A GWAS on Helicobacter pylori strains points to genetic variants associated with gastric cancer risk.
A GWAS on Helicobacter pylori strains points to genetic variants associated with gastric cancer risk.
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DOI：
10.1186/s12915-018-0550-3
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发表时间：
2018-08-02
期刊：
影响因子：
5.4
通讯作者：
Sheppard SK
中科院分区：
文献类型：
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作者：
Berthenet E;Yahara K;Thorell K;Pascoe B;Meric G;Mikhail JM;Engstrand L;Enroth H;Burette A;Megraud F;Varon C;Atherton JC;Smith S;Wilkinson TS;Hitchings MD;Falush D;Sheppard SK
幽门螺杆菌是一种存在于全球约50%人口中的胃部细菌。感染在大多数情况下是无症状的，但它与胃炎、胃溃疡和胃癌有关。流行病学证据表明，癌症的进展取决于宿主和病原体因素，但关于为什么癌症表型在少数感染者中发展的问题仍然存在。在这里，我们使用比较基因组学方法来了解细菌菌株之间的遗传变异是如何影响疾病进展的。我们对来自已知疾病病因的欧洲人群(HpEurope)的173个幽门螺杆菌分离株进行了全基因组关联研究，其中包括49个来自胃癌患者的分离株。我们鉴定了胃癌患者和胃炎患者分离株之间频率不同的SNPs和基因。胃癌的表型与BABA和CAG致病岛基因的存在有关，CAG致病岛是幽门螺杆菌的主要毒力决定因素之一，以及几个研究较少的基因的非同义变异。我们根据存在的相关元素的风险水平设计了一个简单的风险评分，它有可能识别可能导致癌症的菌株，但需要改进和验证。将GWAS应用于细菌感染面临许多挑战，包括难以获得匹配的对照、多菌株定植以及在检测到疾病时可能不存在致病菌株。我们的结果表明，细菌因素对疾病进展有足够强烈的影响，即使是小规模的GWA也能识别它们。因此，幽门螺杆菌感染可以阐明致病机制并指导临床治疗方案，包括对无症状携带者的治疗。本文的在线版本(10.1186/s12915-0180550-3)包含向授权用户提供的补充材料。
Helicobacter pylori are stomach-dwelling bacteria that are present in about 50% of the global population. Infection is asymptomatic in most cases, but it has been associated with gastritis, gastric ulcers and gastric cancer. Epidemiological evidence shows that progression to cancer depends upon the host and pathogen factors, but questions remain about why cancer phenotypes develop in a minority of infected people. Here, we use comparative genomics approaches to understand how genetic variation amongst bacterial strains influences disease progression. We performed a genome-wide association study (GWAS) on 173 H. pylori isolates from the European population (hpEurope) with known disease aetiology, including 49 from individuals with gastric cancer. We identified SNPs and genes that differed in frequency between isolates from patients with gastric cancer and those with gastritis. The gastric cancer phenotype was associated with the presence of babA and genes in the cag pathogenicity island, one of the major virulence determinants of H. pylori, as well as non-synonymous variations in several less well-studied genes. We devised a simple risk score based on the risk level of associated elements present, which has the potential to identify strains that are likely to cause cancer but will require refinement and validation. There are a number of challenges to applying GWAS to bacterial infections, including the difficulty of obtaining matched controls, multiple strain colonization and the possibility that causative strains may not be present when disease is detected. Our results demonstrate that bacterial factors have a sufficiently strong influence on disease progression that even a small-scale GWAS can identify them. Therefore, H. pylori GWAS can elucidate mechanistic pathways to disease and guide clinical treatment options, including for asymptomatic carriers. The online version of this article (10.1186/s12915-018-0550-3) contains supplementary material, which is available to authorized users.