Do we have eczema gene(s) – Time to rethink biologics Dupilumab (Dupixent) 关于湿疹基因—生物药的再思考
In the beginning,
there was simplicity.
— Richard Dawkins, The Selfish Gene
Atopic dermatitis (AD) or eczema, like some other familiar and pervasive chronic illnesses — diabetes, coronary artery disease, hypertension, schizophrenia, depression, they lay on the Many-Genes–Many-Diseases paradigm rather than One-Gene-One-Disease.
Eczema, for instance, comes in different forms and was under the influence of at least 34 known genes (Table 1. susceptibility loci and most plausible candidate gene(s) associated with atopic dermatitis of the genome-wide association GWA study [1,2]).
As 34 specific genomic regions that probably harbour one or more genetic variants associated with AD susceptibility, if any drugs are able to suppress one or few or even all of genes listed on Table 1, it would be helpful on eczema symptoms. For instance, monoclonal antibody Dupilumab (Dupixent) that inhibits interleukin-4 (IL-4) and IL-13 is apporved by the FDA to use on eczema [3,4] .
Table 1. susceptibility loci and most plausible candidate gene(s) associated with atopic dermatitis of the genome-wide association (GWA) study [1,2]
Puzzle I
In the real world clinical practicing of monoclonal antibody [5,6], will you sequence the genome of a patient with eczema/asthma and compare it to the genome of a norm before Dupilumab (Dupixent) given? If no genotype laboratory testing is performed, how can we assure the right patients receive the right biological therapy? A gene specifies a function in an organism, indeed — but a single gene can specify more than a single function. What is the physiological outcome if normal patients with IL4/IL13 genes recieved the inhibitors for those genes?
Puzzle II
Stem cells are the only cells in the body that can renew themselves and therefore provide a long-term solution to a gene deficiency. Without a source of self-renewing or long-lived cells, you might inject IL4/IL13 gene inhibitor into the human body, but the biologically modified cells carrying the genes inhibitors would eventually die and vanish from the blood, does the injection have to be repeated again and again for those who IL4/IL13 genetic variation patients?
Puzzle III
Unlike Sickle Cell Anemia, Cystic Fibrosis, Huntington disease or Down syndrome, where a single potent gene mutation or a chromosomal aberration was necessary and sufficient to cause the disease, however the effect of any individual gene in polygenic syndromes, eg. eczema, was dulled. The dependence on environmental variables — diet, age, alcohol drinking, nutrition, bacterial infection, trauma and prenatal exposures — was stronger. The phenotypes were variable and continuous, and the patterns of inheritance complex. The genetic component of the eczema only acted as one trigger in a many-triggered gun— necessary, but not sufficient to cause the illness.
Puzzle IV
When you sequence the genome of a person with atopic dermatitis (or asthma, hay fever) and compare it to the genome of a normal peer, you are asking, “How are subjects diagnosed with eczema genetically different from ‘normal’ subjects?” The question that you should instead be asking is the following: “If the mutated gene is present in a person, what are the chances that he or she will develop eczema or asthma or hay fever?”
The difference between the two questions is critical. Knowing that a subject has a syndrome, what are the genes that are mutated? But to estimate penetrance and expressivity, we also need to create a deeper question: If a subject has a mutant gene, what are the chances that he or she will develop the syndrome? Is every gene fully predictive of risk? Does the same gene variant or gene combination produce highly variable phenotypes in individuals — e.g. eczema in one, asthma in another, and a relatively mild variant of hay fever in a third? Do some combinations of variants require other mutations, or triggers, to push that risk over an edge?
See Uncertainty with Such Certainty
The variation in a single gene can cause diverse manifestations of disease in diverse organs. The multiple genes could influence a single aspect of physiology. A certain gene can only become actualized into phenotypes (disease?) depending upon environmental triggers or random chance. The mutations are just random variations, a mutation doesn’t imply disease, nor does it specify a gain or loss of function. In a formal sense, a mutation is defined only by its deviation from the norm.
Although we fully understand the genetic code — i.e., how the information in a single gene is used to build a protein — we comprehend virtually nothing of the genomic code — i.e., how multiple genes spread across the human genome coordinate gene expression in space and time to build, maintain, and repair a human organism. The genetic code is simple: DNA is used to build RNA, and RNA is used to be build a protein. A triplet of bases in DNA specifies one amino acid in the protein. However the genomic code is complex: appended to a gene are sequences of DNA that carry information on when and where to express the gene. We do not know why certain genes are located in particular geographic locations in the genome, and how the tracts of DNA that lie between genes regulate and coordinate gene physiology. There are codes beyond codes, mountains beyond mountains !
天地伊始，
万物从简。
— 理查德·道金斯《自私的基因》
湿疹很像日常生活中发病率很高的慢性病，例如糖尿病、冠心病、高血压、精神分裂症、抑郁症等这些多基因遗传病（多对多），它们与单基因遗传病（一对一）有着本质的区别。激发湿疹的因素有成千上万种，而在同期参与调节的基因也涉及几十个之多，其中每个基因都会对湿疹产生叠加效应。特异性皮炎（湿疹）就有多种形式，并受到至少34个已知基因的影响（表1。与全基因组关联的GWA研究相关的特应性皮炎相关的易感基因座和最可能的候选基因[1,2]）。
作为34个可能带有与湿疹易感性相关的一个或多个遗传变异的特定基因组区域，如果有任何药物能够抑制表1所列的一个或几个甚至全部基因，则可能对湿疹症状会有帮助。例如，FDA批准可抑制白介素4（IL-4）和IL-13的单克隆抗体达必妥Dupilumab (Dupixent)可用于湿疹临床治疗[3,4] 。
思考一
在现实世界中单克隆抗体的临床应用中[5,6]，给患者注射达必妥Dupilumab（Dupixent）之前是否会对患有湿疹/哮喘的患者的基因组进行测序，治疗前确认他们的基因是否携带了IL4/IL13的变异？如果没有进行基因型实验室排查测序，我们如何确保适合的患者注射了正确的生物制剂？虽然生物体中某个基因可以对应某种功能，但是单个基因却可以对应多种功能。如果IL4 / IL13基因正常的患者接受IL4 / IL13抑制剂注射，人体的生理功能会发生什么变化？产生什么结果呢？
思考二
由于人体干细胞是唯一能够在体内进行自我更新的细胞，因此才有可能为矫正基因变异提供长久的解决方案。如果细胞不具备自我更新或者长寿的特点，那么我们虽然可以将IL4/IL13基因的抑制剂插入人体中，但是这些携带外源生物蛋白质修饰过的细胞终究还是会逐渐消亡，是否对于那些IL4 / IL13基因变异的患者要重复注射呢？重复多少次呢？
思考三
与镰状细胞性贫血，囊性纤维化，亨廷顿病或唐氏综合症不同，单个基因突变或染色体畸变即可以成为致病的充分且必要条件。但是在多基因遗传病中，任意某个基因的作用却微不足道。它们反而需要依赖饮食、年龄、饮酒、细菌感染，创伤、营养状况以及产前暴露等环境变量才能发挥作用。由于多基因遗传病的表型具有多样性与连续性，因此其遗传模式必定具有不为人知的复杂性。对于此类疾病来说，基因变异仅是众多触发因素中的一员，它只是致病的必要但不充分条件。
思考四
当你对湿疹（哮喘，过敏性鼻炎）患者进行基因组测序，然后将其与正常对照基因组进行比较时，你实际上是在问：“如何从遗传学差异的角度来区分病患与‘正常’呢？” 但是即便如此，你还是无法回答以下这个问题：“如果某位病患携带有变异基因，那么他（她）罹患湿疹（哮喘，过敏性鼻炎）的概率有多大呢？”
这两个问题的不同之处非常关键。假如已知患者存在某种综合征，那么到底是哪些基因发生了突变呢？然而为了预测外显率与表现度，我们还需要知道：假如某位患者携带有某种变异基因，那么他（她）出现该病的概率有多大？每个基因都可以准确地预测患病风险吗？相同的基因变异或基因组合会在不同个体中产生高度变异的表型吗？是否可能出现某人是湿疹，另一个是哮喘，第三个是轻度的过敏性鼻炎？某些变异基因组合是否需要其他变异或激发因素的配合才导致发病呢？
确定的不确定性
单个基因变异可以导致不同器官产生各式各样的临床表现。多个基因可以共同影响某一种生理功能。某些特定基因所控制的功能或形态能否真实表达，取决于环境触发或者随机概率。突变只不过是随机变异而已，突变并不意味着疾病，亦不能代表功能上的增减。从字面意义上理解，突变指的是偏离正常的程度。
尽管我们已经掌握了遗传密码（即单个基因携带的信息如何构建蛋白质）的奥秘，但是我们对于基因组密码（即基因组中的多个基因如何根据时空变化来协调基因表达，然后实现构建、维护以及修复人体的功能）几乎一无所知。遗传密码的作用机制一目了然：DNA经转录后生成RNA，随后RNA通过翻译来合成蛋白质，同时DNA中的三个连续碱基对可以对应蛋白质中的某个氨基酸。相比之下，基因组密码的作用机制十分复杂 ——附着在基因上的调控序列携带有决定基因表达的时空信息。我们并不了解某些基因位于基因组特定位点的原因，也不清楚基因间DNA片段如何调控基因的生理功能。真是密码之上还有密码，青山之外还有青山啊!
你未看此花时，此花与汝心同归于寂；
你来看此花时，则此花颜色一时明白起来。
— 王阳明
Rerence:
- Johansson Å, Rask-Andersen M, Karlsson T, Ek WE. Genome-wide association analysis of 350 000 Caucasians from the UK Biobank identifies novel loci for asthma, hay fever and eczema. Hum Mol Genet. 2019;28(23):4022-4041. doi:10.1093/hmg/ddz175
- Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD. Atopic dermatitis. Nat Rev Dis Primers. 2018;4(1):1. Published 2018 Jun 21. doi:10.1038/s41572-018-0001-z
- INTERLEUKIN 4; IL4 gene 147780 https://omim.org/entry/147780?search=IL4&highlight=il4
- INTERLEUKIN 13; IL13 gene 147683 https://omim.org/entry/147683?search=il13&highlight=il13
- Simpson EL, Bieber T, Guttman-Yassky E, et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med. 2016;375(24):2335-2348. doi:10.1056/NEJMoa1610020
- Castro M, Corren J, Pavord ID, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med. 2018;378(26):2486-2496. doi:10.1056/NEJMoa1804092
