NUDT15 Polymorphism in Native American Populations of Brazil

Suarez‐Kurtz, Guilherme; Brisson, Gisele Dallapicola; Hutz, Mara Helena; Petzl‐Erler, Maria Luiza; Salzano, Francisco M.

doi:10.1002/cpt.1379

Cited by 14 publications

(16 citation statements)

References 5 publications

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“…There is one specific investigation that evaluated the presence of rs116855232 of the NUDT15 gene in Amerindian populations from southern and midwestern Brazil [15]. In this study, the mean frequency of rs116855232 was 25%, ranging from 5% to 32%, generally higher than the frequency recorded in the present study (9.4%).…”

Section: Plos Onecontrasting

confidence: 79%

“…The international population databases show that the frequency of the mutations that reduce the functional activity of the enzyme, such as those described by the PharmVar Consortium, exceeds 1% only in Asians, Latin American and Amerindian populations [14,15,25]. The most frequent mutations of these groups include the rs116855232 variant, either in isolation or combined with rs1272632214.…”

Section: Discussionmentioning

confidence: 99%

“…Previous data demonstrated that Brazilian Native American populations have a high frequency of a polymorphism (rs116855232) that drastically reduces NUDT15 activity, and that these ethnic group contribute 30%, on average, of the genetic makeup of the admixed populations of the Brazilian Amazon region [15,18,19]. Thereafter, a possible cause of the severe toxic effects observed in northern Brazil during the standard thiopurine-based treatment protocol is that individuals of this region have higher frequencies of NUDT15 deleterious alleles, resulting from the genomic contribution inherited of Amerindian groups.…”

Section: Plos Onementioning

confidence: 99%

“…A C>T transition in the rs116855232 (p.Arg139Cys) variant is assigned to two haplotypes (NUDT15 � 2 and NUDT15 � 3), which present an extreme loss of gene function, associated with the presence of the T allele of this polymorphism. The T allele of rs116855232 is found more commonly in East Asian [13], Latin [14] and Native American [15] populations, but is rare in populations from Europe, Africa, and South Asia.…”

Section: Introductionmentioning

confidence: 99%

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Identification of NUDT15 gene variants in Amazonian Amerindians and admixed individuals from northern Brazil

et al. 2020

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Introduction The nudix hydrolase 15 (NUDT15) gene acts in the metabolism of thiopurine, by catabolizing its active metabolite thioguanosine triphosphate into its inactivated form, thioguanosine monophosphate. The frequency of alternative NUDT15 alleles, in particular those that cause a drastic loss of gene function, varies widely among geographically distinct populations. In the general population of northern Brazilian, high toxicity rates (65%) have been recorded in patients treated with the standard protocol for acute lymphoblastic leukemia, which involves thiopurine-based drugs. The present study characterized the molecular profile of the coding region of the NUDT15 gene in two groups, non-admixed Amerindians and admixed individuals from the Amazon region of northern Brazil. Methods The entire NUDT15 gene was sequenced in 64 Amerindians from 12 Amazonian groups and 82 admixed individuals from northern Brazil. The DNA was extracted using phenol-chloroform. The exome libraries were prepared using the Nextera Rapid Capture Exome (Illumina) and SureSelect Human All Exon V6 (Agilent) kits. The allelic variants were annotated in the ViVa ® (Viewer of Variants) software. Results Four NUDT15 variants were identified: rs374594155, rs1272632214, rs147390019, andrs116855232. The variants rs1272632214 and rs116855232 were in complete linkage disequilibrium, and were assigned to the NUDT15*2 genotype. These variants had high

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Section: Plos Onecontrasting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of NUDT15 gene variants in Amazonian Amerindians and admixed individuals from northern Brazil

et al. 2020

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“…The NUDT15 R139C variant is also found in South Americans with Native American ancestry. 35 However, in the Middle East, the frequency of this variant is less than one-tenth of East Asians. 36 The frequency of the NUDT15 R139C variant is also extremely low in Europeans and Africans; 37 however, the allele frequency of another variant of the NUDT15 gene, p.Gly17_ Val18del, is observed at about 2% in Europeans.…”

Section: Role Of Nudt15mentioning

confidence: 99%

NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease

Matsuoka

2020

Intest Res

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Thiopurine has been used to maintain remission and to reduce antidrug antibody formation in monoclonal antibody therapy in patients with inflammatory bowel disease (IBD). The use of thiopurine is limited by side effects such as leukopenia. Thiopurine S-methyltransferase (TPMT) variants are associated with thiopurine-induced leukopenia in Westerners, but the frequency of the risk alleles is low in Asians. Recently, a variant in the nudix hydrolase 15 (NUDT15) gene (R139C, c415C > T) was reported to be associated with early severe leukopenia in Asians. NUDT15 is an enzyme that converts 6-thio-(deoxy)guanosine triphosphate (6-T(d)GTP) to 6-thio-(deoxy)guanosine monophosphate (6-T(d)GMTP). The R139C variant impairs the stability of the protein and increases incorporation of 6-TGTP and 6-TdGTP into RNA and DNA, respectively, resulting in leukopenia. The frequency of C/C, C/T, and T/T are approximately 80%, 20%, and 1%, respectively in East Asians. Early leukopenia occurred in less than 3% of patients with C/C and in around 20% of those with C/T, whereas it occurred in almost all patients with T/T. Patients homozygous for this variant also develop severe hair loss. The measurement of NUDT R139C can increase the safety of thiopurine dramatically and is a successful example of personalized medicine in the field of IBD.

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Why is There Still Debate About Recommending DPYD‐Testing Before Fluoropyrimidine Treatment?

Cascorbi

2023

Clin Pharma and Therapeutics

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NUDT15 Polymorphism in Native American Populations of Brazil

Cited by 14 publications

References 5 publications

Identification of NUDT15 gene variants in Amazonian Amerindians and admixed individuals from northern Brazil

Identification of NUDT15 gene variants in Amazonian Amerindians and admixed individuals from northern Brazil

NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease

Why is There Still Debate About Recommending DPYD‐Testing Before Fluoropyrimidine Treatment?

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