NUDT15 polymorphism in healthy children with Bai nationality in Yunnan of China

Abstract

Background Thiopurine methyltransferase (TPMT) polymorphism is one of the causes of the toxicity of thiopurines, but this is rarely seen in Asian populations. Rather, the nucleoside diphosphate‐linked X‐component motif 15 (NUDT15) gene is frequently linked to mercaptopurine (MP) intolerance and myelotoxicity in children with acute lymphoblastic leukemia (ALL) in East Asians; however, little is known about the NUDT15 polymorphism in healthy children, especially in ethnic minorities in China. Methods A total of 162 cases of healthy children with Bai nationality were enrolled for NUDT15 genotyping. Results Three coding variants were identified in the NUDT15 gene including rs186364861, rs746071566 and rs116855232. Notably, the rs746071566 and rs116855232 in NUDT15 showed much higher frequencies in healthy children with Bai nationality compared with healthy East Asian populations, suggesting a concentrated distribution of these variants in the Bai ethnic group. Conclusions This finding reveals the genetic polymorphism of NUDT15 in children with Chinese Bai nationality, providing a biological genetic background for the individualized therapy of thiopurines for children with Bai nationality in China.

NUDT15 Genetic Variants in Chinese Han, Uighur, Kirghiz, and Dai Nationalities

“…To clarify the distribution of NUDT15 variants in Chinese ethnic minority populations, we conducted a two-by-two comparison of the c.55_56insGAGTCG, c.52G > A, and c.415C > T variant frequencies in seven ethnic groups: Korean ( 23 ), Japanese ( 24 ), Chinese Han, Bai ( 25 ), Uighur, Kirghiz, and Dai, of which Bai is also an ethnic minority in China. The allele frequency of NUDT15 c.55_56insGAGTCG was 5.6% in Korea ( 23 ), 5.4% in Japan ( 24 ), 6.4% in Chinese Han, and 5.6% in Chinese Bai ( 25 ).…”

“…To clarify the distribution of NUDT15 variants in Chinese ethnic minority populations, we conducted a two-by-two comparison of the c.55_56insGAGTCG, c.52G > A, and c.415C > T variant frequencies in seven ethnic groups: Korean ( 23 ), Japanese ( 24 ), Chinese Han, Bai ( 25 ), Uighur, Kirghiz, and Dai, of which Bai is also an ethnic minority in China. The allele frequency of NUDT15 c.55_56insGAGTCG was 5.6% in Korea ( 23 ), 5.4% in Japan ( 24 ), 6.4% in Chinese Han, and 5.6% in Chinese Bai ( 25 ). We found that the c.55_56insGAGTCG variant was significantly less frequent in the Uighur and Kirghiz ethnic groups than in the other ethnic groups, and the frequency of variation at this site in the Dai ethnic group was not significantly different from that of the other ethnic groups.…”

“…The single nucleotide polymorphism (SNP) c.415C > T is the most important variant of NUDT15 related to thiopurine toxicity, which leads to almost complete loss of enzyme activity and protein stability in vitro and induces severe bone marrow suppression. It has been reported that the allele frequency of the NUDT15 c.415C > T variant is 13.2% in South Korea ( 23 ), 12.0% in Japan ( 24 ), and 12.7% in the Bai nationality in China ( 25 ). The distribution of NUDT15 c.415C > T variants in our results for the Han, Uighur and Kirghiz ethnic groups was similar to that for other ethnic groups, except for the Dai nationality group.…”

“…NUDT15 germline variants are closely associated with mercaptopurine-induced hematotoxicity and vary considerably in their distribution across ethnic groups ( 31 , 32 ), with the risk allele of NUDT15 c.415C > T being the most common among East Asians (9.8%), very rare in Europe (0.2%), and not observed in Africa ( 19 ). Among the 56 ethnic groups in China, only the Bai ethnic groups of the Yunnan and Han nationality have been studied for the distribution of the NUDT15 polymorphism ( 25 , 33 ). This study investigated the distribution of NUDT15 gene polymorphisms among healthy Uighur and Kirghiz children in Xinjiang and Dai children in Yunnan, China.…”

NUDT15: A major determinant of thiopurine sensitivity in Asians

“…According to a study by Pu et al ., 5 the Bai people, the second largest minority in Yunnan province of China, have a high frequency of the NUDT15 variants, accounting for ~2% of homozygous variants. As shown in Figure 1, the allele frequency of NUDT15 hypomorphic variants varies according to race, and the Asian and Hispanic populations have a higher frequency of NUDT15 whereas TPMT variants are high frequency in other races.…”