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Computationally identifying novel NF-kappa B-regulated immune genes in the human genome.

ABSTRACT: Identifying novel NF-kappa B-regulated immune genes in the human genome is important to our understanding of immune mechanisms and immune diseases. We fit logistic regression models to the promoters of 62 known NF-kappa B-regulated immune genes, to find patterns of transcription factor binding in the promoters of genes with known immune function. Using these patterns, we scanned the promoters of additional genes to find matches to the patterns, selected those with NF-kappa B binding sites conserved in the mouse or fly, and then confirmed them as NF-kappa B-regulated immune genes based on expression data. Among 6440 previously identified promoters in the human genome, we found 28 predicted immune gene promoters, 19 of which regulate genes with known function, allowing us to calculate specificity of 93%-100% for the method. We calculated sensitivity of 42% when searching the 62 known immune gene promoters. We found nine novel NF-kappa B-regulated immune genes which are consistent with available SAGE data. Our method of predicting gene function, based on characteristic patterns of transcription factor binding, evolutionary conservation, and expression studies, would be applicable to finding genes with other functions.

SUBMITTER: Liu R

PROVIDER: S-EPMC430162 | biostudies-literature | 2003 Apr

REPOSITORIES: biostudies-literature

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Computationally identifying novel NF-kappa B-regulated immune genes in the human genome.

Liu Rongxiang R McEachin Richard C RC States David J DJ

Genome research 20030312 4

Identifying novel NF-kappa B-regulated immune genes in the human genome is important to our understanding of immune mechanisms and immune diseases. We fit logistic regression models to the promoters of 62 known NF-kappa B-regulated immune genes, to find patterns of transcription factor binding in the promoters of genes with known immune function. Using these patterns, we scanned the promoters of additional genes to find matches to the patterns, selected those with NF-kappa B binding sites conser ...[more]

PMID: 12654722

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Project description:PurposeTo select individuals and families with a low genetic burden for age-related macular degeneration (AMD), to inform the clinical diagnosis of macular disorders, and to find novel genetic variants associated with maculopathies.DesignGenetic association study based on targeted and whole-exome sequencing.ParticipantsA total of 758 subjects (481 individuals with maculopathy and 277 controls), including 316 individuals in 72 families.MethodsWe focused on 150 genes involved in the complement, coagulation, and inflammatory pathways. Single-variant tests were performed on 7755 variants shared among ≥ 5 subjects using logistic regression. Gene-based tests were used to evaluate aggregate effects from rare and low-frequency variants (at minor allele frequency [MAF] ≤ 5% or ≤ 1%) in a gene using burden tests. For families whose affected members had a low burden of genetic risk based on known common and rare variants related to AMD, we searched for rare variants (MAF < 0.001) whose risk alleles occurred in ≥ 80% of affected individuals but not in controls. Immunohistochemistry was performed to determine the protein expression of a novel gene (coagulation factor II thrombin receptor-like 2 [F2RL2]) in retinal tissues.Main outcome measuresGenotypes and phenotypes of macular degeneration.ResultsWe confirmed the association of a synonymous variant in complement factor H (Ala473, rs2274700, proxy to intronic rs1410996, r 2 = 1) with maculopathy (odds ratio, 0.64; P = 4.5 × 10-4). Higher AMD polygenic risk scores (PRSs) were associated with intermediate and advanced AMD. Among families with low PRSs and no known rare variants for maculopathy, we identified 2 novel, highly penetrant missense rare variants in ADAM15, A disintegrin and metalloprotease, metallopeptidase domain 15 (p.Arg288Cys) and F2RL2 (p.Leu289Arg). Immunohistochemistry analyses revealed F2RL2 protein expression in cone photoreceptor outer segments and Müller glia cells of human and pig retinas. Coagulation factor II thrombin receptor-like 2 expression appeared increased in fibrotic areas in advanced AMD samples with neovascularization, suggesting that F2RL2 may play a role in the progression to advanced macular disease.ConclusionsNew missense rare variants in the genes ADAM15 and F2RL2 were associated with maculopathies. Results suggest that novel genes related to the coagulation and immune pathways may be involved in the pathogenesis of macular diseases.

Dataset Information

Computationally identifying novel NF-kappa B-regulated immune genes in the human genome.

Publications

Computationally identifying novel NF-kappa B-regulated immune genes in the human genome.

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