The Trp719Arg polymorphism of the KIF6 gene and coronary heart disease risk: systematic review and meta-analysis

Ruíz-Ramos, David; Hernández‐Díaz, Yazmín; Tovilla-Zárate, Carlos Alfonso; Juárez-Rojop, Isela; López‐Narváez, María Lilia; González‐Castro, Thelma Beatriz; Torres-Hernández, Manuel Eduardo; Baños-González, Manuel Alfonso

doi:10.1186/s41065-015-0004-7

Cited by 5 publications

(4 citation statements)

References 35 publications

(46 reference statements)

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“…We found that there was a statistically significant correlation between being a sufferer of MACE and being a carrier of c.2155T> C variant of KIF6 when taking into consideration all patients prior to treatment with statins (p = 0.049). This outcome is consistent with the current literature [ 35 , 36 , 37 ].…”

Section: Discussionsupporting

confidence: 94%

KIF6 gene as a pharmacogenetic marker for lipid-lowering effect in statin treatment

et al. 2018

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IntroductionThe therapeutic response to statins has a high interindividual variability with respect to reductions in plasma LDL-cholesterol (c-LDL) and increases in HDL cholesterol (c-HDL). Many studies suggest that there is a relationship between the rs20455 KIF6 gene variant (c.2155T> C, Trp719Arg) and a lower risk of cardiovascular disease in patients being treated with statins.AimThe aim of this study was to investigate whether or not the c.2155T> C KIF6 gene variant modulates the hypercholesteremic effects of treatment with simvastatin, atorvastatin, or rosuvastatin.Materials and methodsThis was a prospective, observational and multicenter study. Three hundred and forty-four patients who had not undergone prior lipid-lowering treatment were recruited. Simvastatin, atorvastatin or rosuvastatin were administered. Lipid profiles and multiple clinical and biochemical variables were assessed before and after treatment.ResultsThe c.2155T> C variant of the KIF6 gene was shown to influence physiological responses to treatment with simvastatin and atorvastatin. Patients who were homozygous for the c.2155T> C variant (CC genotype, ArgArg) had a 7.0% smaller reduction of LDL cholesterol levels (p = 0.015) in response to hypolipidemic treatment compared to patients with the TT (TrpTrp) or CT (TrpArg) genotype. After pharmacological treatment with rosuvastatin, patients carrying the genetic variant had an increase in c-HDL that was 21.9% lower compared to patients who did not carry the variant (p = 0.008).ConclusionBeing a carrier of the c.2155T> C variant of the KIF6 gene negatively impacts patient responses to simvastatin, atorvastatin or rosuvastatin in terms of lipid lowering effect. Increasing the intensity of hypolipidemic therapy may be advisable for patients who are positive for the c.2155T> C variant.

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Section: Discussionsupporting

confidence: 94%

KIF6 gene as a pharmacogenetic marker for lipid-lowering effect in statin treatment

et al. 2018

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“…The KIF6 c.2155T>C variant was reported to increase the risk of CHD in statin-free patients [47]. However, it was shown to reduce coronary events while on statin therapy [48,49].…”

Section: Discussionmentioning

confidence: 99%

Predicted deleterious variants in ABCA1, LPL, LPA and KIF6 are associated with statin response and adverse events in patients with familial hypercholesterolemia and disturb protein structure and stability

Dagli-Hernandez,

Ferreira,

Freitas

et al. 2024

Pharmacogenetics and Genomics

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Objectives This study explored the association of deleterious variants in pharmacodynamics (PD) genes with statin response and adverse effects in patients with familial hypercholesterolemia (FH) and analyzed their potential effects on protein structure and stability. Methods Clinical and laboratory data were obtained from 144 adult FH patients treated with statins. A panel of 32 PD genes was analyzed by exon-targeted gene sequencing. Deleterious variants were identified using prediction algorithms and their structural effects were analyzed by molecular modeling studies. Results A total of 102 variants were predicted as deleterious (83 missense, 8 stop-gain, 4 frameshift, 1 indel, 6 splicing). The variants ABCA1 rs769705621 (indel), LPA rs41267807 (p.Tyr2023Cys) and KIF6 rs20455 (p.Trp719Arg) were associated with reduced low-density lipoprotein cholesterol (LDLc) response to statins, and the LPL rs1801177 (p.Asp36Asn) with increased LDLc response (P < 0.05). LPA rs3124784 (p.Arg2016Cys) was predicted to increase statin response (P = 0.022), and ABCA1 rs769705621 to increase the risk of statin-related adverse events (SRAE) (P = 0.027). LPA p.Arg2016Cys and LPL p.Asn36Asp maintained interactions with solvent, LPA p.Tyr2023Cys reduced intramolecular interaction with Gln1987, and KIF6 p.Trp719Arg did not affect intramolecular interactions. DDMut analysis showed that LPA p.Arg2016Cys and p.Tyr2023Cys and LPL p.Asp36Asn caused energetically favorable changes, and KIF6 p.Trp719Arg resulted in unfavorable energetic changes, affecting protein stability. Conclusion Deleterious variants in ABCA1, LPA, LPL and KIF6 are associated with variability in LDLc response to statins, and ABCA1 rs769705621 is associated with SRAE risk in FH patients. Molecular modeling studies suggest that LPA p.Tyr2023Cys and KIF6 p.Trp719Arg disturb protein conformational structure and stability.

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“…In the present era, the world is focusing on studying the role of genetic variants and their role in the pathogenesis of CAD (37). KIF6 is a member of a family of molecular motors involved in the intracellular transport of protein complexes, membrane organelles, and messenger ribonucleic acid (mRNA) along microtubules in an ATP-dependent process (15).…”

Section: Discussionmentioning

confidence: 99%

Impact of KIF6 Trp719Arg gene variant on Coronary Artery Disease Development

Desouky

Abd-Elazim

Elhakim

et al. 2023

Preprint

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Coronary artery disease (CAD) is a multifactorial disease resulting from the interaction of genetic varia-tion and environmental traditional risk factors (TRFs), including diabetes mellitus, smoking, dyslipidemia, and hypertension. KIF6 Trp719Arg (rs20455; A>G) is an interesting gene variant reported as one of the most important risk factors for CAD in different populations. The study enrolled 150 participants belong-ing to the National Heart Institute (NHI) catheterization unit in Egypt, who were grouped into three main study groups regarding the presence of different TRFs. Biochemical investigations and clinical data were assessed and recorded. Analysis for KIF6 Trp719Arg polymorphism (rs20455; A>G) was performed for all participants using the TaqMan genotyping real-time PCR assay (rs20455). The study demonstrated that diabetes mellitus, hypertension, dyslipidemia, and smoking were highly statistically significant among CAD with TRF and non-CAD with TRF patients with p-values of 0.009*, 0.003*, 0.046*, and 0.001**, re-spectively. The family history of premature CAD represents a high percentage of CAD without TRF pa-tients compared to the other groups with a statistical difference of p-value= 0.004*. A high prevalence of AG+GG genotypes among the different groups was obtained, representing 66.0% of CAD with TRF, 76.0% of CAD without TRF, and 60% of non-CAD with TRF patients. The present study elucidated the impact of KIF6 Trp719Arg as a dependent risk factor for CAD, as it could have a significant role in CAD develop-ment when it interacts with one or more of the other traditional risk factors.

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The Trp719Arg polymorphism of the KIF6 gene and coronary heart disease risk: systematic review and meta-analysis

Cited by 5 publications

References 35 publications

KIF6 gene as a pharmacogenetic marker for lipid-lowering effect in statin treatment

KIF6 gene as a pharmacogenetic marker for lipid-lowering effect in statin treatment

Predicted deleterious variants in ABCA1, LPL, LPA and KIF6 are associated with statin response and adverse events in patients with familial hypercholesterolemia and disturb protein structure and stability

Impact of KIF6 Trp719Arg gene variant on Coronary Artery Disease Development

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