Using the method of Multifactor Dimensionality Reduction (MDR) and its modifications for analysis of gene-gene and gene-environment interactions in genetic-epidemiological studies (review)

Ponomarenko, Irina

doi:10.18413/2313-8955-2019-5-1-0-1

Cited by 18 publications

(8 citation statements)

References 9 publications

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Section: Statistical and Bioinformatic Analysismentioning

confidence: 62%

“…A joint contribution of genes to the risk of IS was evaluated by method multifactor dimensionality reduction (MDR), a data-mining and model-free bioinformatic approach to identifying high-order gene-gene and geneenvironment interactions determining susceptibility to complex multifactorial disorders. 21,22 In the present study, T A B L E 1 Baseline and clinical characteristics of the study population we utilized the model-based multifactor dimensionality reduction method (MB-MDR), an extension of the MDR method, which measures the association between multilocus genotypes and the phenotype, providing a set of statistically significant interactions instead of a single best model. 23 The mbmdr package for R was used to perform modeling gene-gene interactions underlying stroke susceptibility.…”

Section: Statistical and Bioinformatic Analysismentioning

confidence: 99%

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Matrix metalloproteinases as target genes for gene regulatory networks driving molecular and cellular pathways related to a multistep pathogenesis of cerebrovascular disease

Polonikov

Рымарова

Klyosova

et al. 2019

J of Cellular Biochemistry

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The present study investigated a joint contribution of matrix metalloproteinases (MMPs) genes to ischemic stroke (IS) development and analyzed interactions between MMP genes and genome‐wide associated loci for IS. A total of 1288 unrelated Russians (600 IS patients and 688 healthy individuals) from Central Russia were recruited for the study. Genotyping of seven single nucleotide polymorphisms (SNPs) of MMP genes (rs1799750, rs243865, rs3025058, rs11225395, rs17576, rs486055, and rs2276109) and eight genome‐wide associated loci for IS were done using Taq‐Man–based assays and MALDI‐TOF mass spectrometry iPLEX platform, respectively. Allele − 799T at rs11225395 of the MMP8 gene was significantly associated with a decreased risk of IS after adjustment for sex and age (OR = 0.82; 95%CI, 0.70‐0.96; P = 0.016). The model‐based multifactor dimensionality reduction method has revealed 21 two‐order, 124 three‐order, and 474 four‐order gene‐gene (G×G) interactions models meaningfully (Pperm < 0.05) associated with the IS risk. The bioinformatic analysis enabled establishing the studied MMP gene polymorphisms possess a clear regulatory potential and may be targeted by gene regulatory networks driving molecular and cellular pathways related to the pathogenesis of IS. In conclusion, the present study was the first to identify an association between polymorphism rs11225395 of the MMP8 gene and IS risk. The study findings also indicate that MMPs deserve special attention as a potential class of genes influencing the multistep mechanisms of cerebrovascular disease including atherosclerosis in cerebral arteries, acute cerebral artery occlusion as well as the ischemic injury of the brain and its recovery.

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Section: Statistical and Bioinformatic Analysismentioning

confidence: 62%

Section: Statistical and Bioinformatic Analysismentioning

confidence: 99%

Matrix metalloproteinases as target genes for gene regulatory networks driving molecular and cellular pathways related to a multistep pathogenesis of cerebrovascular disease

Polonikov

Рымарова

Klyosova

et al. 2019

J of Cellular Biochemistry

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“…There was calculated the agreement of SNP genotype observed frequencies (KOA/KOA-free cohorts) to HWE [ 46 , 47 ]. To investigate the statistical dependence between individual SNP variants (allelic, additive, recessive, and dominant models have been employed [ 48 ]) and SNP interactions (simulation epistatic models were executed [ 49 ] with KOA using gPLINK [ 50 ] and MB-MDR [ 51 , 52 ] programs taking into account a number of confounders such as age, BMI, sex, hereditary, occupation-associated physical workload, leisure time physical activity, and the concomitant pathology availability (the musculoskeletal, cardiovascular, and endocrine systems) ( Table 1 ). Parameters OR and 95% CI (odd ratio and confidence intervals of OR, respectively) have been utilized for the SNP-KOA dependence strength estimates [ 53 , 54 ].…”

Section: Methodsmentioning

confidence: 99%

Intergenic Interactions of SBNO1, NFAT5 and GLT8D1 Determine the Susceptibility to Knee Osteoarthritis among Europeans of Russia

Novakov

Novakova

Churnosova

et al. 2023

Life

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This study was conducted to examine the associations between genome-wide association studies (GWAS)-important single nucleotide polymorphisms (SNPs) and knee osteoarthritis (KOA) among Europeans of Russia. The present replicative study (“patient-control” design has been used) was carried out on 1000 DNA samples from KOA (n = 500) and KOA-free (n = 500) participants. Ten GWAS-important for KOA SNPs of eight candidate genes (LYPLAL1, GNL3, GLT8D1, SBNO1, WWP2, NFAT5, TGFA, GDF5) were studied. To assess the link between SNPs and KOA susceptibility, logistic regression (to establish independent SNP effects) and MB-MDR (to identify SNP–SNP interactions) were used. As a result of this genetic analysis, the associations of individual SNPs with KOA have not been proven. Eight loci out of ten tested SNPs interacted with each other (within twelve genetic models) and determined susceptibility to KOA. The greatest contribution to the disease development were made by three polymorphisms/genes such as rs6976 (C>T) GLT8D1, rs56116847 (G>A) SBNO1, rs6499244 (T>A) NFAT5 (each was included in 2/3 [8 out 12] KOA-responsible genetic interaction models). A two-locus epistatic interaction of rs56116847 (G >A) SBNO1 × rs6499244 (T>A) NFAT5 determined the maximum percentage (0.86%) of KOA entropy. KOA-associated SNPs are regulatory polymorphisms that affect the expression/splicing level, epigenetic modification of 72 genes in KOA-pathogenetically significant organs such as skeletal muscles, tibial arteries/nerves, thyroid, adipose tissue, etc. These putative KOA-effector genes are mainly involved in the organization/activity of the exoribonuclease complex and antigen processing/presentation pathways. In conclusion, KOA susceptibility among Europeans of Russia is mediated by intergenic interactions (but not the main effects) of GWAS-important SNPs.

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“…The cross-validation of the most significant models of intergenic interactions associated with EH was conducted by MDR (Multifactor Dimensionality Reduction) 47 , as implemented in the MDR software (v.3.0.2) ( http://sourceforge.net/projects/mdr ). The MDR method was used to assess the nature and strength (contribution to entropy) of gene–gene interactions and visualize them in graph form 48 .…”

Section: Methodsmentioning

confidence: 99%

Polymorphisms of the matrix metalloproteinase genes are associated with essential hypertension in a Caucasian population of Central Russia

Moskalenko

Ponomarenko

Reshetnikov

et al. 2021

Sci Rep

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This study aimed to determine possible association of eight polymorphisms of seven MMP genes with essential hypertension (EH) in a Caucasian population of Central Russia. Eight SNPs of the MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, and MMP12 genes and their gene–gene (epistatic) interactions were analyzed for association with EH in a cohort of 939 patients and 466 controls using logistic regression and assuming additive, recessive, and dominant genetic models. The functional significance of the polymorphisms associated with EH and 114 variants linked to them (r2 ≥ 0.8) was analyzed in silico. Allele G of rs11568818 MMP7 was associated with EH according to all three genetic models (OR = 0.58–0.70, pperm = 0.01–0.03). The above eight SNPs were associated with the disorder within 12 most significant epistatic models (OR = 1.49–1.93, pperm < 0.02). Loci rs1320632 MMP8 and rs11568818 MMP7 contributed to the largest number of the models (12 and 10, respectively). The EH-associated loci and 114 SNPs linked to them had non-synonymous, regulatory, and eQTL significance for 15 genes, which contributed to the pathways related to metalloendopeptidase activity, collagen degradation, and extracellular matrix disassembly. In summary, eight studied SNPs of MMPs genes were associated with EH in the Caucasian population of Central Russia.

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Using the method of Multifactor Dimensionality Reduction (MDR) and its modifications for analysis of gene-gene and gene-environment interactions in genetic-epidemiological studies (review)

Abstract: Использование метода Multifactor Dimensionality Reduction (MDR) и его модификаций для анализа ген-генных и генно-средовых взаимодействий Обзор Review

Cited by 18 publications

References 9 publications

Matrix metalloproteinases as target genes for gene regulatory networks driving molecular and cellular pathways related to a multistep pathogenesis of cerebrovascular disease

Matrix metalloproteinases as target genes for gene regulatory networks driving molecular and cellular pathways related to a multistep pathogenesis of cerebrovascular disease

Intergenic Interactions of SBNO1, NFAT5 and GLT8D1 Determine the Susceptibility to Knee Osteoarthritis among Europeans of Russia

Polymorphisms of the matrix metalloproteinase genes are associated with essential hypertension in a Caucasian population of Central Russia

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