Single nucleotide polymorphism seeking long term association with complex disease

Abstract The primary inhibitor of plasmin, α2-antiplasmin (α2AP), is secreted by the liver into plasma with Met as the amino-terminus. During circulation, Met-α2AP is cleaved by antiplasmin-cleaving enzyme (APCE), yielding Asn-α2AP, which is crosslinked into fibrin approximately 13 times faster than Met-α2AP. The Met-α2AP gene codes for either Arg or Trp as the sixth amino acid, with both polymorphic forms found in human plasma samples. We determined the Arg6Trp genotype frequency in a healthy population and its effects on Met-α2AP cleavage and fibrinolysis. Genotype frequencies were RR 62.5%, RW 34.0%, and WW 3.5%. The polymorphism related to the percentage of Met-α2AP in plasma was WW (56.4%), RW (40.6%), and RR (23.6%). WW plasma tended to have shorter lysis times than RR and RW plasmas. APCE cleaved purified Met-α2AP(Arg6) approximately 8-fold faster than Met-α2AP(Trp6), which is reflected in Asn-α2AP/Met-α2AP ratios with time in RR, RW, and WW plasmas. Removal of APCE from plasma abrogated cleavage of Met-α2AP. We conclude that the Arg6Trp polymorphism is functionally significant, as it clearly affects conversion of Met-α2AP to Asn-α2AP, and thereby, the rate of α2AP incorporation into fibrin. Therefore, the Arg6Trp polymorphism may play a significant role in governing the long-term deposition/removal of intravascular fibrin.

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Single-Nucleotide Polymorphism–Defined Class I and Class III Major Histocompatibility Complex Genetic Subregions Contribute to Natural Long-term Nonprogression in HIV Infection

The Journal of Infectious Diseases ◽

10.1093/infdis/jir833 ◽

2012 ◽

Vol 205 (5) ◽

pp. 718-724 ◽

Cited By ~ 22

Author(s):

J. Guergnon ◽

C. Dalmasso ◽

P. Broet ◽

L. Meyer ◽

S. J. Westrop ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Major Histocompatibility Complex ◽

Hiv Infection ◽

Class I ◽

Major Histocompatibility ◽

Class Iii ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Histocompatibility Complex

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Deoxyribonuclease 1 Q222R single nucleotide polymorphism and long-term mortality after acute myocardial infarction

Basic Research in Cardiology ◽

10.1007/s00395-021-00864-w ◽

2021 ◽

Vol 116 (1) ◽

Author(s):

Thomas M. Hofbauer ◽

Andreas Mangold ◽

Anna S. Ondracek ◽

Adelheid Panzenböck ◽

Thomas Scherz ◽

...

Keyword(s):

Myocardial Infarction ◽

Single Nucleotide Polymorphism ◽

Cox Regression ◽

Dnase Activity ◽

Circulating Dna ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Dnase 1 ◽

All Cause Mortality

AbstractUpon activation, neutrophils release neutrophil extracellular traps (NETs), which contribute to circulating DNA burden and thrombosis, including ST-segment elevation myocardial infarction (STEMI). Deoxyribonuclease (DNase) 1 degrades circulating DNA and NETs. Lower DNase activity correlates with NET burden and infarct size. The DNase 1 Q222R single nucleotide polymorphism (SNP), impairing DNase 1 function, is linked with myocardial infarction. We assessed whether the Q222R SNP is connected to increased NET burden in STEMI and influences long-term outcomes. We enrolled 711 STEMI patients undergoing primary percutaneous coronary intervention (pPCI), and 1422 controls. Genotyping was performed for DNase 1 Q222R SNP. DNase activity, double-stranded (ds)DNA and citrullinated histone H3 were determined in culprit site and peripheral plasma during pPCI. The association of the Q222R variant on cardiovascular and all-cause mortality was assessed by multivariable Cox regression adjusted for cardiovascular risk factors. Homozygous Q222R DNase 1 variant was present in 64 (9.0%) STEMI patients, at the same frequency as in controls. Patients homozygous for Q222R displayed less DNase activity and increased circulating DNA burden. In overall patients, median survival was 60 months. Homozygous Q222R variant was independently associated with cardiovascular and all-cause mortality after STEMI. dsDNA/DNase ratio independently predicted cardiovascular and all-cause mortality. These findings highlight that the Q222R DNase 1 SNP is associated with increased NET burden and decreased compensatory DNase activity, and may serve as an independent risk factor for poor outcome after STEMI.

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Association of a single nucleotide polymorphism in the ubxn6 gene with long-term non-progression phenotype in HIV-positive individuals

Clinical Microbiology and Infection ◽

10.1016/j.cmi.2019.05.015 ◽

2020 ◽

Vol 26 (1) ◽

pp. 107-114 ◽

Cited By ~ 2

Author(s):

F. Díez-Fuertes ◽

H.E. De La Torre-Tarazona ◽

E. Calonge ◽

M. Pernas ◽

M. Bermejo ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Hiv Positive ◽

Nucleotide Polymorphism ◽

Single Nucleotide

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Genome-Wide Single-Nucleotide Polymorphism-Array Can Improve Prognostic Stratification of Core Binding Factor Acute Myeloid Leukemia, Especially in the Subgroup with Inv(16)/t(16;16) or without D816 C-KIT Mutation,

Blood ◽

10.1182/blood.v118.21.3515.3515 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3515-3515

Author(s):

Jungwon Huh ◽

Heeje Kim ◽

Woo-Sung Min ◽

Chul Won Jung ◽

Hee-Jin Kim ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Prognostic Value ◽

Nucleotide Polymorphism ◽

Core Binding Factor ◽

Single Nucleotide ◽

Kit Mutation ◽

Genome Wide ◽

Binding Factor ◽

Kit Gene

Abstract Abstract 3515 Background: The core binding factor (CBF) AML can be achieved long-term remission with high dose cytarabine-based chemotherapy alone. However, those with C-KIT gene mutation (esp. D816 C-KIT mutation) showed worse treatment outcomes compared to those with wild type C-KIT gene. The remaining cases without D816 C-KIT mutation is around 75% of CBF AML, which implies requirement of more sophisticated dissection of the patients according to their prognosis. Single nucleotide polymorphism (SNP) array (SNP-A) could detect cryptic abnormal genomic lesions, not identified by metaphase cytogenetics(MC). In this study, we analyzed the prognostic value of SNP-A based karyotyping combined with MC and its association with C-KIT mutation to facilitate further stratification of CBF AML patients. Methods and Materials: A total of 98 CBF AML patients were included and of whom, 63 (64%) and 35 patients (36%) were t(8;21) and inv(16)/t(16;16), respectively. Genome-Wide Human SNP 6.0 Array (Affymetrix, CA, USA) was performed using DNAs from marrow samples taken at diagnosis. Results: A total of 40 abnormal genomic lesions in 25 patients (26%) were detected by SNP-A karyotyping analysis, with a mean of 1.6 lesions per affected case (median size 33.6 Mb; range 0.4–145.9 Mb), including 3 CN-LOH lesions, 17 gain lesions, and 20 loss lesions. Survival of the patients with abnormal lesion(s) detected by SNP-A or/and MC was worse than those without any lesions in terms of 2 years' overall survival (OS; 57.5% vs 76.4%, p=0.028), event-free (EFS; 45.7% vs 66.2%, p=0.072) and leukemia free survival (LFS; 49.0% vs 77.4%, p=0.015). In contrast, MC alone could not stratify patients according to their long-term prognosis. Especially, in the subgroup with inv(16)/t(16;16), survival of patients with abnormal SNP-A/MC lesion showed worse than that of those without lesion (40.9±12.7% vs 80.2±10.4% at 2 yrs, p=0.040), but not in the subgroup with t(8;21) (66.85±9.1% vs 74.4±7.8% at 2 yrs, p=0.240). As for the subgroup with D816 C-KIT mutation, there were no differences of OS (p=0.417), EFS (p=0.380) and LFS (p=0.218) according to the presence of abnormal lesions detected by either SNP-A or MC. However, in the subgroup without D816 C-KIT mutation, those with abnormal lesions detected by either SNP-A or MC showed worse survival compared to those without abnormal lesions with respect to OS (61.6±8.7% vs 82.7±5.6% at 2 yrs, p=0.038). Multivariate analysis confirmed prognostic impact of abnormal SNP/MC lesions on OS (HR 2.743, p=0.020), EFS (HR 2.434, p=0.025), and LFS (HR 3.350, p=0.012). Conclusion: This study suggests that combined use of SNP-A with MC in the initial evaluation of CBF AML can provide an important prognostic value, especially in the inv(16)/t(16;16) subgroup or in the patients without having D816 C-KIT mutation. Disclosures: No relevant conflicts of interest to declare.

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Caveolin-1 rs4730751 single-nucleotide polymorphism may not influence kidney transplant allograft survival

Scientific Reports ◽

10.1038/s41598-019-52079-8 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Mehdi Maanaoui ◽

Rémi Lenain ◽

Aghilès Hamroun ◽

Cynthia Van der Hauwaert ◽

Benjamin Lopez ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Graft Survival ◽

Mixed Model ◽

Linear Mixed Model ◽

Graft Loss ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Caveolin 1 ◽

Significant Difference

Abstract Caveolin-1 is a protein (encoded by the CAV1 gene) supposedly harboring a protective effect against fibrosis. CAV1 rs4730751 single nucleotide polymorphism (SNP) AA genotype was initially associated with lower graft survival compared to non-AA. However, subsequent studies could not find the same effect. CAV1 rs4730751 SNP was investigated on 918 kidney donors. Multivariate Cox-model analyses were performed to evaluate risk factors for graft loss. Longitudinal changes on long-term estimated glomerular filtration rate (eGFRs) were evaluated with a linear mixed model. Histopathological findings from protocolled biopsies after 3 months post transplantation were also analyzed. Donor CAV1 rs4730751 genotyping proportions were 7.1% for AA, 41.6% for AC and 51.3% for CC. The AA genotype, compared to non-AA, was not associated with lower graft survival censored or not for death (multivariate analysis: HR = 1.23 [0.74–2.05] and HR = 1.27 [0.84–1.92]). Linear mixed model on long-term eGFRs revealed also no significant difference according to the genotype, yet we observed a trend. AA genotype was also not associated with a higher degree of fibrosis index on protocolled kidney biopsies at 3 months. To conclude, donor CAV1 rs4730751 SNP may impact on kidney transplantation outcomes, but this study could not confirm this hypothesis.

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The Prevalence of the Val66Met Polymorphism in Musicians: Possible Evidence for Compensatory Neuroplasticity from a pilot study

10.1101/2020.12.23.424122 ◽

2020 ◽

Author(s):

T.L. Henechowicz ◽

J.L. Chen ◽

L.G. Cohen ◽

M.H. Thaut

Keyword(s):

Single Nucleotide Polymorphism ◽

Pilot Study ◽

Motor Learning ◽

Neurotrophic Factor ◽

Human Genome Project ◽

Genome Project ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Val66met Polymorphism

AbstractIt has been reported that MET carriers may express deficits in motor learning and neuroplasticity, possibly deterring musicianship. Here, we compared the prevalence of the Val66Met Brain-derived Neurotrophic Factor single nucleotide polymorphism (rs6265) in a sample of musicians (N=50) and an ethnically matched subset from the 1000 Human Genome Project (N-424). We report no differences in genotype or allele frequencies. Results are consistent with the view that hypothesized Met-dependent deficits in neuroplasticity are either mild or can be overcome by long-term practice.

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