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]eczema gene

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?

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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 !

eczema gene5.jpg

— 理查德·道金斯《自私的基因》


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] 。


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?


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?




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?”




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!

— 王阳明


  1. 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
  2. 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
  3. INTERLEUKIN 4; IL4 gene 147780
  4. INTERLEUKIN 13; IL13 gene 147683
  5. 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
  6. 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