A genome-wide methylation study of severe vitamin d deficiency in African American adolescents

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Abstract

Objectives: To test the hypothesis that changes in DNA methylation are involved in vitamin D deficiency-related immune cell regulation using an unbiased genome-wide approach combined with a genomic and epigenomic integrative approach. Study design: We performed a genome-wide methylation scan using the Illumina HumanMethylation 27 BeadChip on leukocyte DNA of 11 cases of vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] ≤ 25 nmol/L) and 11 age-matched controls ([25(OH)D] > 75 nmol/L); the subjects were African American normal-weight (body mass index <85th percentile) males aged 14-19 years. The Limma package was used to analyze each CpG site for differential methylation between cases and controls. To correct for multiple testing, the set of raw P values were converted to false discovery rates (FDRs). We also compared our findings with the recent data from Genome-Wide Association Studies of circulating 25(OH)D levels and then performed a permutation test to examine whether the "double hit" genes were randomly enriched. Results: A total of 79 CpG sites achieved raw P < .001. Of the 79 CpG sites, 2 CpG sites survived multiple testing: cg16317961 (raw P = 3.5 × 10-6, FDR = 0.078, in MAPRE2) and cg04623955 (raw P = 5.9 × 10-6, FDR = 0.078, in DIO3). Furthermore, 3 out of the 4 genes previously identified in the 2 Genome-Wide Association Studies were also significant at the methylation level (DHCR7: cg07487535, P = .015 and cg10763288, P = .017; CYP2R1: cg25454890, P = .040; CYP24A1: cg18956481, P = .022), reflecting significant enrichment (P = .0098). Conclusion: Severe vitamin D deficiency is associated with methylation changes in leukocyte DNA. The genomic and epigenomic approach reinforce the crucial roles played by the DHCR7, CYP2R1, and CYP24A1 genes in vitamin D metabolism.

Original languageEnglish (US)
JournalJournal of Pediatrics
Volume162
Issue number5
DOIs
StatePublished - Jan 1 2013

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Avitaminosis
African Americans
Methylation
Vitamin D Deficiency
Genome
Genome-Wide Association Study
Epigenomics
Leukocytes
Genes
DNA
DNA Methylation
Vitamin D
Body Mass Index
Weights and Measures
Serum
Vitamin D3 24-Hydroxylase

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

@article{7448952768194ef7bac1ba39c45f83cd,
title = "A genome-wide methylation study of severe vitamin d deficiency in African American adolescents",
abstract = "Objectives: To test the hypothesis that changes in DNA methylation are involved in vitamin D deficiency-related immune cell regulation using an unbiased genome-wide approach combined with a genomic and epigenomic integrative approach. Study design: We performed a genome-wide methylation scan using the Illumina HumanMethylation 27 BeadChip on leukocyte DNA of 11 cases of vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] ≤ 25 nmol/L) and 11 age-matched controls ([25(OH)D] > 75 nmol/L); the subjects were African American normal-weight (body mass index <85th percentile) males aged 14-19 years. The Limma package was used to analyze each CpG site for differential methylation between cases and controls. To correct for multiple testing, the set of raw P values were converted to false discovery rates (FDRs). We also compared our findings with the recent data from Genome-Wide Association Studies of circulating 25(OH)D levels and then performed a permutation test to examine whether the {"}double hit{"} genes were randomly enriched. Results: A total of 79 CpG sites achieved raw P < .001. Of the 79 CpG sites, 2 CpG sites survived multiple testing: cg16317961 (raw P = 3.5 × 10-6, FDR = 0.078, in MAPRE2) and cg04623955 (raw P = 5.9 × 10-6, FDR = 0.078, in DIO3). Furthermore, 3 out of the 4 genes previously identified in the 2 Genome-Wide Association Studies were also significant at the methylation level (DHCR7: cg07487535, P = .015 and cg10763288, P = .017; CYP2R1: cg25454890, P = .040; CYP24A1: cg18956481, P = .022), reflecting significant enrichment (P = .0098). Conclusion: Severe vitamin D deficiency is associated with methylation changes in leukocyte DNA. The genomic and epigenomic approach reinforce the crucial roles played by the DHCR7, CYP2R1, and CYP24A1 genes in vitamin D metabolism.",
author = "Haidong Zhu and Xiaoling Wang and Huidong Shi and Shaoyong Su and Harshfield, {Gregory A} and Bernard Gutin and Harold Snieder and Yanbin Dong",
year = "2013",
month = "1",
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doi = "10.1016/j.jpeds.2012.10.059",
language = "English (US)",
volume = "162",
journal = "Journal of Pediatrics",
issn = "0022-3476",
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T1 - A genome-wide methylation study of severe vitamin d deficiency in African American adolescents

AU - Zhu, Haidong

AU - Wang, Xiaoling

AU - Shi, Huidong

AU - Su, Shaoyong

AU - Harshfield, Gregory A

AU - Gutin, Bernard

AU - Snieder, Harold

AU - Dong, Yanbin

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Objectives: To test the hypothesis that changes in DNA methylation are involved in vitamin D deficiency-related immune cell regulation using an unbiased genome-wide approach combined with a genomic and epigenomic integrative approach. Study design: We performed a genome-wide methylation scan using the Illumina HumanMethylation 27 BeadChip on leukocyte DNA of 11 cases of vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] ≤ 25 nmol/L) and 11 age-matched controls ([25(OH)D] > 75 nmol/L); the subjects were African American normal-weight (body mass index <85th percentile) males aged 14-19 years. The Limma package was used to analyze each CpG site for differential methylation between cases and controls. To correct for multiple testing, the set of raw P values were converted to false discovery rates (FDRs). We also compared our findings with the recent data from Genome-Wide Association Studies of circulating 25(OH)D levels and then performed a permutation test to examine whether the "double hit" genes were randomly enriched. Results: A total of 79 CpG sites achieved raw P < .001. Of the 79 CpG sites, 2 CpG sites survived multiple testing: cg16317961 (raw P = 3.5 × 10-6, FDR = 0.078, in MAPRE2) and cg04623955 (raw P = 5.9 × 10-6, FDR = 0.078, in DIO3). Furthermore, 3 out of the 4 genes previously identified in the 2 Genome-Wide Association Studies were also significant at the methylation level (DHCR7: cg07487535, P = .015 and cg10763288, P = .017; CYP2R1: cg25454890, P = .040; CYP24A1: cg18956481, P = .022), reflecting significant enrichment (P = .0098). Conclusion: Severe vitamin D deficiency is associated with methylation changes in leukocyte DNA. The genomic and epigenomic approach reinforce the crucial roles played by the DHCR7, CYP2R1, and CYP24A1 genes in vitamin D metabolism.

AB - Objectives: To test the hypothesis that changes in DNA methylation are involved in vitamin D deficiency-related immune cell regulation using an unbiased genome-wide approach combined with a genomic and epigenomic integrative approach. Study design: We performed a genome-wide methylation scan using the Illumina HumanMethylation 27 BeadChip on leukocyte DNA of 11 cases of vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] ≤ 25 nmol/L) and 11 age-matched controls ([25(OH)D] > 75 nmol/L); the subjects were African American normal-weight (body mass index <85th percentile) males aged 14-19 years. The Limma package was used to analyze each CpG site for differential methylation between cases and controls. To correct for multiple testing, the set of raw P values were converted to false discovery rates (FDRs). We also compared our findings with the recent data from Genome-Wide Association Studies of circulating 25(OH)D levels and then performed a permutation test to examine whether the "double hit" genes were randomly enriched. Results: A total of 79 CpG sites achieved raw P < .001. Of the 79 CpG sites, 2 CpG sites survived multiple testing: cg16317961 (raw P = 3.5 × 10-6, FDR = 0.078, in MAPRE2) and cg04623955 (raw P = 5.9 × 10-6, FDR = 0.078, in DIO3). Furthermore, 3 out of the 4 genes previously identified in the 2 Genome-Wide Association Studies were also significant at the methylation level (DHCR7: cg07487535, P = .015 and cg10763288, P = .017; CYP2R1: cg25454890, P = .040; CYP24A1: cg18956481, P = .022), reflecting significant enrichment (P = .0098). Conclusion: Severe vitamin D deficiency is associated with methylation changes in leukocyte DNA. The genomic and epigenomic approach reinforce the crucial roles played by the DHCR7, CYP2R1, and CYP24A1 genes in vitamin D metabolism.

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