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公共データの統合・再解析に基づく乾癬発症リスクと関連する機能多型の網羅的探索

久保田, 直人 KUBOTA, Naoto クボタ, ナオト 九州大学

2020.07.31

概要

ヒト疾患の多くは一塩基多型(Single Nucleotide Polymorphisms: SNPs)などの複数の遺伝的要因の積み重ねによって引き起こされる多因子疾患である.これまで,SNPs と疾患を含む様々な形質との関連を調べる手法であるゲノムワイド関連解析(Genome-Wide Association Study: GWAS)が様々な形質に対して実施されており,多くの疾患リスク SNPs が同定されているが,報告されている SNPs はマーカーに過ぎず,実際に影響を及ぼしている機能多型の多くは未だ不明なままである.分子病態の詳細を理解するためには,機能多型を同定した上でそれぞれが遺伝子機能にどのような影響を及ぼしているのか,その作用機序を明らかにする必要がある.本論文では,代表的な多因子疾患である慢性皮膚角化疾患の乾癬を対象として,公共ゲノム・エピゲノム・トランスクリプトームデータの統合・再解析による機能多型の網羅的探索を行った.

本解析の結果,22 個の乾癬関連機能多型候補を同定した.その内,non-coding 領域に位置するものは 8 個であり,全てが未報告であった.とくに,1 番染色体に存在する多型(rs72635708)が EGF signaling 制御因子をコードする ERRFI1 遺伝子の遠位エンハンサー領域に存在することを発見した.このエンハンサー領域には AP-1 転写因子を構成するタンパク質の結合が認められ, rs72635708 はその認識配列に位置していたことから,この多型は AP-1 転写因子の結合レベルを変化させ転写活性を減少させる可能性が考えられた.また, DNase-seq データの allele-specific mapping の結果を参照すると,この多型はクロマチン構造を変化させることも明らかになった.以上の結果より,乾癬発症に関与する機能多型およびターゲット遺伝子の具体例を初めて示すことができた.

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