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Understanding the role of the chromosome 15q25.1 in COPD through epigenetics and transcriptomics

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Abstract
Chronic obstructive pulmonary disease (COPD) is a major health burden in adults and cigarette smoking is considered the most important environmental risk factor of COPD. Chromosome 15q25.1 locus is associated with both COPD and smoking. Our study aims at understanding the mechanism underlying the association of chromosome 15q25.1 with COPD through epigenetic and transcriptional variation in a population-based setting. To assess if COPD-associated variants in 15q25.1 are methylation quantitative trait loci, epigenome-wide association analysis of four genetic variants, previously associated with COPD (P < 5 x 10(-8)) in the 15q25.1 locus (rs12914385: C>T-CHRNA3, rs8034191: T> C-HYKK, rs13180: C> T-IREB2 and rs8042238: C> T-IREB2), was performed in the Rotterdam study (n = 1489). All four variants were significantly associated (P < 1.4 x 10(-6)) with blood DNA methylation of IREB2, CHRNA3 and PSMA4, of which two, including IREB2 and PSMA4, were also differentially methylated in COPD cases and controls (P < 0.04). Further additive and multiplicative effects of smoking were evaluated and no significant effect was observed. To evaluate if these four genetic variants are expression quantitative trait loci, transcriptome-wide association analysis was performed in 1087 lung samples. All four variants were also significantly associated with differential expression of the IREB2 3'UTR in lung tissues (P < 5.4 x 10(-95)). We conclude that regulatory mechanisms affecting the expression of IREB2 gene, such as DNA methylation, may explain the association between genetic variants in chromosome 15q25.1 and COPD, largely independent of smoking.
Keywords
OBSTRUCTIVE PULMONARY-DISEASE, GENOME-WIDE ASSOCIATION, DNA METHYLATION, LEVELS, LUNG-CANCER, SUSCEPTIBILITY LOCUS, NICOTINE DEPENDENCE, CIGARETTE-SMOKING, GENES, RISK, LOCALIZATION

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Citation

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MLA
Nedeljkovic, Ivana, Elena Carnero-Montoro, Lies Lahousse, et al. “Understanding the Role of the Chromosome 15q25.1 in COPD Through Epigenetics and Transcriptomics.” EUROPEAN JOURNAL OF HUMAN GENETICS 26.5 (2018): 709–722. Print.
APA
Nedeljkovic, I., Carnero-Montoro, E., Lahousse, L., van der Plaat, D. A., de Jong, K., Vonk, J. M., van Diemen, C. C., et al. (2018). Understanding the role of the chromosome 15q25.1 in COPD through epigenetics and transcriptomics. EUROPEAN JOURNAL OF HUMAN GENETICS, 26(5), 709–722.
Chicago author-date
Nedeljkovic, Ivana, Elena Carnero-Montoro, Lies Lahousse, Diana A van der Plaat, Kim de Jong, Judith M Vonk, Cleo C van Diemen, et al. 2018. “Understanding the Role of the Chromosome 15q25.1 in COPD Through Epigenetics and Transcriptomics.” European Journal of Human Genetics 26 (5): 709–722.
Chicago author-date (all authors)
Nedeljkovic, Ivana, Elena Carnero-Montoro, Lies Lahousse, Diana A van der Plaat, Kim de Jong, Judith M Vonk, Cleo C van Diemen, Alen Faiz, Maarten van den Berge, Ma’en Obeidat, Yohan Bosse, David C Nickle, Andre G Uitterlinden, Joyce JB van Meurs, Bruno CH Stricker, Guy Brusselle, Dirkje S Postma, H Marike Boezen, Cornelia M van Duijn, and Najaf Amin. 2018. “Understanding the Role of the Chromosome 15q25.1 in COPD Through Epigenetics and Transcriptomics.” European Journal of Human Genetics 26 (5): 709–722.
Vancouver
1.
Nedeljkovic I, Carnero-Montoro E, Lahousse L, van der Plaat DA, de Jong K, Vonk JM, et al. Understanding the role of the chromosome 15q25.1 in COPD through epigenetics and transcriptomics. EUROPEAN JOURNAL OF HUMAN GENETICS. 2018;26(5):709–22.
IEEE
[1]
I. Nedeljkovic et al., “Understanding the role of the chromosome 15q25.1 in COPD through epigenetics and transcriptomics,” EUROPEAN JOURNAL OF HUMAN GENETICS, vol. 26, no. 5, pp. 709–722, 2018.
@article{8570029,
  abstract     = {Chronic obstructive pulmonary disease (COPD) is a major health burden in adults and cigarette smoking is considered the most important environmental risk factor of COPD. Chromosome 15q25.1 locus is associated with both COPD and smoking. Our study aims at understanding the mechanism underlying the association of chromosome 15q25.1 with COPD through epigenetic and transcriptional variation in a population-based setting. To assess if COPD-associated variants in 15q25.1 are methylation quantitative trait loci, epigenome-wide association analysis of four genetic variants, previously associated with COPD (P < 5 x 10(-8)) in the 15q25.1 locus (rs12914385: C>T-CHRNA3, rs8034191: T> C-HYKK, rs13180: C> T-IREB2 and rs8042238: C> T-IREB2), was performed in the Rotterdam study (n = 1489). All four variants were significantly associated (P < 1.4 x 10(-6)) with blood DNA methylation of IREB2, CHRNA3 and PSMA4, of which two, including IREB2 and PSMA4, were also differentially methylated in COPD cases and controls (P < 0.04). Further additive and multiplicative effects of smoking were evaluated and no significant effect was observed. To evaluate if these four genetic variants are expression quantitative trait loci, transcriptome-wide association analysis was performed in 1087 lung samples. All four variants were also significantly associated with differential expression of the IREB2 3'UTR in lung tissues (P < 5.4 x 10(-95)). We conclude that regulatory mechanisms affecting the expression of IREB2 gene, such as DNA methylation, may explain the association between genetic variants in chromosome 15q25.1 and COPD, largely independent of smoking.},
  author       = {Nedeljkovic, Ivana and Carnero-Montoro, Elena and Lahousse, Lies and van der Plaat, Diana A and de Jong, Kim and Vonk, Judith M and van Diemen, Cleo C and Faiz, Alen and van den Berge, Maarten and Obeidat, Ma'en and Bosse, Yohan and Nickle, David C and Uitterlinden, Andre G and van Meurs, Joyce JB and Stricker, Bruno CH and Brusselle, Guy and Postma, Dirkje S and Boezen, H Marike and van Duijn, Cornelia M and Amin, Najaf},
  issn         = {1018-4813},
  journal      = {EUROPEAN JOURNAL OF HUMAN GENETICS},
  keywords     = {OBSTRUCTIVE PULMONARY-DISEASE,GENOME-WIDE ASSOCIATION,DNA METHYLATION,LEVELS,LUNG-CANCER,SUSCEPTIBILITY LOCUS,NICOTINE DEPENDENCE,CIGARETTE-SMOKING,GENES,RISK,LOCALIZATION},
  language     = {eng},
  number       = {5},
  pages        = {709--722},
  title        = {Understanding the role of the chromosome 15q25.1 in COPD through epigenetics and transcriptomics},
  url          = {http://dx.doi.org/10.1038/s41431-017-0089-8},
  volume       = {26},
  year         = {2018},
}

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