scholarly journals Polymorphisms in the cytotoxic T lymphocyte-associated protein-4 immune regulatory gene and their impact on inhibitor development in patients with hemophilia A

2019 ◽  
Vol 47 (10) ◽  
pp. 4981-4992
Author(s):  
Aveen M. Raouf Abdulqader ◽  
Ali Ibrahim Mohammed ◽  
Shwan Rachid
Keyword(s):  
T Lymphocyte ◽  
Hemophilia A ◽  
Fragment Length Polymorphism ◽  
Cytotoxic T Lymphocyte ◽  
Direct Sequencing ◽  
Regulatory Gene ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Inhibitor Development ◽  
The Impact

Objective The development of inhibitors against infused factor VIII represents the most severe complication of substitution therapy in hemophilia A (HA) patients. Data on risk factors for inhibitor formation in Iraqi Kurdish patients with HA are unavailable. This study aimed to evaluate the impact of two single nucleotide polymorphisms (SNPs) in an immune regulatory gene in the emergence of inhibitors. Methods We focused on 126 patients with either severe or mild/moderate HA presenting with and without inhibitors. We analyzed the frequency of two polymorphisms in the cytotoxic T lymphocyte-associated protein-4 gene ( CTLA-4; CTLA-4-318C > T and CTLA-4 + 49A > G). Genotyping was performed using restriction fragment length polymorphism–PCR and direct sequencing. Results We found no significant correlation between the CTLA-4-318 C > T T allele and inhibitor development among patients with severe or mild/moderate HA. However, a significantly high inhibitor risk was detected for the CTLA-4 + 49 A > G G allele (odds ratio [OR] = 3.1, 95% confidence interval [CI] = 1.383–7.024) and (OR = 4, 95% CI = 1.719–9.437) among patients with severe and mild/moderate HA, respectively. Conclusion We conclude that the CTLA-4 +49 A > G SNP plays a substantial role as a potential risk determinant for inhibitor formation in Iraqi Kurdish patients with HA.

scholarly journals Correlation of TSHR and CTLA-4 Single Nucleotide Polymorphisms with Graves Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Weihua Sun ◽  
Xiaomei Zhang ◽  
Jing Wu ◽  
Wendi Zhao ◽  
Shuangxia Zhao ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Thyroid Stimulating Hormone ◽  
Taqman Probe ◽  
Graves Disease ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Han Population ◽  
Positive Correlations

This study was designed to explore the association between Graves disease (GD) and thyroid-stimulating hormone receptor (TSHR) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) single nucleotide polymorphisms (SNPs). We studied a total of 1217 subjects from a Han population in northern Anhui province in China. Six SNPs within TSHR (rs179247, rs12101261, rs2284722, rs4903964, rs2300525, and rs17111394) and four SNPs within CTLA-4 (rs10197319, rs231726, rs231804, and rs1024161) were genotyped via a Taqman probe technique using a Fluidigm EP1 platform. The TSHR alleles rs179247-G, rs12101261-C, and rs4903964-G were negatively correlated with GD, whereas the rs2284722-A and rs17111394-C alleles were positively correlated with GD. Analyzing TSHR SNPs at rs179247, rs2284722, rs12101261, and rs4903964 yielded 8 different haplotypes. There were positive correlations between GD risk and the haplotypes AGTA and AATA (OR=1.27, 95%CI=1.07‐1.50, P=0.005; OR=1.45, 95%CI=1.21‐1.75, P<0.001, respectively). There were negative correlations between GD risk and the haplotype GGCG (OR=0.56, 95%CI=0.46‐0.67, P<0.001). With respect to haplotypes based on SNPs at the TSHR rs2300525 and rs17111394 loci, the CC haplotype was positively correlated with GD risk (OR=1.32, 95%CI=1.08‐1.60, P=0.006). Analyzing CTLA-4 SNPs at rs231804, rs1024161, and rs231726 yielded four haplotypes, of which AAA was positively correlated with GD risk (OR=1.21, 95%CI=1.02‐1.43, P=0.029). Polymorphisms at rs179247, rs12101261, rs2284722, rs4903964, and rs17111394 were associated with GD susceptibility. Haplotypes of both TSHR and CTLA-4 were additionally related to GD risk.

scholarly journals Single Nucleotide Polymorphisms of Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) and Susceptibility to Chronic Viral Hepatitis B and C Infections

2018 ◽  
Vol 2 (1) ◽  
pp. 10-17 ◽  
Author(s):  
Moisés Enciso-Vargas ◽  
Bertha Ruíz-Madrigal ◽  
Zamira Helena Hernández-Nazara ◽  
Montserrat Maldonado-González
Keyword(s):  
Hepatitis C ◽  
Hepatitis B ◽  
Single Nucleotide Polymorphisms ◽  
Viral Hepatitis ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Hcv Infection ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Lymphocyte Antigen

The cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene is a negative regulator of T lymphocyte activation and proliferation. Single nucleotide polymorphisms (SNPs) occurring on the CTLA-4 gene can modify the ability to control the proliferation of T lymphocytes, thereby impacting the clearance of hepatitis B (HBV) and hepatitis C (HCV) virus infections. The -319C/T and +49A/G SNPs of CTLA-4 gene have been associated with autoimmune disorders and liver infections. Studies show that the +49G allele confers susceptibility to HBV and HCV infection in chronic disease (without cirrhosis), associates with the risk of chronic HCV infection in males, confers protective effect against the development of hepatocellular carcinoma, and favors viral elimination. Furthermore, the +49G allele alone or in haplotype with the -319C favors chronic infection with genotype 3 HCV; has an inverse association with HCV genotype 1; and decreases viral load in chronic hepatitis C associated with sustained viral response (SVR). These findings support an important role of the SNPs of CTLA-4 gene in viral hepatitis; however, the mechanisms by which they influence immune response against viral infections is not fully understood. This review gives an overview of the current understanding of the association between CTLA4 SNPs and HBV/HCV infections.

scholarly journals The Interplay between miRNA-Related Variants and Age-Related Macular Degeneration: EVIDENCE of Association of MIR146A and MIR27A

2019 ◽  
Vol 20 (7) ◽  
pp. 1578 ◽  
Author(s):  
Claudia Strafella ◽  
Valeria Errichiello ◽  
Valerio Caputo ◽  
Gianluca Aloe ◽  
Federico Ricci ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Direct Sequencing ◽  
Bioinformatic Analysis ◽  
Age Related Macular Degeneration ◽  
Italian Population ◽  
Nucleotide Polymorphisms ◽  
Complex Interplay ◽  
Single Nucleotide ◽  
Age Related ◽  
The Impact

The complex interplay among genetic, epigenetic, and environmental variables is the basis for the multifactorial origin of age-related macular degeneration (AMD). Previous results highlighted that single nucleotide polymorphisms (SNPs) of CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA, and COL8A1 were significantly associated with the risk of AMD in the Italian population. Given these data, this study aimed to investigate the impact of SNPs in genes coding for MIR146A, MIR31, MIR23A, MIR27A, MIR20A, and MIR150 on their susceptibility to AMD. Nine-hundred and seventy-six patients with exudative AMD and 1000 controls were subjected to an epigenotyping analysis through real-time PCR and direct sequencing. Biostatistical and bioinformatic analysis was performed to evaluate the association with susceptibility to AMD. These analyses reported that the SNPs rs11671784 (MIR27A, G/A) and rs2910164 (MIR146A, C/G) were significantly associated with AMD risk. Interestingly, the bioinformatic analysis showed that MIR27A and MIR146A take part in the angiogenic and inflammatory pathways underlying AMD etiopathogenesis. Thus, polymorphisms within the pre-miRNA sequences are likely to affect their functional activity, especially the interaction with specific targets. Therefore, our study represents a step forward in the comprehension of the mechanisms leading to AMD onset and progression, which certainly include the involvement of epigenetic modifications.

Pharmacokinetics of Gemcitabine in Japanese Cancer Patients: The Impact of a Cytidine Deaminase Polymorphism

2007 ◽  
Vol 26 (1) ◽  
pp. 32-42 ◽  
Author(s):  
Emiko Sugiyama ◽  
Nahoko Kaniwa ◽  
Su-Ryang Kim ◽  
Ruri Kikura-Hanajiri ◽  
Ryuichi Hasegawa ◽  
...  
Keyword(s):  
Cancer Patients ◽  
High Performance ◽  
Cytidine Deaminase ◽  
Direct Sequencing ◽  
Pharmacokinetic Parameters ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Inactive Metabolite ◽  
Grade 3 ◽  
The Impact

PurposeGemcitabine is rapidly metabolized to its inactive metabolite, 2′,2′-difluorodeoxyuridine (dFdU), by cytidine deaminase (CDA). We previously reported that a patient with homozygous 208A alleles of CDA showed severe adverse reactions with an increase in gemcitabine plasma level. This study extended the investigation of the effects of CDA genetic polymorphisms on gemcitabine pharmacokinetics and toxicities.Patients and MethodsGenotyping of CDA was performed by a direct sequencing of DNA obtained from the peripheral blood of Japanese gemcitabine-naïve cancer patients (n = 256). The patients recruited to the association study received a 30-minute intravenous infusion of gemcitabine at a dose of either 800 or 1,000 mg/m2, and eight blood samples were periodically collected (n = 250). Plasma levels of gemcitabine and dFdU were measured by high-performance liquid chromatography. Plasma CDA activities toward cytidine and gemcitabine were also measured (n = 121).ResultsTwenty-six genetic variations, including 14 novel ones and two known nonsynonymous single nucleotide polymorphisms (SNPs), were detected. Haplotypes harboring the nonsynonymous SNPs 79A>C (Lys27Gln) and 208G>A (Ala70Thr) were designated *2 and *3, respectively. The allelic frequencies of the two SNPs were 0.207 and 0.037, respectively. Pharmacokinetic parameters of gemcitabine and plasma CDA activities significantly depended on the number of haplotype *3. Haplotype *3 was also associated with increased incidences of grade 3 or higher neutropenia in the patients who were coadministered fluorouracil, cisplatin, or carboplatin. Haplotype *2 showed no significant effect on gemcitabine pharmacokinetics.ConclusionHaplotype *3 harboring a nonsynonymous SNP, 208G>A (Ala70Thr), decreased clearance of gemcitabine, and increased incidences of neutropenia when patients were coadministered platinum-containing drugs or fluorouracil.

Allelically Mismatched Replacement Therapy Due to Common African−Restricted Haplotypes of the Factor (F)VIII Protein May Underlie the Increased Incidence of FVIII Inhibitors Observed in Hemophilia−A Patients of African−Descent.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 765-765
Author(s):  
Tom E. Howard ◽  
Kevin R. Viel ◽  
Karl M. Fernstrom ◽  
Seema Deshpande ◽  
Afshin Ameri ◽  
...  
Keyword(s):  
Replacement Therapy ◽  
Odds Ratio ◽  
Preliminary Analysis ◽  
Hemophilia A ◽  
African Descent ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Inhibitor Development ◽  
Minor Alleles ◽  
True Association

Abstract Alloantibodies that inhibit the function of wildtype (wt) FVIII molecules constitute the most serious complication of replacement therapy for hemophilia (H)A patients. Although it is not possible to accurately predict which patients will develop inhibitors, ethnicity is a known risk factor as alloimmunization occurs ~2−fold more often in African Americans (AAs) than in Caucasians (Cs). Analysis of data from a resequencing study revealed that the FVIII gene (F8) contains four nonsynonymous−single nucleotide polymorphisms (ns−SNPs) that encode six distinct wt FVIII proteins designated haplotype (H)1−H6. While AAs express all but H6, only H1 and H2, the two recombinant (r)−FVIII proteins used clinically, are expressed by Cs. About 25% of AAs express H3, H4, or H5, proteins that differ structurally from r−FVIII at three ns−SNPs (R484H, D1241E, M2238V), two of which are located in dominant inhibitor epitopes and have AA−restricted minor−alleles. We designed the Pharmacogenetics of Inhibitor Risk (PIR) study to test the hypothesis that these ns−SNPs, when allelically mismatched in replacement therapy, are pharmacogenetic risk factors that contribute to the greater incidence of inhibitor development in patients of African−descent. We enrolled 94 of 223 total AA HA patients from collaborating treatment centers. Table 1 presents characteristics of the first 47 subjects (whose functional F8 regions have been resequenced entirely) including: FVIII haplotype (exposure) − H3/H4/H5 vs H1/H2; inhibitor status (outcome) − yes/no; F8 mutation − high−risk vs low−risk types; other covariates and potential confounders. A preliminary analysis demonstrated an odds ratio of 3.6 for inhibitors developing in the exposed subjects (P=0.10; 95% CI=0.7–17.6). Our finding suggests that pharmacogenetic factors may indeed contribute to the increased incidence of this alloimmune complication in AAs. To increase the power to detect a true association and allow adjustment for confounders, we are currently completing F8 resequencing in the next 47 patients. Table 1. Relevant characteristics of the first 47 African-American hemophilia-A PIR study patients*

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