NEW YORK – Polygenic risk scores (PRS) for coronary artery disease (CAD) and breast cancer may reflect levels of risk similar to that of rare monogenic mutation carriers, which could argue for the inclusion of PRS in wider screening programs.

纽约-冠状动脉疾病（CAD）和乳腺癌的多基因风险评分（PRS）可能反映出与罕见的单基因突变携带者相似的风险水平，这可能有理由将PRS纳入更广泛的筛查计划。

Researchers from the UK-based firm Genomics Plc evaluated PRS for 28 diseases and 25 quantitative traits using data from the UK Biobank (UKB) Polygenic Risk Score Release. They evaluated these scores' performance compared to a set of previously released PRS, also from the UKB, and for their possible clinical utility. .

英国基因组学公司的研究人员使用英国生物库（UKB）多基因风险评分发布的数据评估了28种疾病和25种数量性状的PRS。他们评估了这些分数与之前发布的一组PR（也来自UKB）的表现，以及它们可能的临床效用。。

The company said the similarity in risk between PRS and pathogenic mutations in certain cases advances the argument for including PRS in screening programs. The firm published its results, along with a benchmarking software tool for directly comparing the performance of different PRSs for the same disease or trait, in the journal PLOS One. .

该公司表示，在某些情况下，PRS与致病突变之间的风险相似，这推动了将PRS纳入筛查计划的论点。该公司在《公共科学图书馆·综合》（PLOS One）杂志上公布了其结果，以及一个用于直接比较不同PRS对同一疾病或性状的表现的基准软件工具。。

Overall, the new risk scores, or Enhanced PRS Set, outperformed the prior, so-called Standard PRS Set, in terms of correlations between PRS and disease occurrence and between PRS and the effect size of quantitative traits such as body mass index, total triglycerides, and resting heart rate.

总体而言，就PRS与疾病发生之间以及PRS与体重指数，总甘油三酯和静息心率等数量性状的影响大小之间的相关性而言，新的风险评分或增强的PRS集优于之前所谓的标准PRS集。

'Basically, what the paper shows is that those scores are more powerful than any of the others that have been developed,' said Peter Donnelly, CEO and cofounder of Genomics Plc.

基因组学公司（Genomics Plc）首席执行官兼联合创始人彼得·唐纳利（PeterDonnelly）说，基本上，论文显示的是，这些分数比其他任何已经开发的分数都更强大。

The strongest examples of equivalent risks in the study came from CAD and breast cancer, which the researchers assessed by evaluating odds ratios and area under the curve as performance metrics. The study found that PRS indicating a high disease risk reflects a risk level similar to that of people with known single-gene pathogenetic mutations. .

研究中同等风险的最强例子来自CAD和乳腺癌，研究人员通过评估优势比和曲线下面积作为性能指标来评估。该研究发现，表明高疾病风险的PRS反映了与已知单基因致病突变人群相似的风险水平。。

But people with high risk due to the accumulation of common, lower-risk variants that are captured by PRS outnumber people who are carriers of rare high-risk variants, 'often massively so,' Donnelly said, suggesting that adding PRS to some screening programs might significantly improve diagnosis rates. .

但Donnelly说，由于PRS捕获的常见低风险变异的积累，高风险人群的数量超过了罕见高风险变异携带者的数量，“通常是大量的”，这表明将PRS添加到某些筛查程序中可能会显着提高诊断率。。

For instance, the researchers examined individuals in the UKB who were not taking statins and found the top 8 percent of individuals with high CAD PRS had a similar level of CAD risk as people carrying genetic variants associated with familial hypercholesterolemia (FH), a known risk factor for developing CAD.

例如，研究人员检查了英国不列颠哥伦比亚省没有服用他汀类药物的个体，发现前8%的CAD PR高的个体与携带与家族性高胆固醇血症（FH）相关的遗传变异的人具有相似的CAD风险水平，家族性高胆固醇血症（FH）是患CAD的已知风险因素。

The study estimated that there were between 18 and 29 times the number of CAD events, depending on age, among the individuals within that top 8 percent as compared to FH carriers, suggesting that PRS can identify more at-risk people..

该研究估计，与FH携带者相比，在这8%的人群中，根据年龄的不同，CAD事件的数量是其18至29倍，这表明PRS可以识别更多的高危人群。。

Donnelly noted that while FH mutations are currently included in many CAD screening programs, PRS are not.

唐纳利指出，虽然FH突变目前已包括在许多CAD筛查程序中，但PRS却没有。

In Germany, for example, the southern state of Bavaria initiated an FH carrier screening program in 2021 as part of its broader DigiMed program to advance predictive, preventive, personalized, and participatory public health measures by combining datasets of patients diagnosed with atherosclerotic diseases, such as coronary heart disease and stroke, or with genetic risk factors.

例如，在德国，南部巴伐利亚州于2021年启动了一项FH携带者筛查计划，作为其更广泛的数字化计划的一部分，通过结合诊断为动脉粥样硬化疾病（如冠心病和中风）或遗传危险因素的患者数据集，推进预测性，预防性，个性化和参与性公共卫生措施。

The FH screening program, called VRONI, has since spread throughout the country and across Europe. .

FH筛查项目，称为VRONI，自那以后已经在全国和整个欧洲传播。。

'It seems impossible to argue that you should go out of your way to look out for one group of people because they happen to have a genetic change that makes [disease] more [likely] and then ignore another group of people who are at exactly the same level of risk because of their genetics,' he said.

他说：“似乎不可能争辩说，你应该千方百计地寻找一组人，因为他们碰巧有一种基因改变，使[疾病]更有可能发生，然后忽视另一组由于遗传因素而处于完全相同风险水平的人。”。

Similarly, individuals in the top 0.3 percent of PRS for breast cancer in the study showed equivalent lifetime risks as carriers of pathogenic BRCA1 and BRCA2 mutations.

同样，在该研究中，乳腺癌PR最高的0.3%的个体显示出与致病性BRCA1和BRCA2突变携带者相同的终生风险。

Jonathan Mosley, a professor of medicine at the Vanderbilt University's Center for Precision Medicine, who was not involved in the study but whose research frequently involves PRS, cautioned that one known issue in using the UKB to benchmark PRS is that it consists entirely of observational data and the outcomes are not gold standard assessments for any given disease, as opposed to a cohort study where complete outcomes are actively ascertained at frequent intervals..

范德比尔特大学精准医学中心的医学教授乔纳森·莫斯利（JonathanMosley）没有参与这项研究，但他的研究经常涉及PRS，他警告说，使用UKB对PRS进行基准测试的一个已知问题是，它完全由观察性数据组成，结果并不是任何特定疾病的金标准评估，而不是经常积极确定完整结果的队列研究。。

'In the end,' he said via email, 'it would be important to benchmark the PRS against a number of different study populations, as populations vary with respect to environmental exposures and other compositional features.'

“最后，”他通过电子邮件说，“重要的是要将PRS与许多不同的研究人群进行对比，因为人群在环境暴露和其他组成特征方面有所不同。”

Mosley also pointed out that the study focuses largely on association metrics such as odds ratios and cumulative incidence plots and less on metrics related to discrimination, such as concordance statistics, or on reclassification statistics, which might better help understand any potential clinical utility of PRS..

莫斯利还指出，该研究主要关注优势比和累积发病率图等关联指标，而较少关注与歧视相关的指标，如一致性统计或重新分类统计，这可能有助于更好地了解PRS的任何潜在临床效用。。

Further, with respect to the findings regarding CAD and breast cancer, Mosley said that direct comparisons were complicated by the 'fundamental difference' of distinct biological mechanisms measured via PRS versus pathogenic mutations.

此外，关于CAD和乳腺癌的发现，莫斯利说，通过PRS与致病突变测量的不同生物学机制的“根本差异”使直接比较变得复杂。

'The risk associated with FH variants is linked to a specific underlying disease mechanism, which can be targeted, while the PRS does not point to a targetable disease mechanism,' Mosley said. 'So the utility of the risk estimates from PRS versus pathogenic variants is not necessarily comparable. If a person carries a high-risk FH variant, you will want to direct therapy towards lowering their cholesterol levels; a PRS does not provide a specific therapeutic target.'.

莫斯利说：“与FH变异相关的风险与特定的潜在疾病机制有关，这种机制可以被靶向，而PRS并没有指出可靶向的疾病机制。”因此，PRS与致病变异的风险估计值的效用不一定具有可比性。如果一个人携带高风险的FH变异，你将希望指导治疗以降低其胆固醇水平；PRS不提供特定的治疗靶点。”。

Donnelly acknowledged that PRS currently tend not to shed light on specific biological mechanisms but said they can still function as good predictors of disease by aggregating many tiny effects from different biological processes. Finding PRS that capture specific aspects of biology is a 'big hope' in the field, he said..

唐纳利承认，PRS目前倾向于不揭示特定的生物学机制，但他说，它们仍然可以通过汇总来自不同生物过程的许多微小影响来作为疾病的良好预测因子。他说，寻找能够捕捉生物学特定方面的PRS是该领域的“巨大希望”。。

'It's certainly something we look at in some of the work we do with drug companies,' he said, adding that the hope is to leverage PRS to identify which individuals will be most likely to respond to specific therapies.

他说，“这当然是我们在与制药公司合作的一些工作中所看到的，”他补充说，我们希望利用PRS来确定哪些人最有可能对特定疗法产生反应。

Still, Genomics' findings, particularly with respect to FH mutation carriers, are in line with findings from other groups. Last year, genomics software company Allelica published a set of ancestry-specific PRS for CAD, in which the company also identified high-PRS individuals with equivalent risk as FH mutation carriers, even when their LDL-C levels were not elevated..

尽管如此，基因组学的发现，特别是关于FH突变携带者的发现，与其他研究小组的发现一致。去年，基因组学软件公司Allelica发布了一套针对CAD的血统特异性PRS，该公司在其中还确定了高PRS个体，即使其LDL-C水平没有升高，其风险也与FH突变携带者相当。。

'These individuals with high PRS escape traditional risk assessments and walk around thinking their LDL-C levels are fine, while in reality they are at extremely high risk [of CAD],' Allelica CEO Giordano Bottà said in an email.

Allelica首席执行官佐丹诺·博塔（GiordanoBottà）在一封电子邮件中说：“这些高PRS的人逃避了传统的风险评估，认为自己的低密度脂蛋白胆固醇水平很好，而实际上他们（患CAD）的风险极高。”。

The PRS published in Genomics' study, Bottà said, 'confirm what the field already knew: We can stratify disease based on common variants, and in some cases, the risk conferred is equivalent to monogenic mutations.'

博塔说，发表在基因组学研究中的PRS证实了该领域已经知道的：我们可以根据常见变异对疾病进行分层，在某些情况下，所带来的风险相当于单基因突变

Bottà did caution, however, that PRS must be evaluated on a case-by-case basis, as there are nuances to consider in calculating them, and while they might provide lifesaving results in certain disease contexts, they could prove 'completely useless' in others.

然而，博塔提醒说，必须逐个评估PRS，因为在计算它们时需要考虑细微差别，虽然它们可能在某些疾病背景下提供挽救生命的结果，但在其他情况下可能证明它们“完全无用”。

Despite the ongoing debate regarding the clinical utility of PRS, they are finding their way into various aspects of the overall molecular diagnostics industry, from diagnostic and screening assays to pharmacogenetic research and clinical trial design.

尽管关于PRS的临床实用性仍存在争议，但他们正在寻找进入整个分子诊断行业各个方面的途径，从诊断和筛选分析到药物遗传学研究和临床试验设计。

Myriad Genetics, for example, added its RiskScore PRS test to its MyRisk hereditary cancer risk test and has forged numerous partnerships aimed at screening women for breast cancer risk, including with Onsite Women's Health and SimonMed Imaging.

例如，Myriad Genetics将其RiskScore PRS测试添加到其MyRisk遗传性癌症风险测试中，并建立了许多旨在筛查女性乳腺癌风险的合作伙伴关系，包括现场女性健康和SimonMed成像。

Genomics Plc itself has been studying the clinical utility of PRS as well as the feasibility of including them in routine clinical care. Earlier this year, the company published a study that found high levels of acceptance and understanding of PRS among both physicians and patients in the primary care setting..

基因组学Plc本身一直在研究PRS的临床实用性以及将其纳入常规临床护理的可行性。今年早些时候，该公司发表了一项研究，发现初级保健机构的医生和患者对PRS的接受程度和理解程度都很高。。

The study addressed the concern that the complexity of PRS would make using them confusing and difficult for both patients and physicians. However, results showed that, given a measure of education concerning what PRS are and how they work, both patients and practitioners reported feeling confident in using them. .

。然而，结果表明，在对PRS是什么以及它们如何工作进行一定程度的教育后，患者和从业者都表示对使用它们有信心。。

'I think we can allay a lot of the fears that some people have had about putting [PRS] into practice,' Donnelly said.

唐纳利说：“我认为我们可以减轻一些人对实施PRS的担忧。”。

Another perennial issue in the PRS field is obtaining scores that work well in populations of non-European ancestry, as these are generally underrepresented in genome-wide association studies. As in past studies, all the PRS in the current PLOS One study performed best in people of European genetic heritage and declined for other populations, with some of the biggest declines seen in those of African ancestry. .

PRS领域的另一个长期问题是获得在非欧洲血统人群中效果良好的分数，因为这些分数在全基因组关联研究中通常代表性不足。与过去的研究一样，当前PLOS One研究中的所有PR在欧洲遗传遗产的人群中表现最好，而在其他人群中则下降了，其中一些下降幅度最大的是非洲血统。。

Genomics Plc continues to seek new partnerships across the life sciences spectrum in its pursuit of nudging PRS into routine clinical and pharmaceutical practice, and Donnelly said that the company hopes to be able to announce several new collaborations within the coming six months or so.

基因组学公司继续在生命科学领域寻求新的合作伙伴关系，以推动PRS进入常规临床和制药实践，Donnelly表示，该公司希望能够在未来六个月左右宣布几项新的合作。

'Going forward, we certainly want to be very focused on continuing to be at the cutting edge of having the most powerful tools,' he said.

他说：“展望未来，我们当然希望继续专注于拥有最强大工具的前沿。”。