FUT2 Variants Confer Susceptibility to Familial Otitis Media
FUT2 Variants Confer Susceptibility to Familial Otitis Media
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DOI：
10.1016/j.ajhg.2018.09.010
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发表时间：
2018-11-01
影响因子：
9.8
通讯作者：
Ahmed, Zubair M.
中科院分区：
文献类型：
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作者：
Santos-Cortez, Regie Lyn P.;Chiong, Charlotte M.;Ahmed, Zubair M.
由于共同FUT 2变异纯合性导致的非分泌状态c. 461 G> A（p.Trp154 *）与自身免疫性疾病的风险或对病毒性腹泻和HIV的保护相关。我们通过从609个多民族中耳炎家系和单纯病例中获取DNA样本，确定FUT 2在中耳炎易感性中的作用。进行外显子组和桑格测序、连锁分析以及Fisher精确和传递不平衡检验（TDT）。FUT2 C。604 C> T（p.Arg202 *）变异体在菲律宾家系中与中耳炎共分离（LOD = 4.0）。此外，一种罕见的变异，C。412 C> T（p.Arg138Cys）与欧美儿童（p = 1.2310（-5））和美国三人组（TDT p = 0.01）的复发/慢性中耳炎相关。梭461 G> A（p.Trp154 *）变异体在美国三人组中也过度传播（TDT p = 0.01），并与中耳微生物群组成的变化（PERMANOVA p < 10（-7））和生物多样性增加有关。当将CADD> 20的多种族美国三人组中鉴定出的所有错义和无义变体合并时，FUT 2变体在三人组中过度传播（TDTp = 0.001）。小鼠中耳接种流感嗜血杆菌后Fut 2表达瞬时上调四种FUT 2变异体，即p.Ala104Val、p.Arg138Cys、p.Trp154 * 和p.Arg202 *，减少了mu-1转染的COS-7细胞中的A抗原，而无义变异体也减少了FUT 2蛋白水平。常见和罕见的FUT 2变体赋予中耳炎的易感性，可能是通过调节上皮细胞中的A抗原水平来修饰中耳微生物组。我们的家庭表现出明显的家族内遗传异质性，这表明常见和罕见变异的多种组合加上环境因素会影响个体中耳炎表型，这是一种复杂的特征。
Non-secretor status due tohomozygosity for the commonFUT2 variant c. 461G> A(p. Trp154*) is associated witheither risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjectswith otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c. 604C> T (p. Arg202*) variant co-segregates with otitismedia in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c. 412C> T (p. Arg138Cys), is associated with recurrent/ chronic otitismedia in European-American children (p = 1.2310(-5)) and US trios (TDT p = 0.01). The c. 461G> A (p. Trp154*) variant was also overtransmitted in US trios (TDT p = 0.01) and was associated with shifts inmiddle ear microbiota composition (PERMANOVA p < 10(-7)) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios withCADD> 20 were combined, FUT2 variantswere over-transmitted in trios (TDTp = 0.001). Fut2 is transiently upregulated inmouse middle ear after inoculation withnon-typeable Haemophilus influenzae. Four FUT2 variants-namely p. Ala104Val, p. Arg138Cys, p. Trp154*, and p. Arg202*-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our familiesdemonstratemarked intra-familial genetic heterogeneity, suggesting thatmultiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.