口唇口蓋裂やアトピー性皮膚炎の発症に関連する一塩基多型の機能的役割を解明~非コード領域にある1塩基の違いが、上皮初期分化を担う遺伝子発現制御の鍵を握る~

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2025-05-16 東京科学大学

東京科学大学とオックスフォード大学の研究チームは、非コード領域にある一塩基多型(SNP)rs3741442が、非症候群性口唇口蓋裂やアトピー性皮膚炎の発症に関与することを明らかにした。エピジェネティック解析やゲノム編集実験により、このSNPが上皮初期分化関連遺伝子の発現制御に影響を及ぼすことを確認。非コード領域にある遺伝的変異が疾患発症に重要な役割を果たすことを示し、今後の治療法開発にも寄与が期待される。

口唇口蓋裂やアトピー性皮膚炎の発症に関連する一塩基多型の機能的役割を解明~非コード領域にある1塩基の違いが、上皮初期分化を担う遺伝子発現制御の鍵を握る~口唇口蓋裂の発症に関わる一塩基多型rs3741442の解析

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非コードSNP rs3741442の顔面裂隙に対する機能的影響 The Functional Impact of the Noncoding SNP rs3741442 on Orofacial Clefting

N. Funato and S.R.F. Twigg
Journal of Dental Research  Published:May 12, 2025
DOI:https://doi.org/10.1177/00220345251334385

Abstract

Orofacial cleft (OFC) is a common congenital anomaly in humans with variable birth prevalence in different ethnic groups. Although genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with nonsyndromic OFC (nsOFC), understanding of the underlying biological mechanisms of causative SNPs and genes in nsOFC remains limited. Here, we report that the noncoding SNP, rs3741442, has an expression quantitative trait locus (eQTL) effect on epithelial genes associated with periderm differentiation. Using a combination of epigenetic markers and in silico analysis, we prioritized the intergenic SNP rs3741442 as a potential causal factor in nsOFC. The risk allele of rs3741442 is prevalent in East Asian populations, and its presence in CRISPR-edited cells leads to reduced expression of neighboring KRT18 and EIF4B. The transcription factor SP1 differentially binds the risk versus nonrisk alleles of rs3741442. Alongside this cis-eQTL impact, rs3741442 has a trans-eQTL effect on the epithelial gene TP63 that is associated with syndromic forms of OFC and psoriasis. These findings provide insights into the mechanism by which an intergenic SNP can affect palatogenesis through the modulation of gene expression.

医療・健康
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