Research press release


Nature Biotechnology

Discovery of healthy people carrying severe disease-causing mutations



Stephen Friend、Eric Schadt、Rong Chenたちは、589,306人の遺伝子データを利用して、584種類の重篤な小児メンデル疾患に対する抵抗性を持つ人を探した。874の遺伝子について病気の原因となる、完全な浸透性を示す変異を探し、認定資格を持つ臨床遺伝学者、医療コンサルタント、生物情報科学者、遺伝カウンセラーからなるチームで、その信頼性を確認した。この専門家チームは、入手可能な健康情報の精査も行って、健康と見なされた人たちの中に、この変異と関連する病気の兆候がわずかでも報告されている人がいないことを確認した。


同時掲載のNews & Views記事では、Daniel MacArthurが「さらに研究を進めようにも、研究者たちは、抵抗性を持つ人たちの大半に再度接触することができなかった。必要となる承諾が得られていなかったためである。遺伝的な超人的“英雄”を見つけるためには、それとはまた違った“英雄”的行為が必要だろう。ゲノムデータ、臨床データを積極的に提供するという参加者の“心意気”と、世界規模でデータ共有をするために面倒な問題を厭わず乗り越えるという、研究者、規制担当者の“献身”である。」と述べている。

A genomic analysis of more than half a million people reveals 13 individuals who appear to remain healthy despite carrying genetic mutations linked to severe childhood diseases. The findings are reported online in Nature Biotechnology this week. Although the biological reasons for this resilience are not yet understood, the study provides a first step towards pinpointing genetic variants that may protect against such diseases and highlights the need to re-evaluate previous assumptions about the causal link between genetic mutations and some severe diseases.

Mendelian disorders, such as cystic fibrosis, can begin early in childhood and are generally caused by mutations in just one gene. These mutations are assumed to be completely penetrant - any individuals who carry the mutations will inevitably develop the associated disease symptoms. However, genetic testing has been largely limited to people who exhibited disease symptoms and their families, opening up the possibility that these mutations may have gone unnoticed in a small number of healthy people.

Stephen Friend, Eric Schadt, Rong Chen and colleagues used genetic data from 589,306 individuals to look for candidates resilient to 584 severe Mendelian childhood disorders. They searched 874 genes for completely penetrant disease-causing mutations, which were verified by a team of board-certified clinical geneticists, medical consultants, bioinformaticians, and genetic counselors. This expert panel also screened available health information to ensure that none of the individuals deemed to be healthy reported any subtle associated disease symptoms.

Their analysis uncovered 13 individuals who appeared to be completely resilient to one of eight Mendelian childhood conditions. The authors suggest that these individuals may hold the key to identifying factors that mediate the effects of highly penetrant disease-causing mutations and could aid in the development of much-needed targeted therapies. However, they note this will require the identification and analysis of many more resilient individuals, which itself will depend on the analysis of many millions of genomes.

In an accompanying News & Views article, Daniel MacArthur writes that “the researchers could not recontact the majority of resilient individuals for further study because of a lack of necessary consent forms…Finding genetic superheroes will require other kinds of heroism - a willingness of participants to donate their genomic and clinical data and a commitment by researchers and regulators to overcome the daunting obstacles to data sharing on a global scale.”

doi: 10.1038/nbt.3514


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