scholarly journals Multicenter Study on Differential Human Neutrophil Antigen 2 Expression and Underlying Molecular Mechanisms

2020 ◽  
Vol 47 (5) ◽  
pp. 385-395
Author(s):  
Brigitte K. Flesch ◽  
Angelika Reil ◽  
Núria Nogués ◽  
Carme Canals ◽  
Peter Bugert ◽  
...  
Keyword(s):  
Expression Pattern ◽  
Human Neutrophil ◽  
Molecular Mechanisms ◽  
Normal Population ◽  
Regulatory Elements ◽  
Population Exposure ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Immune Neutropenia ◽  
The Impact

Background: The human neutrophil antigen 2 (HNA-2), which is expressed on CD177, is undetectable in 3–5% of the normal population. Exposure of these HNA-2null individuals to HNA-2-positive cells can cause immunization and pro­duction of HNA-2 antibodies, which can induce immune neutropenia and transfusion-related acute lung injury. In HNA-2-positive individuals, neutrophils are divided into a CD177pos. and a CD177neg. subpopulation. The molecular background of HNA-2 deficiency and the bimodal expression pattern, however, are not completely decoded. Study Design: An international collaboration was conducted on the genetic analysis of HNA-2-phenotyped blood samples, including HNA-2-deficient individuals, mothers, and the respective children with neonatal immune neutropenia and regular blood donors. Results: From a total of 54 HNA-2null individuals, 43 were homozygous for the CD177*787A>T substitution. Six carried the CD177*c.1291G>A single nucleotide polymorphism. All HNA-2-positive samples with >40% CD177pos. neutrophils carried the *787A wild-type allele, whereas a lower rate of CD177pos. neutrophils was preferentially associated with *c.787AT heterozygosity. Interestingly, only the *c.787A allele sequence was detected in complementary DNA (cDNA) sequence analysis carried out on all *c.787AT heterozygous individuals. However, cDNA analysis after sorting of CD177pos. and CD177neg. neutrophil subsets from HNA-2-positive individuals showed identical sequences, which makes regulatory elements within the promoter unlikely to affect CD177 gene transcription in different CD177 neutrophil subsets. Conclusion: This comprehensive study clearly demonstrates the impact of single nucleotide polymorphisms on the expression of HNA-2 on the neutrophil surface but challenges the hypothesis of regulatory epigenetic effects being implicated in the bimodal CD177 expression pattern.

scholarly journals A mouse model of human TLR4 D299G/T399I SNPs reveals mechanisms of altered LPS and pathogen responses

2020 ◽  
Vol 218 (2) ◽  
Author(s):  
Katharina Richard ◽  
Kurt H. Piepenbrink ◽  
Kari Ann Shirey ◽  
Archana Gopalakrishnan ◽  
Shreeram Nallar ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Differential Susceptibility ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Tlr4 Signaling ◽  
The Impact ◽  
Signaling Efficiency

Two cosegregating single-nucleotide polymorphisms (SNPs) in human TLR4, an A896G transition at SNP rs4986790 (D299G) and a C1196T transition at SNP rs4986791 (T399I), have been associated with LPS hyporesponsiveness and differential susceptibility to many infectious or inflammatory diseases. However, many studies failed to confirm these associations, and transfection experiments resulted in conflicting conclusions about the impact of these SNPs on TLR4 signaling. Using advanced protein modeling from crystallographic data of human and murine TLR4, we identified homologous substitutions of these SNPs in murine Tlr4, engineered a knock-in strain expressing the D298G and N397I TLR4 SNPs homozygously, and characterized in vivo and in vitro responses to TLR4 ligands and infections in which TLR4 is implicated. Our data provide new insights into cellular and molecular mechanisms by which these SNPs decrease the TLR4 signaling efficiency and offer an experimental approach to confirm or refute human data possibly confounded by variables unrelated to the direct effects of the SNPs on TLR4 functionality.

scholarly journals Impact of PD-1 gene polymorphism and its interaction with tea drinking on susceptibility to tuberculosis

2021 ◽  
Vol 149 ◽  
Author(s):  
Jing Wang ◽  
Mian Wang ◽  
Zihao Li ◽  
Xinyin Wu ◽  
Xian Zhang ◽  
...  
Keyword(s):  
Case Control Study ◽  
Preventive Measures ◽  
Nucleotide Polymorphisms ◽  
Unconditional Logistic Regression ◽  
Negative Interaction ◽  
Single Nucleotide ◽  
High Risk Populations ◽  
Tea Drinking ◽  
The Impact ◽  
Control Study

Abstract The aim of this study was to explore the impact of polymorphism of PD-1 gene and its interaction with tea drinking on susceptibility to tuberculosis (TB). A total of 503 patients with TB and 494 controls were enrolled in this case–control study. Three single-nucleotide polymorphisms of PD-1 (rs7568402, rs2227982 and rs36084323) were genotyped and unconditional logistic regression analysis was used to identify the association between PD-1 polymorphism and TB, while marginal structural linear odds models were used to estimate the interactions. Genotypes GA (OR 1.434), AA (OR 1.891) and GA + AA (OR 1.493) at rs7568402 were more prevalent in the TB patients than in the controls (P < 0.05). The relative excess risk of interaction (RERI) between rs7568402 of PD-1 genes and tea drinking was −0.3856 (95% confidence interval −0.7920 to −0.0209, P < 0.05), which showed a negative interaction. However, the RERIs between tea drinking and both rs2227982 and rs36084323 of PD-1 genes were not statistically significant. Our data demonstrate that rs7568402 of PD-1 genes was associated with susceptibility to TB, and there was a significant negative interaction between rs7568402 and tea drinking. Therefore, preventive measures through promoting the consumption of tea should be emphasised in the high-risk populations.

scholarly journals Nonsynonymous single nucleotide polymorphisms of NHE3 differentially decrease NHE3 transporter activity

2015 ◽  
Vol 308 (9) ◽  
pp. C758-C766 ◽  
Author(s):  
Xinjun Cindy Zhu ◽  
Rafiquel Sarker ◽  
John R. Horton ◽  
Molee Chakraborty ◽  
Tian-E Chen ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Large Fraction ◽  
Regulatory Protein ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Single Nucleotide ◽  
Mutant Proteins ◽  
Homologous Protein ◽  
Genetic Abnormalities ◽  
The Impact

Genetic determinants appear to play a role in susceptibility to chronic diarrhea, but the genetic abnormalities involved have only been identified in a few conditions. The Na+/H+ exchanger 3 (NHE3) accounts for a large fraction of physiologic intestinal Na+ absorption. It is highly regulated through effects on its intracellular COOH-terminal regulatory domain. The impact of genetic variation in the NHE3 gene, such as single nucleotide polymorphisms (SNPs), on transporter activity remains unexplored. From a total of 458 SNPs identified in the entire NHE3 gene, we identified three nonsynonymous mutations (R474Q, V567M, and R799C), which were all in the protein's intracellular COOH-terminal domain. Here we evaluated whether these SNPs affect NHE3 activity by expressing them in a mammalian cell line that is null for all plasma membrane NHEs. These variants significantly reduced basal NHE3 transporter activity through a reduction in intrinsic NHE3 function in variant R474Q, abnormal trafficking in variant V567M, or defects in both intrinsic NHE3 function and trafficking in variant R799C. In addition, variants NHE3 R474Q and R799C failed to respond to acute dexamethasone stimulation, suggesting cells with these mutant proteins might be defective in NHE3 function during postprandial stimulation and perhaps under stressful conditions. Finally, variant R474Q was shown to exhibit an aberrant interaction with calcineurin B homologous protein (CHP), an NHE3 regulatory protein required for basal NHE3 activity. Taken together, these results demonstrate decreased transport activity in three SNPs of NHE3 and provide mechanistic insight into how these SNPs impact NHE3 function.

scholarly journals Effect of P450 Oxidoreductase Polymorphisms on the Metabolic Activities of Ten Cytochrome P450s Varied by Polymorphic CYP Genotypes in Human Liver Microsomes

2018 ◽  
Vol 47 (4) ◽  
pp. 1604-1616 ◽  
Author(s):  
Yan Fang ◽  
Na Gao ◽  
Xin Tian ◽  
Jun Zhou ◽  
Hai-Feng Zhang ◽  
...  
Keyword(s):  
Gene Polymorphisms ◽  
High Performance ◽  
Liver Microsomes ◽  
Nucleotide Polymorphisms ◽  
Liquid Chromatograph ◽  
Single Nucleotide ◽  
P450 Oxidoreductase ◽  
Human Livers ◽  
Metabolic Activities ◽  
The Impact

Background/ Aims: Little is known about the effect of P450 oxidoreductase (POR) gene polymorphisms on the activities of CYPs with multiple genotypes. Methods: We genotyped 102 human livers for 18 known POR single nucleotide polymorphisms (SNPs) with allelic frequencies greater than 1% as well as for 27 known SNPs in 10 CYPs. CYP enzyme activities in microsomes prepared from these livers were determined by measuring probe substrate metabolism by high performance liquid chromatograph. Results: We found that the effects of the 18 POR SNPs on 10 CYP activities were CYP genotype-dependent. The POR mutations were significantly associated with decreased overall Km for CYP2B6 and 2E1, and specific genotypes within CYP1A2, 2A6, 2B6, 2C8, 2D6 and 2E1 were identified as being affected by these POR SNPs. Notably, the effect of a specific POR mutation on the activity of a CYP genotype could not be predicted from other CYP genotypes of even the same CYP. When combining one POR SNP with other POR SNPs, a hitherto unrecognized effect of multiple-site POR gene polymorphisms (MSGP) on CYP activity was uncovered, which was not necessarily consistent with the effect of either single POR SNP. Conclusions: The effects of POR SNPs on CYP activities were not only CYP-dependent, but more importantly, CYP genotype-dependent. Moreover, the effect of a POR SNP alone and in combination with other POR SNPs (MSGP) was not always consistent, nor predictable. Understanding the impact of POR gene polymorphisms on drug metabolism necessitates knowing the complete SNP complement of POR and the genotype of the relevant CYPs.

Association of β-defensin 1 gene Polymorphism and dental caries susceptibility in Tamil Ethnicity

2021 ◽  
pp. 4731-4735
Author(s):  
Harini Venkata Subbiah ◽  
Usha Subbiah ◽  
Athira Ajith
Keyword(s):  
Dental Caries ◽  
Odds Ratio ◽  
Regulatory Elements ◽  
Microbial Colonization ◽  
Nucleotide Polymorphisms ◽  
First Line ◽  
Single Nucleotide ◽  
Variant Genotype ◽  
Dental Caries Susceptibility ◽  
Genetic And Environmental Factors

Dental caries is a multifactorial disease that affects a large proportion of the population with both genetic and environmental factors contributing to the disease. Even in healthy oral environmental conditions, some individuals are susceptible to dental caries due to potential genetic contribution. Antimicrobial peptides are expressed in oral cavity and play an important role against microbial colonization and form an important first line defense against cariogenic bacteria. In the present study, we attempt to identify genetic variants that would cause significant functional impact towards susceptibility to dental caries. We investigated single nucleotide polymorphisms (SNPs) of beta-defensin 1 (DEFB1) as predictors of dental caries in tamil ethnic population. A total of 120 subjects were recruited for this study, which included 60 dental caries patients (DMFT>5) and 60 healthy controls (DMFT=0). Three SNPs of 5’UTR regulatory elements of DEFB1 were genotyped by PCR followed by Sanger sequencing. The genotypes associated with susceptibility to caries were found to be significant between rs11362 (p=.025, odds ratio = 3.72, 95% confidence interval (CI) = 1.289-10.742), rs1799946 (p=.023, odds ratio=4.32, 95% CI = 1.33-14.028) gene polymorphisms and risk of dental caries (DMFT>5) in tamil ethnicity. The variant genotype GG of rs1800972 polymorphism was found to be high in cases than controls but was not significant (p=0.136). Our data suggested that β-defensin 1 polymorphisms play a role in the susceptibility to dental caries.

scholarly journals The Impact of Single Nucleotide Polymorphisms on Human Aldehyde Oxidase

2012 ◽  
Vol 40 (5) ◽  
pp. 856-864 ◽  
Author(s):  
Tobias Hartmann ◽  
Mineko Terao ◽  
Enrico Garattini ◽  
Christian Teutloff ◽  
Joshua F. Alfaro ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Aldehyde Oxidase ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
The Impact
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