Genome-wide polygenic analysis of multiple sclerosis markers

Objective: to perform a genome-wide polygenic analysis of multiple sclerosis (MS) markers in the ethnic groups of Bashkirs, Russians, and Tatars living in the Republic of Bashkortostan (Russian Federation).Patients and methods. Genotyping was performed using allele-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism analysis of genes of the human leukocyte differentiation antigens CD6 (rs17824933), CD40 (rs6074022), CD58 (rs2300747), CD86 (rs9282641), transcription factors SOX8 (rs2744148) and ZBTB46 (rs6062314), beta-mannosidase MANBA (rs228614), C-type lectin domain CLEC16A (rs12708716), ribosomal protein S6 kinase B1 RPS6KB1 (rs180515), and long noncoding RNA gene PVT1 (rs759648) in 644 patients with MS and 1408 controls. Multilocus analysis of the disease associations with combinations of genotypes and alleles of the studied polymorphic loci was performed using the APSampler algorithm.Results and discussion. We determined the distribution of genotype and allele frequencies of the studied polymorphic loci in the ethnic groups of Bashkirs, Russians, and Tatars. We also observed disease associations with CD58 (rs2300747) and RPS6KB1 (rs180515) polymorphic loci in Russian men, CD86 (rs9282641) in Russian, PVT1 (rs759648) in Tatar women, CD40 (rs6074022) in Bashkir men, and identified 19 combinations of genotypes and/or alleles significantly associated with MS.Conclusion. Based on the genome-wide polygenic analysis of MS markers, we identified ethno- and gender-specific combined markers of the disease susceptibility.

Download Full-text

Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis

Blood ◽

10.1182/blood-2008-04-147884 ◽

2008 ◽

Vol 112 (7) ◽

pp. 2709-2712 ◽

Cited By ~ 161

Author(s):

Maria E. Sarasquete ◽

Ramon García-Sanz ◽

Luis Marín ◽

Miguel Alcoceba ◽

Maria C. Chillón ◽

...

Keyword(s):

Multiple Myeloma ◽

Cytochrome P450 ◽

Genome Wide Association Study ◽

Osteonecrosis Of The Jaw ◽

Bisphosphonate Therapy ◽

Polymorphism Analysis ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Genome Wide ◽

A Genome

Abstract We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients under bisphosphonate therapy. A genome-wide association study was performed using 500 568 single nucleotide polymorphisms (SNPs) in 2 series of homogeneously treated MM patients, one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four SNPs (rs1934951, rs1934980, rs1341162, and rs17110453) mapped within the cytochrome P450-2C gene (CYP2C8) showed a different distribution between cases and controls with statistically significant differences (P = 1.07 × 10−6, P = 4.231 × 10−6, P = 6.22 × 10−6, and P = 2.15 × 10−6, respectively). SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni correction (P corrected value = .02). Genotyping results displayed an overrepresentation of the T allele in cases compared with controls (48% vs 12%). Thus, individuals homozygous for the T allele had an increased likelihood of developing ONJ (odds ratio 12.75, 95% confidence interval 3.7-43.5).

Download Full-text

A genome-wide screen for association in Hungarian multiple sclerosis

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2003.08.017 ◽

2003 ◽

Vol 143 (1-2) ◽

pp. 84-87 ◽

Cited By ~ 9

Author(s):

Cecilia Rajda ◽

Krisztina Bencsik ◽

Erika Seres ◽

Aslaug Jonasdottir ◽

Thomas Foltynie ◽

...

Keyword(s):

Multiple Sclerosis ◽

Genome Wide ◽

A Genome

Download Full-text

Genome-wide pathway analysis of a genome-wide association study on multiple sclerosis

Molecular Biology Reports ◽

10.1007/s11033-012-2341-1 ◽

2012 ◽

Vol 40 (3) ◽

pp. 2557-2564 ◽

Cited By ~ 12

Author(s):

Gwan Gyu Song ◽

Sung Jae Choi ◽

Jong Dae Ji ◽

Young Ho Lee

Keyword(s):

Multiple Sclerosis ◽

Association Study ◽

Pathway Analysis ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

Download Full-text

A genome-wide screen for linkage disequilibrium in Australian HLA-DRB1*1501 positive multiple sclerosis patients

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2003.08.012 ◽

2003 ◽

Vol 143 (1-2) ◽

pp. 60-64 ◽

Cited By ~ 13

Author(s):

M. Ban ◽

S.J. Sawcer ◽

R.N.S. Heard ◽

B.H. Bennetts ◽

S. Adams ◽

...

Keyword(s):

Multiple Sclerosis ◽

Linkage Disequilibrium ◽

Positive Multiple ◽

Genome Wide ◽

A Genome ◽

Multiple Sclerosis Patients

Download Full-text

A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis

Genes and Immunity ◽

10.1038/sj.gene.6363866 ◽

2002 ◽

Vol 3 (5) ◽

pp. 279-285 ◽

Cited By ~ 57

Author(s):

E Akesson ◽

A Oturai ◽

J Berg ◽

S Fredrikson ◽

O Andersen ◽

...

Keyword(s):

Multiple Sclerosis ◽

Genome Wide ◽

A Genome ◽

Sib Pairs

Download Full-text

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

Science Advances ◽

10.1126/sciadv.1501678 ◽

2016 ◽

Vol 2 (6) ◽

pp. e1501678 ◽

Cited By ~ 53

Author(s):

Till F. M. Andlauer ◽

Dorothea Buck ◽

Gisela Antony ◽

Antonios Bayas ◽

Lukas Bechmann ◽

...

Keyword(s):

Multiple Sclerosis ◽

Genome Wide Association Study ◽

Immune Cell ◽

Susceptibility Loci ◽

Genome Wide ◽

A Genome ◽

Genetic Substructure ◽

Epigenetic Signatures ◽

Folate Cycle ◽

Ms Pathogenesis

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genesL3MBTL3,MAZ,ERG, andSHMT1. The lead variant atSHMT1was replicated in an independent Sardinian cohort. Products of the genesL3MBTL3,MAZ, andERGplay important roles in immune cell regulation.SHMT1encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

Download Full-text

Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials

Multiple Sclerosis Journal ◽

10.1177/1352458518763089 ◽

2018 ◽

Vol 25 (4) ◽

pp. 565-573 ◽

Cited By ~ 4

Author(s):

Dorothea Buck ◽

Till FM Andlauer ◽

Wilmar Igl ◽

Eva-Maria Wicklein ◽

Mark Mühlau ◽

...

Keyword(s):

Multiple Sclerosis ◽

Genetic Variants ◽

Neutralizing Antibodies ◽

Genome Wide Association Study ◽

Phase Iii ◽

Interferon Β ◽

Hla Alleles ◽

Genome Wide ◽

A Genome ◽

Increased Risk

Background: Treatment of multiple sclerosis (MS) with interferon β can lead to the development of antibodies directed against interferon β that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon β. Objective: To validate the proposed genetic markers and to identify new markers. Methods: Associations of genetic candidate markers with antibody presence and development were examined in a post hoc analysis in 941 patients treated with interferon β-1b in the Betaferon® Efficacy Yielding Outcomes of a New Dose (BEYOND) and BEtaseron®/BEtaferon® in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) prospective phase III trials. All patients were treated with interferon β-1b for at least 6 months. In addition, a genome-wide association study was conducted to identify new genetic variants. Results: We confirmed an increased risk for carriers of HLA-DRB1*04:01 (odds ratio (OR) = 3.3, p = 6.9 × 10−4) and HLA-DRB1*07:01 (OR = 1.8, p = 3.5 × 10−3) for developing neutralizing antibodies (NAbs). Several additional, previously proposed HLA alleles and genetic variants showed nominally significant associations. In the exploratory analysis, variants in the HLA region were associated with NAb development at genome-wide significance (OR = 2.6, p = 2.30 × 10−15). Conclusion: The contribution of HLA alleles and HLA-associated single-nucleotide polymorphisms (SNPs) to the development and titer of antibodies against interferon β was confirmed in the combined analysis of two multi-national, multi-center studies.

Download Full-text

Integrative analysis of genome-wide DNA methylation and single-nucleotide polymorphism identified ACSM5 as a suppressor of lumbar ligamentum flavum hypertrophy

Arthritis Research & Therapy ◽

10.1186/s13075-021-02625-5 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Yanlin Cao ◽

Yenan Zhan ◽

Sujun Qiu ◽

Zhong Chen ◽

Kaiqin Gong ◽

...

Keyword(s):

Dna Methylation ◽

Single Nucleotide Polymorphism ◽

Ligamentum Flavum ◽

Global Analysis ◽

Integrated Analysis ◽

Polymorphism Analysis ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Genome Wide ◽

A Genome

Abstract Background Hypertrophy of ligamentum flavum (HLF) is a common lumbar degeneration disease (LDD) with typical symptoms of low back pain and limb numbness owing to an abnormal pressure on spinal nerves. Previous studies revealed HLF might be caused by fibrosis, inflammatory, and other bio-pathways. However, a global analysis of HLF is needed severely. Methods A genome-wide DNA methylation and single-nucleotide polymorphism analysis were performed from five LDD patients with HLF and five LDD patients without HLF. Comprehensive integrated analysis was performed using bioinformatics analysis and the validated experiments including Sanger sequencing, methylation-specific PCR, qPCR and ROC analysis. Furthermore, the function of novel genes in ligamentum flavum cells (LFCs) was detected to explore the molecular mechanism in HLF through knock down experiment, overexpression experiment, CCK8 assay, apoptosis assay, and so on. Results We identified 69 SNP genes and 735 661 differentially methylated sites that were enriched in extracellular matrix, inflammatory, and cell proliferation. A comprehensive analysis demonstrated key genes in regulating the development of HLF including ACSM5. Furthermore, the hypermethylation of ACSM5 that was mediated by DNMT1 led to downregulation of ACSM5 expression, promoted the proliferation and fibrosis, and inhibited the apoptosis of LFCs. Conclusion This study revealed that DNMT1/ACSM5 signaling could enhance HLF properties in vitro as a potential therapeutic strategy for HLF.

Download Full-text

Genome-wide Development of Insertion-deletion (InDel) Markers Database for Cannabis and its uses for Genetic Structure Analysis of Chinese Germplasm and Identification of Sex-linked Marker

10.21203/rs.3.rs-265241/v1 ◽

2021 ◽

Author(s):

Gen Pan ◽

Zheng Li ◽

Siqi Huang ◽

Jie Tao ◽

Yaliang Shi ◽

...

Keyword(s):

Genetic Structure ◽

Cannabis Sativa ◽

Economic Value ◽

Germplasm Conservation ◽

Polymorphism Analysis ◽

Indel Markers ◽

Genome Wide ◽

A Genome ◽

Indel Polymorphisms ◽

Chinese Germplasm

Abstract Background: Cannabis sativa L., a dioecious plant, derived from China, demonstrates important medicinal properties and economic value worldwide. Cannabis properties were usually harnessed depending on the sex of the plant. To analyze the genetic structure of Chinese cannabis and identify sex-linked makers, the genome-wide insertion-deletion (InDel) markers were designed and used. Results: In this study, a genome-wide analysis of insertion–deletion (InDel) polymorphisms was performed based on the recent genome sequences. In total, 47558 InDels were detected between the two varieties, and the length of InDels ranged from 4 bp to 87 bp. The most common InDels were tetranucleotides, followed by pentanucleotides. Chromosome 5 had the highest number of InDels among the cannabis chromosomes, while chromosome 10 had the lowest number. Additionally, a total of 47558 InDel markers were designed, and 84 primers evenly distributed in the cannabis genome were chosen for polymorphism analysis. A total of 38 primers exhibited polymorphisms among three accessions, and of the polymorphism primers, 14 biallelic primers were further used to analyse the genetic structure. A total of 39 fragments were detected, and the PIC value ranged from 0.1209 to 0.6351. According to the Indel markers as well as the flowering time, the 115 Chinese germplasms were divided in two subgroups, which were mainly composed of cultivars from the most north and south regions, respectively. Additional, the marker “ I1-10” was found to amplify two bands (398bp and 251bp) in the male plants, while a 389bp bands in female plants. Using this marker, the feminized and dioecious varieties can also be distinguished.Conclusion: This study will facilitate the genetic improvement and germplasm conservation of cannabis in China, and the sex-linked InDel markers will provide accurate sex identification strategies for cannabis breeding and production.

Download Full-text