Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants.
Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants.
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耳炎培养基的敏感性和由于Spink5变体引起的头部和颈部微生物组的变化。
DOI：
10.1136/jmedgenet-2020-106844
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发表时间：
2021-07
影响因子：
4
通讯作者：
Santos-Cortez RLP
中科院分区：
文献类型：
--
作者：
Frank DN;Giese APJ;Hafren L;Bootpetch TC;Yarza TKL;Steritz MJ;Pedro M;Labra PJ;Daly KA;Tantoco MLC;Szeremeta W;Reyes-Quintos MRT;Ahankoob N;Llanes EGDV;Pine HS;Yousaf S;Ir D;Einarsdottir E;de la Cruz RAR;Lee NR;Nonato RMA;Robertson CE;Ong KMC;Magno JPM;Chiong ANE;Espiritu-Chiong MC;San Agustin ML;Cruz TLG;Abes GT;Bamshad MJ;Cutiongco-de la Paz EM;Kere J;Nickerson DA;Mohlke KL;Riazuddin S;Chan A;Mattila PS;Leal SM;Ryan AF;Ahmed ZM;Chonmaitree T;Sale MM;Chiong CM;Santos-Cortez RLP
中耳炎（OM）的易感性有显着的遗传性，但在OM的罕见变异的作用大多是未知的。我们的目标是确定赋予OM易感性的新的罕见变异。我们对来自551个患有OM的多种族家庭和无关个体的> 1，000个DNA样本进行了外显子组和桑格测序，RNA测序，以及微生物组测序和外耳，中耳，鼻咽和口腔拭子分析。我们还研究了感染和健康中耳组织中的蛋白定位和基因表达。一个包括81个受OM影响的个体和53个未受影响的个体的大型通婚家系共分离了SPINK5内的两种已知罕见A2ML1变体，一种常见的FUT2变体和一种罕见的新型致病性变体c.1682A>G（p.Glu561Gly）（LOD=4.09）。SPINK 5错义变体的携带导致中耳中微杆菌科的相对丰度增加，沿着外耳和口腔中而不是鼻咽中微杆菌科的出现。在12个OM家族和个体中鉴定出另外8种新的SPINK5变体。SPINK5在OM易感性中的作用进一步得到以下方面的支持：变异载体中较低的RNA计数、SPINK5在外耳皮肤中的强定位、对中耳粘膜和鼓膜的微弱定位以及SPINK5在人中耳瘤中的表达增加。SPINK5变体赋予非综合征性OM的易感性。这些变体可能通过破坏粘膜和上皮屏障、免疫缺陷（如疫苗接种反应差）、改变头颈部微生物群以及促进机会性病原体进入中耳而导致中耳病理。
Otitis media (OM) susceptibility has significant heritability, however the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility. We performed exome and Sanger sequencing of >1,000 DNA samples from 551 multi-ethnic families with OM and unrelated individuals, RNA-sequencing, and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined protein localization and gene expression in infected and healthy middle ear tissues. A large, intermarried pedigree that includes 81 OM-affected and 53 unaffected individuals co-segregates two known rare A2ML1 variants, a common FUT2 variant and a rare, novel pathogenic variant c.1682A>G (p.Glu561Gly) within SPINK5 (LOD=4.09). Carriage of the SPINK5 missense variant resulted in increased relative abundance of Microbacteriaceae in the middle ear, along with occurrence of Microbacteriaceae in the outer ear and oral cavity but not the nasopharynx. Eight additional novel SPINK5 variants were identified in twelve families and individuals with OM. A role for SPINK5 in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localization in outer ear skin, faint localization to middle ear mucosa and eardrum, and increased SPINK5 expression in human cholesteatoma. SPINK5 variants confer susceptibility to non-syndromic OM. These variants potentially contribute to middle ear pathology through breakdown of mucosal and epithelial barriers, immunodeficiency such as poor vaccination response, alteration of head and neck microbiota, and facilitation of entry of opportunistic pathogens into the middle ear.
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影响因子：
2.6
作者：
Chan, Chun Ling;Wabnitz, David;Psaltis, Alkis James
通讯作者：
Psaltis, Alkis James
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
4.1
作者：
Maatouk, I.;Moutran, R.;Tomb, R.
通讯作者：
Tomb, R.
影响因子：
120.7
作者：
Casselbrant, ML;Mandel, EM;Ferrell, RE
通讯作者：
Ferrell, RE
影响因子：
8
作者：
Chonmaitree, Tasnee;Trujillo, Rocio;McCormick, David P.
通讯作者：
McCormick, David P.