Gaitanidis Apostolos, Christensen Mathias A, Dorken Gallastegi Ander, Breen Kerry A, Velmahos George C, Kaafarani Haytham M A, Farhat Maha R
Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, Boston, Massachusetts, USA.
Department of Anesthesia, Center of Head and Orthopedics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
World J Surg. 2025 May;49(5):1282-1289. doi: 10.1002/wjs.12575. Epub 2025 Apr 8.
Intestinal malrotation is a congenital malformation of the embryonic gut that may cause midgut volvulus either in children or adults. Our understanding of its genetic background stems from reports of syndromic or familial forms and no genome-wide association studies (GWAS) have been reported. We perform the first GWAS to identify common variants associated with this malformation.
Subjects were enrolled and genotyped as part of the Mass General Brigham Biobank and individuals with diagnosis of intestinal malrotation were identified. Single nucleotide polymorphisms (SNPs) with minor allele frequency ≥ 5% were examined for association with intestinal malrotation using mixed linear model association analysis. SNPs that surpassed the significance threshold (p < 5E-08) were further examined in a separate validation cohort.
The derivation cohort included 11,106 individuals (70 [0.6%] cases), and the validation cohort included 4134 individuals (21 [0.5%] cases). Five exonic SNPs in two loci at chromosomes 17p13 (lead SNP rs75147837, beta = 0.0044, and p = 7.97E-10) and 10q26 (lead SNP rs3121846, beta = 0.0057, p = 3.28E-08) had p < 5E-08. After validation, 2 SNPs at 17p13 were associated with the phenotype (rs72631499 adjusted-p = 0.010 and rs148094507 adjusted-p = 0.014). eQTL (expression Quantitative Trait Loci) analysis mapped 6 genes to the identified locus (PITPNA, TRARG1, INPP5K, YWHAE, PITPNA-AS1, and FAM57A).
We report results from the first GWAS on intestinal malrotation. A locus at 17p13 is associated with intestinal malrotation and may guide genetic guidance and improve our understanding of this malformation. Rs72631499 was found to be a binding site for HNF4A, a transcription factor that plays important roles in normal embryonic gut development.
肠旋转不良是胚胎肠道的一种先天性畸形，可在儿童或成人中导致中肠扭转。我们对其遗传背景的了解源于综合征性或家族性形式的报告，尚未有全基因组关联研究（GWAS）的报道。我们开展了首例GWAS以识别与此畸形相关的常见变异。
作为麻省总医院布莱根生物样本库的一部分，招募受试者并进行基因分型，识别出诊断为肠旋转不良的个体。使用混合线性模型关联分析检查次要等位基因频率≥5%的单核苷酸多态性（SNP）与肠旋转不良的关联。超过显著性阈值（p < 5E - 08）的SNP在一个单独的验证队列中进一步检查。
推导队列包括11106名个体（70例[0.6%]），验证队列包括4134名个体（21例[0.5%]）。17号染色体p13区域两个位点（主SNP rs75147837，β = 0.0044，p = 7.97E - 10）和10号染色体q26区域（主SNP rs3121846，β = 0.0057，p = 3.28E - 08）的五个外显子SNP的p < 5E - 08。验证后，17p13区域的2个SNP与该表型相关（rs72631499校正p = 0.010，rs148094507校正p = 0.014）。表达数量性状基因座（eQTL）分析将6个基因定位到已识别的位点（PITPNA、TRARG1、INPP5K、YWHAE、PITPNA - AS1和FAM57A）。
我们报告了首例关于肠旋转不良的GWAS结果。17p13区域的一个位点与肠旋转不良相关，可能为遗传指导提供依据并增进我们对这种畸形的理解。发现rs72631499是HNF4A的一个结合位点，HNF4A是一种在正常胚胎肠道发育中起重要作用的转录因子。
