|Ahead of print publication
A clinical aid to precision medicine
Sakir Ahmed1, Latika Gupta2
1 Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India
2 Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Although we share 99.9% of our genes, no two humans are alike. The prediction of efficacy and toxicity of drugs based on genetics is the science of pharmacogenomics. By the turn of the 21st century, the practical importance of pharmacogenomics has been acknowledged. Now, with the advent of the multi-omics: proteomics, transcriptomics, methylomics, metabolomics, etc., this has expanded to precision medicine. Precision medicine is the application of “systems biology” (that is the integrated-omics) for the prediction of drug efficacy and toxicity.
Just imagine a rheumatologist who can look at a person's system biology profile and find out that he/she would respond to methotrexate alone for his rheumatoid arthritis (RA)! That will save both costs, time of experimentation, side effects, and risks for adverse effects of combination therapy! Currently, various models are being devised to predict methotrexate responsiveness for RA. Similarly, 1 day, precision medicine may help to predict which lupus nephritis would respond best to cyclophosphamide, or to rituximab, or to tacrolimus. However, precision medicine has to come of age for this to happen.
Under the Obama administration in the United States, precision medicine had received a shot in the arm. The felt need for precision medicine is spreading fast, all across the world. Nowadays, in many malignancies such as chronic myeloid leukemia and colon cancer, pharmacodynamics has become the standard of care. Even in the field of rheumatology, pharmacogenomic-guided therapy is approved for azathioprine (AZA) in the United States. Testing for thiopurine S-methyltransferase (TPMT deficiency: MIM #187680) can be done both by commercially available genetic testing and functional assays.
The prevalence of polymorphisms in drug-metabolizing enzymes varies across populations. A major concern is that most of the pharmacogenomic data are available for Caucasoid populations. It has been shown that the genetic polymorphism of the TMPT gene prevalent in the Caucasoid populations may not be significant in case of Asian populations. In India, the prevalence of heterozygotes for TPMT is <5%., Thus, cost–benefit ratios merit consideration when routine testing is contemplated here. However, not to forget that the occurrence of pancytopenia even in one person harboring such mutations amounts to ginormous cost as well as risk of mortality.
A search on SCOPUS on April 11, 2019, with the keyword “pharmacogenomics” revealed 12,006 hits, of which 331 (2.8%) were from India. Limiting the search to only original articles, there were 4785 hits, of which 132 (2.8%) were from India. Refining based on rheumatology, there were only nine hits [“(TITLE-ABS-KEY (pharmacogenomics)) AND (rheumatology OR rheumatoid) AND (LIMIT-TO (DOCTYPE, “ar”)) AND (LIMIT-TO (AFFILCOUNTRY, “India”))”].
In the current issue, Mishra et al. have published a case-based review that has elaborated AZA-induced alopecia and pancytopenia in a middle age woman with mutations in the NUDT15 gene. Searches on SCOPUS, MEDLINE, and Web of Science revealed 28 articles dealing with alopecia and AZA and NUDT15. These include three meta-analyses. The first reveals that rs116855232, rs554405994, and rs186364861 polymorphisms of NUDT15 are associated with leukopenia. The second meta-analysis confirmed that the rs116855232 (R139C) polymorphism is strongly associated with risk of (both early and late) thiopurineinduced leukopenia in Asians. The same rs116855232 has also been validated by the third metaanalysis. This R139C polymorphism has been shown to destabilize the catalytic site of the NUDT15 enzyme. This affects the enzymatic activity of the NUDT15 hydrolase due to decreased protein stability in vivo.
In a study of 15 Japanese patients with thiopurine-induced leukopenia, two (13.3%) had NUDT15 mutations and both had presented with alopecia. In a study of 87 Chinese patients, 27 subjects were NUDT15 R139C heterozygote (CT, 31.0%) while only one carried homozygote (TT). Of the 27 patients with heterozygous NUDT15 R139C (CT), 17 patients (63.0%) developed leukopenia and one patient with the homozygotes (TT, 100%) suffered leukopenia and severe hair loss. The case reported by Mishra et al. was also homozygous for the R139C polymorphism. Similarly, as reported in their article, an Indian study Shah et al. had investigated 69 patients of whom nine had the R139 polymorphism. Of these, alopecia was reported in one patient with homogenous (NUDT15*TT) polymorphism and in another one patient out of the five having heterozygous (NUDT15*CT) polymorphisms. Thus, alopecia may be a manifestation of severely depressed activity of NUDT15 hydrolase in the presence of thiopurines, and may herald consequent leucopenia.
A GWAS-based study including 2630 Japanese patients has concluded that genotyping the NUDT15 codon for R139C may be sufficient (as opposed to both TPMT and NUDT15 genotyping) to predict thiopurine-induced acute severe leukopenia as well as alopecia in Japanese (inflammatory bowel disease) patients. Even in India, NUDT15 genotyping may possibly be more important than TPMT screening. However, this needs to be proven.
Most drug polymorphisms, when not tested, are first reported upon the onset of the sinister pathology they cause. This is a unique case where uniform affliction of rapidly dividing cells by the drug brings in potential for clinical diagnosis of AZA-induced pancytopenia even before counts fall. The lead time allows a physician to buy time for remedial measures before pathogens get hold of the immunosuppressed host. Early identification of neutropenia can be the single most important predictive factor for better outcomes. Thus, one should always bear in mind that alopecia in a patient on AZA could possibly herald the onset of more sinister pathology. A keen eye for hair loss alongside preemptive patient counseling should be practiced.
In this era of changing paradigms and a clear shift to investigation-based clinical approaches, this rare case beautifully illustrates that a simple finding of alopecia can signal impending disaster. Our initial search had shown that genetic studies in India are limited. Nevertheless, the medical fraternity needs to be reminded that such clinical clues can be part of precision medicine too!
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