Science、MIT高调关注：1/5的健康人携带有与疾病相关的基因突变
23 小时前
来源：生物探索
6月26日，Science、MIT网站都推出一篇围绕“健康人群基因组测序”主题的新闻，揭示两个科研项目的最新成果：1/5“健康”的成年人携带有与疾病相关的基因突变！ 这一结论无疑再一次引爆关于基因测序的争论：有人认为它的出现和发展让预测、诊疗疾病变得更加简便和精准，有望成为预防医学的基石；也有人认为基因检测会造成不必要的医疗费用和心理负担。 首个针对健康人群的随机性全基因组测序项目 第一个研究项目被称为“MedSeq”，由来自于VA波士顿医疗系统、布莱根妇女医院、哈佛医学院、贝勒医学院、俄勒冈健康与科学大学、Broad研究所等研究机构组成的研究团队完成。他们招募100名健康成年人作为研究对象，从中随机挑选50名，接受全基因组测序。通过对每个人的30亿碱基对的深入解读，寻找其中的突变。 这一首个针对健康人群进行的随机性全基因组测序试验表明：5个健康成年人中就有1个人携带有罕见疾病的风险标记或者癌症相关的基因突变。相关研究成果发表在《Annals of Internal Medicine》期刊。 Peter Ting是一名已经退休了的60岁老人，他看起来很健康，除了眼睛很难适应黑暗之外。他从未想过这一症状与基因突变有关，直至他参加了MedSeq项目。基因组测序结果显示，他携带有一种与罕见遗传性眼疾有关的基因突变。 研究团队将筛选的范围拓宽至近5000个与罕见遗传相关的基因。结果显示， 50个健康人中，有11人（22%）至少携带一个与罕见遗传病相关的基因突变。但是，大多数人未表现出任何病症。其中有两个志愿者携带有导致心率异常的基因突变，但是他们的心脏检测结果均正常。 文章一作、哈佛医学院的初级护理医师、助理教授Jason Vassy表示：“这意味着，你可能并没有病，或者说你尚未患病。” 11个携带罕见突变的人中，只有2个人表现出病症，其中一个就是有视力障碍的Peter Ting，另外一个人患有一种罕见疾病——杂色斑驳卟啉症，患者皮肤对阳光异常敏感。“现在，我们找到了原因，知道通过避开阳光或者某些药物刺激可以减轻患者皮肤灼伤的情况。” Jason Vassy解释道。 17%的人携带有一至多个基因突变 与MedSeq项目一样，来自于斯坦福大学的Michael Snyder教授带领团队对70个健康的成年人进行全外显子测序。结果显示，其中有12个人（17%）在不知情的情况下携带一个或多个增加遗传病风险的DNA突变。 这一研究于6月18日发表在bioRxiv，尚未接受同行评审。Michael Snyder主张，全基因组测序应该“自动”纳入初级卫生保健。 加州大学旧金山分校生命伦理学的医学人类学家Barbara Koenig认为：“基因信息类似于一个重要的文化象征，我们需要赋予它更多的权利。但是这些测序技术在临床上的应用还处于初期。” 重新定义健康？健康人是否应该接受全基因组检测？ “健康的标准是什么？我认为，基因组学将重新定义它。” Jason Vassy表示。 健康人接受基因检测是否利大于弊？目前并没有答案，因为我们不知道健康人携带隐藏基因突变的概率。这些研究打开了一个窗口，但是仍不足以证明基因测序应该得到广泛应用。 Illumina 公司科学顾问Erica Ramos认为，这些发现表明，除了基因之外，包括年龄、性别、生活方式和环境等因素也会影响疾病的发生、发展。她认为，特定的基因突变并不一定会引发疾病，即便它确实与疾病有关联。 一些研究人员担心，全基因组测序会引发额外的医疗费用或者造成不必要的心理负担。但是MedSeq项目除了最初的测序成本之外（研究项目承担），患者在随后6个月内的医疗保健费用仅平均额外增加了350美元。对于心理负担，研究人员发现，无论是测序组还是对照组都未表现出焦虑或者抑郁等情绪变化。 Ramos认为，这一研究并不意味着所有人都需要赶潮流接受基因测序。在某些情况下，全基因组测序会有所帮助，例如家族病史未知。对于参与研究被发现携带有突变基因但是并未表现出疾病症状的人而言，这一结果对家庭其他成员而言也是有意义的。 参考资料： DNA Testing Reveals the Chance of Bad News in Your Genes One in five 'healthy' adults may carry disease-related genetic mutations
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 High Frequency Actionable Pathogenic Exome Mutations in an Average-Risk CohortWhole exome sequencing (WES) is increasingly utilized in both clinical and non-clinical settings, but little is known about the utility of WES in healthy individuals. In order to determine the frequency of both medically actionable and non-actionable but medically relevant exome findings in the general population we assessed the exomes of 70 participants who have been extensively characterized over the past several years as part of a longitudinal integrated multi-omics profiling study at Stanford University. We assessed exomes for rare likely pathogenic and pathogenic variants in genes associated with Mendelian disease in the Online Mendelian Inheritance in Man (OMIM) database. We used American College of Medical Genetics (ACMG) guidelines were used for the classification of rare sequence variants, and additionally we assessed pharmacogenetic variants. Twelve out of 70 (17%) participants had medically actionable findings in Mendelian disease genes, including 6 (9%) with mutations in genes not currently included in the ACMG's list of 59 actionable genes. This number is higher than that reported in previous studies and suggests added benefit from utilizing expanded gene lists and manual curation to assess actionable findings. A total of 60 participants (89%) had non-actionable findings identified including 57 who were found to be mutation carriers for recessive diseases and 21 who have increased Alzheimer's disease risk due to heterozygous or homozygous APOE e4 alleles (18 participants had both). These results suggest that exome sequencing may have considerably more utility for health management in the general population than previously thought. 展开 The Impact of Whole-Genome Sequencing on the Primary Care and Outcomes of Healthy Adult Patients: A Pilot Randomized TrialBackground: Whole-genome sequencing (WGS) in asymptomatic adults might prevent disease but increase health care use without clinical value. Objective: To describe the effect on clinical care and outcomes of adding WGS to standardized family history assessment in primary care. Design: Pilot randomized trial. (ClinicalTrials.gov: NCT01736566) Setting: Academic primary care practices. Participants: 9 primary care physicians (PCPs) and 100 generally healthy patients recruited at ages 40 to 65 years. Intervention: Patients were randomly assigned to receive a family history report alone (FH group) or in combination with an interpreted WGS report (FH + WGS group), which included monogenic disease risk (MDR) results (associated with Mendelian disorders), carrier variants, pharmacogenomic associations, and polygenic risk estimates for cardiometabolic traits. Each patient met with his or her PCP to discuss the report. Measurements: Clinical outcomes and health care use through 6 months were obtained from medical records and audio-recorded discussions between PCPs and patients. Patients' health behavior changes were surveyed 6 months after receiving results. A panel of clinician-geneticists rated the appropriateness of how PCPs managed MDR results. Results: Mean age was 55 years; 58% of patients were female. Eleven FH + WGS patients (22% [95% CI, 12% to 36%]) had new MDR results. Only 2 (4% [CI, 0.01% to 15%]) had evidence of the phenotypes predicted by an MDR result (fundus albipunctatus due to RDH5 and variegate porphyria due to PPOX). Primary care physicians recommended new clinical actions for 16% (CI, 8% to 30%) of FH patients and 34% (CI, 22% to 49%) of FH + WGS patients. Thirty percent (CI, 17% to 45%) and 41% (CI, 27% to 56%) of FH and FH + WGS patients, respectively, reported making a health behavior change after 6 months. Geneticists rated PCP management of 8 MDR results (73% [CI, 39% to 99%]) as appropriate and 2 results (18% [CI, 3% to 52%]) as inappropriate. Limitation: Limited sample size and ancestral and socioeconomic diversity. Conclusion: Adding WGS to primary care reveals new molecular findings of uncertain clinical utility. Nongeneticist providers may be able to manage WGS results appropriately, but WGS may prompt additional clinical actions of unclear value. 展开 |
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来自： 成靖 > 《医学探讨/从头到脚》
