced the antiplatelet potency of clopidogrel and increased the risk of HTPR, while CRISPLD1 rs12115090 A>C polymorphism increased the antiplatelet potency of clopidogrel. Genetic tests, especially for CYP2C19*2 are recommended in Han Chinese CAD patients before using of clopidogrel.

Serum IL 4 and its gene polymorphism (rs79071878) in Egyptian children with familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an autoinflammatory disorder. It is caused by mutations in the MEFV gene encoding the pyrin protein, which regulates the innate inflammatory response. The aim of the current study was to investigate the relationship between serum Interleukin-4 (IL-4) and its gene polymorphism, namely rs79071878, and FMF occurrence, severity, and response to treatment in Egyptian children harboring the disease. Fifty Egyptian children diagnosed as having FMF were included in this study. They were divided equally into two groups according to disease activity. Forty controls, age- and gender-matched, were also included. Serum IL-4 levels were measured by enzyme-linked immunosorbent assay (ELISA). The IL-4 rs79071878 polymorphism was determined by polymerase chain reaction (PCR) analysis. There was no significant difference in genotype distribution of IL-4 gene rs79071878 between patients and controls (p = 0.286) and had no correlation with FMF severity or response to colchicine therapy. Serum IL-4 level had no significant difference between children with FMF attack and those in attack-free period compared to controls (p = 0. 794) and had no correlation with any of demographic, or clinical characteristics, disease severity, or response to colchicine therapy. Serum IL-4 level and its gene polymorphism were not found to have any increase risk of FMF occurrence, disease severity, or response to treatment in the Egyptian children. Further studies are needed to verify these results.

Association between the -174 C/G polymorphism in the interleukin-6 (IL-6) gene and gastrointestinal involvement in patients with systemic sclerosis

Genetic predisposition to systemic sclerosis (SSc) has still not been fully revealed. Interleukin-6 (IL-6) is a mediator of T cell proliferation and fibrotic events in SSc. Polymorphisms in the IL-6 are found to be important in susceptibility to development of SSc. We aimed to assess the frequency of -174 C/G of IL-6 gene polymorphism in SSc patients and healthy controls, as well as correlation with disease manifestations. In the case-control study, 102 patients with SSc and 93 controls were included. PCR-RFLP method was performed for genotyping promotor variants -174 C/G of IL-6 gene. The expression level of IL-6 was determined by qRT-PCR on subset of 50 patients and 13 healthy controls with different IL-6 genotypes. We used UCLA GIT 2.0 questionnaire to assess gastrointestinal involvement in SSc patients. The expression level of IL-6 gene was significantly higher in patients with SSc in comparison with healthy controls (p < 0.05). Carriers of C-allele of IL-6 gene compared to those with G allele, showed higher expression of IL-6 gene (95.8 vs. 41.2, p < 0.05), higher GIT total score (0.85 vs. 0.5, p < 0.05) and higher distension scale score (1.4 ± 0.9 vs. 0.78 ± 0.8, p = 0.05). No significant differences in genotype distribution and allele frequency were observed between patients and controls. The expression of IL6 gene varies significantly during the course of SSc. The IL-6 gene variant -174 C/G (presence of C-allele) is associated with higher IL-6 gene expression and greater GIT impairment in patients with SSc.

Genetic variation in the CLOCK gene is associated with idiopathic recurrent spontaneous abortion.

Physiological studies in animals and human support an important role of circadian system in reproduction. The aim of this study was to investigate the potential association of CLOCK gene polymorphisms with idiopathic recurrent spontaneous abortion (IRSA). We performed a case-control study. The study group consisted of 268 women with a history of three or more idiopathic recurrent spontaneous abortions and 284 women with at least two live births and no history of pathologic pregnancies all from Slovenia and Serbia. Two SNPs in the CLOCK gene were chosen and genotyped. The results showed a statistically significant difference in genotype distribution between the two groups in the CLOCK gene for rs6850524 and rs11932595. Our analysis showed that G allele under dominant model (GG+GC/CC) for rs6850524 (p = 2∙10−4, OR = 2.28, 95%CI = 1.46–3.56) as well as G allele under dominant model (GA+AA/AA) for rs11932595 (p = 0.04, OR = 1.47, 95%CI = 1.01–2.04) might be risk factors against IRSA. Our data suggest that genetic variability in the CLOCK gene is associated with IRSA warranting further confirmation and mechanistic investigations.

A molecular validation of serotonin signaling systems association with major depressive disorder (MDD) in South Indian population

Major depressive disorder (MDD) is a multi factorial disease that affects morbidity, mortality and quality of life. It is chronic and recurrent phenotype of complex etiological relationship between genetic and environmental factors. The serotonergic system plays an important role in the modulation of brain function. Tryptophan hydroxylase (TPH) converts tryptophan in the brain to 5‐hydroxytryptophan (5‐HTP). TPH is the rate‐limiting enzyme in 5‐HT synthesis. Most tissues synthesize 5‐HT, a relatively unstable substance at low levels. Minor changes in TPH abundance or the activity can dramatically alter 5‐HT content and serotonergic function. With regard to MDD, there is a strong evidence for serotonergic abnormalities. The present study was performed to validate the association of single nucleotide polymorphisms (SNPs) in several functional variants of serotonergic genes [serotonin‐transporter‐linked polymorphic region (5HTTLPR), TPH1 and TPH2] with MDD in South Indian population. We have analyzed genotypic polymorphism in well characterized sample of MDD patients and controls with PCR‐RFLP methods. We identified a significant difference in the frequency of 5HTTLPR, TPH1 and TPH2 gene alleles between patients and controls. In addition, there was a significant difference in genotypic distribution of 5HTTLPR and TPH2 alleles between these two groups. The distribution of 5HTTLPR genotype frequencies SS, SL, LL and TPH2 GG, TT, GT and SS, GG allele showed strong association with MDD. To our knowledge, the present study reveals for the first time that polymorphism in 5HTTLPR and TPH2 genes may play a role in susceptibility to MDD in South Indian population.Support or Funding InformationThis work was supported by research grant from the Karpagam Research Foundation, Karpagam Faculty of Medical Sciences and Research, Coimbatore, India.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Insertion/Deletion Within the KDM6A Gene Is Significantly Associated With Litter Size in Goat.

A previous whole-genome association analysis identified lysine demethylase 6A (KDM6A), which encodes a type of histone demethylase, as a candidate gene associated to goat fecundity. KDM6A gene knockout mouse disrupts gametophyte development, suggesting that it has a critical role in reproduction. In this study, goat KDM6A mRNA expression profiles were determined, insertion/deletion (indel) variants in the gene identified, indel variants effect on KDM6A gene expression assessed, and their association with first-born litter size analyzed in 2326 healthy female Shaanbei white cashmere goats. KDM6A mRNA was expressed in all tissues tested (heart, liver, spleen, lung, kidney, muscle, brain, skin and testis); the expression levels in testes at different developmental stages [1-week-old (wk), 2, 3 wk, 1-month-old (mo), 1.5 and 2 mo] indicated a potential association with the mitosis-to-meiosis transition, implying that KDM6A may have an essential role in goat fertility. Meanwhile, two novel intronic indels of 16 bp and 5 bp were identified. Statistical analysis revealed that only the 16 bp indel was associated with first-born litter size (P < 0.01), and the average first-born litter size of individuals with an insertion/insertion genotype higher than that of those with the deletion/deletion genotype (P < 0.05). There was also a significant difference in genotype distributions of the 16 bp indel between mothers of single-lamb and multi-lamb litters in the studied goat population (P = 0.001). Consistently, the 16 bp indel also had a significant effect on KDM6A gene expression. Additionally, there was no significant linkage disequilibrium (LD) between these two indel loci, consistent with the association analysis results. Together, these findings suggest that the 16 bp indel in KDM6A may be useful for marker-assisted selection (MAS) of goats.

Genetic Variability in eIF2α Gene Is Associated with Islet β-Cell Function in the Development of Diabetes in a Chinese Han Population.

Aims Protein kinase-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2 alpha (eIF2α) pathway mutations lead to failure of β-cell function. The aim of this article was to assess the association between eIF2α and the risk of glucose metabolism abnormalities. Methods Two eIF2α SNPs (rs9840992 T>C and rs13072593 A>G) were selected based on CHB data from HapMap, and 1466 unrelated nondiabetes individuals were genotyped. All subjects were examined by the 75 g oral glucose tolerance test, and 733 participated in a subsequent insulin release test. Various indicators of insulin resistance and islet β-cell function were examined. Results There were no significant differences in genotype distribution and allele frequency between the prediabetes and controls. CC genotype carriers at rs9840992 showed higher insulin levels at 120 min after a 75 g glucose load than noncarriers. Also, CC homozygotes had higher ΔI30/ΔG30 and ΔI120/ΔG120 than noncarriers, even after adjusting for insulin resistance. CC homozygotes had greater AUCi values than noncarriers. Subjects aged ≥ 65 yrs, those with a BMI ≥ 24 kg/m2 and those carrying the rs9840992 risk allele, had a 2.5-fold higher risk of glucose abnormalities than subjects who had none of these risk factors. Conclusion The eIF2α polymorphism is associated with islet β-cell function in a Chinese population.