Catherine Metayer, Logan G Spector, Michael E Scheurer, Soyoung Jeon, Rodney J Scott, Masatoshi Takagi, Jacqueline Clavel, Atsushi Manabe, Xiaomei Ma, Elleni M Hailu, Philip J Lupo, Kevin Y Urayama, Audrey Bonaventure, Motohiro Kato, Aline Meirhaeghe, Charleston W K Chiang, Libby M Morimoto, Joseph L Wiemels
{"title":"叶酸代谢与儿童急性淋巴细胞白血病风险:儿童癌症和白血病国际联盟的遗传途径分析。","authors":"Catherine Metayer, Logan G Spector, Michael E Scheurer, Soyoung Jeon, Rodney J Scott, Masatoshi Takagi, Jacqueline Clavel, Atsushi Manabe, Xiaomei Ma, Elleni M Hailu, Philip J Lupo, Kevin Y Urayama, Audrey Bonaventure, Motohiro Kato, Aline Meirhaeghe, Charleston W K Chiang, Libby M Morimoto, Joseph L Wiemels","doi":"10.1158/1055-9965.EPI-24-0189","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Prenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results.</p><p><strong>Methods: </strong>We evaluated whether ∼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software.</p><p><strong>Results: </strong>None of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10-6 and less-stringent P-value of 3.5 × 10-5 accounting for the number of \"independent\" SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups.</p><p><strong>Conclusions: </strong>This large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups.</p><p><strong>Impact: </strong>Genetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. Other mechanisms such as gene-folate interaction, DNA methylation, or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.</p>","PeriodicalId":9458,"journal":{"name":"Cancer Epidemiology Biomarkers & Prevention","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369612/pdf/","citationCount":"0","resultStr":"{\"title\":\"Folate Metabolism and Risk of Childhood Acute Lymphoblastic Leukemia: A Genetic Pathway Analysis from the Childhood Cancer and Leukemia International Consortium.\",\"authors\":\"Catherine Metayer, Logan G Spector, Michael E Scheurer, Soyoung Jeon, Rodney J Scott, Masatoshi Takagi, Jacqueline Clavel, Atsushi Manabe, Xiaomei Ma, Elleni M Hailu, Philip J Lupo, Kevin Y Urayama, Audrey Bonaventure, Motohiro Kato, Aline Meirhaeghe, Charleston W K Chiang, Libby M Morimoto, Joseph L Wiemels\",\"doi\":\"10.1158/1055-9965.EPI-24-0189\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Prenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results.</p><p><strong>Methods: </strong>We evaluated whether ∼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software.</p><p><strong>Results: </strong>None of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10-6 and less-stringent P-value of 3.5 × 10-5 accounting for the number of \\\"independent\\\" SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups.</p><p><strong>Conclusions: </strong>This large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups.</p><p><strong>Impact: </strong>Genetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. 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引用次数: 0
摘要
背景:产前补充叶酸一直与降低儿童淋巴细胞白血病(ALL)风险相关。以前对一碳(叶酸)代谢途径进行的种系遗传学研究在样本量、范围和人群多样性方面都很有限,结果也不确定:我们利用儿童癌症和白血病国际联盟(Childhood Cancer and Leukemia International Consortium)中九项病例对照研究的全基因组数据(n=9,058 例病例,包括 4,510 名欧洲裔儿童、3,018 名拉丁裔儿童、1,406 名亚洲裔儿童,以及 92,364 例对照),评估了涉及叶酸代谢途径的 46 个候选基因中的约 2,900 个单核苷酸多态性(SNPs)是否会影响儿童 ALL 的发病风险。每项研究都遵循标准化方案对全基因组数据进行质量控制和估算,并使用 METAL 软件对所有儿童和主要血统群体的汇总统计数据进行了元分析:所选 SNP 均未达到统计学显著性,无论是在总体上还是在主要祖先群体中(使用调整后的 5x10-6 Bonferroni p 值和考虑到 "独立 "SNP 数量的较宽松 p 值 3.5x10-5)。10 个顶级(非显著)SNPs 和相应基因在不同祖先群体中均无重叠:这项对原始数据的大型荟萃分析并未揭示叶酸代谢途径中的许多常见遗传变异与不同血统群体中的儿童 ALL 之间的关联:影响:仅叶酸代谢途径中的遗传变异似乎不会对儿童 ALL 风险产生重大影响。其他机制,如基因与叶酸的相互作用、DNA甲基化或母体遗传效应,可能解释了所观察到的与自我报告的产前叶酸摄入量之间的关联。
Folate Metabolism and Risk of Childhood Acute Lymphoblastic Leukemia: A Genetic Pathway Analysis from the Childhood Cancer and Leukemia International Consortium.
Background: Prenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results.
Methods: We evaluated whether ∼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software.
Results: None of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10-6 and less-stringent P-value of 3.5 × 10-5 accounting for the number of "independent" SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups.
Conclusions: This large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups.
Impact: Genetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. Other mechanisms such as gene-folate interaction, DNA methylation, or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.
期刊介绍:
Cancer Epidemiology, Biomarkers & Prevention publishes original peer-reviewed, population-based research on cancer etiology, prevention, surveillance, and survivorship. The following topics are of special interest: descriptive, analytical, and molecular epidemiology; biomarkers including assay development, validation, and application; chemoprevention and other types of prevention research in the context of descriptive and observational studies; the role of behavioral factors in cancer etiology and prevention; survivorship studies; risk factors; implementation science and cancer care delivery; and the science of cancer health disparities. Besides welcoming manuscripts that address individual subjects in any of the relevant disciplines, CEBP editors encourage the submission of manuscripts with a transdisciplinary approach.