Related Experiment Video
Updated: May 9, 2026
11:37
QTL Mapping and CRISPR/Cas9 Editing to Identify a Drug Resistance Gene in Toxoplasma gondii
Published on: June 22, 2017
Trans-ancestral studies fine map the SLE-susceptibility locus TNFSF4
Harinder Manku1, Carl D Langefeld, Sandra G Guerra
1Department of Medical & Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.
Plos Genetics
|July 23, 2013
Summary
This study identifies a specific genetic variant, rs2205960-T, strongly associated with Systemic Lupus Erythematosus (SLE) across diverse populations. This variant influences autoantibody production and lymphocyte function, highlighting TNFSF4
Area of Science:
- Genetics and Immunology
- Autoimmune Diseases
- Molecular Biology
Background:
- An 80 kb haplotype upstream of TNFSF4 was previously identified as a susceptibility locus for Systemic Lupus Erythematosus (SLE).
- SLE-associated alleles at this locus are linked to inflammatory conditions such as atherosclerosis and ischemic stroke.
- Identifying causal variants within the TNFSF4 region has been challenging in European populations due to strong linkage disequilibrium.
Purpose of the Study:
- To fine-map the TNFSF4 susceptibility locus using a trans-ancestral approach across diverse ethnic groups.
- To identify specific causal variants and their functional mechanisms contributing to SLE pathogenesis.
- To investigate the association of genetic variants with clinical manifestations like autoantibody production and lymphopenia.
Main Methods:
- A trans-ancestral fine-mapping approach utilizing a large cohort of 17,900 SLE cases and controls from European, Amerindian/Hispanic, African-American, and East Asian populations.
- Fine-scale recombination rate inference to resolve haplotypes across different ancestries.
- Conditional regression analyses, electrophoretic mobility shift assays (EMSA), and chromatin immunoprecipitation sequencing (ChIP-seq) to delineate causal variants and their molecular interactions.
Main Results:
- Strong association of risk alleles with SLE was observed across all tested ethnicities, with significant replication in African-American Gullah populations.
- Two adjacent markers, rs2205960-T and rs1234317-T, showed the strongest evidence of association.
- rs2205960-T was identified as a key risk variant in African-Americans, associated with autoantibody production and lymphopenia, and predicted to enhance binding to NF-κBp65.
Conclusions:
- The study confirms a global association signal at the TNFSF4 locus for SLE, with rs2205960-T being a significant risk variant across multiple populations.
- rs2205960-T's functional impact on NF-κB binding suggests a role in lymphocyte dysregulation during SLE pathogenesis.
- The trans-ancestral mapping approach proved effective in dissecting complex genetic loci associated with autoimmune diseases.
More Related Videos
Related Concept Videos
01:11Genome-wide Association Studies-GWAS
Genome-wide association studies or GWAS are used to identify whether common SNPs are associated with certain diseases. Suppose specific SNPs are more frequently observed in individuals with a particular disease than those without the disease. In that case, those SNPs are said to be associated with the disease. Chi-square analysis is performed to check the probability of the allele likely to be associated with the disease.
GWAS does not require the identification of the target gene involved in...
GWAS does not require the identification of the target gene involved in...
01:43Incomplete Dominance
Gregor Mendel's work (1822 - 1884) was primarily focused on pea plants. Through his initial experiments, he determined that every gene in a diploid cell has two variants called alleles inherited from each parent. He suggested that amongst these two alleles, one allele is dominant in character and the other recessive. The combination of alleles determines the phenotype of a gene in an organism.
01:05Single Nucleotide Polymorphisms-SNPs
A single nucleotide polymorphism or SNP is a single nucleotide variation at a specific genomic position in a large population. It is the most prevalent type of sequence variation found in the human genome. Point mutations that occur in more than 1% of the population qualify as SNPs. These are present once every 1000 nucleotides on an average in the human genome. Replacement of a purine with another purine (A/G) or a pyrimidine with another pyrimidine (C/T) is known as a transition. In contrast,...
01:33Pleiotropy
Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
01:35Pedigree Analysis
Overview
03:18Non-LTR Retrotransposons
As the name suggests, non-LTR retrotransposons lack the long terminal repeats characteristic of the LTR retrotransposons. Additionally, both LTR and non-LTR retrotransposons use distinct mechanisms of mobilization. Non-LTR retrotransposons are further divided into two classes - Long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs), both of which occur abundantly in most mammals, including humans. Some of the active non-LTR retrotransposons in humans are L1...