Interaction of prenatal maternal smoking, interleukin 13 genetic variants and DNA methylation influencing airflow and airway reactivity

Clinical Epigenetics

Wilfried Karmaus¹  S Hasan Arshad³  Susan Ewart²  Nelis Soto-Ramirez¹  Hongmei Zhang¹  John W Holloway⁴  Veeresh K Patil³ 

[1] Division of Epidemiology, Biostatistics, & Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA;Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA;Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK;Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK

关键词: Maternal smoking during pregnancy;    Lung functions;    IL13 gene;    DNA methylation;    Airway reactivity;    Asthma genetics and epigenetics;   

Others  :  790724
DOI  :  10.1186/1868-7083-5-22

 received in 2013-06-25, accepted in 2013-11-01,  发布年份 2013

【 摘 要 】

Background

Asthma is characterized by airflow limitation and airway reactivity (AR). Interleukin-13 (IL-13) is involved in the pathogenesis of asthma. Two functional SNPs, rs20541 and rs1800925, of the IL-13 gene (IL13) have been frequently associated with asthma-related lung functions. However, genetic variation alone does not fully explain asthma risk. DNA-methylation (DNA-M) is an epigenetic mechanism that regulates gene expression and can be influenced by both environment and genetic variants. To explore the interplay of prenatal maternal smoking, genetic variants and DNA-M, we used a two-stage model: (1) identifying cytosine phosphate guanine (CpG) sites where DNA-M is influenced by the interaction between genetic variants and maternal smoking during pregnancy (conditional methQTL (methylation quantitative trait loci)); and (2) determining the effect of the interaction between DNA-M of CpG (from stage 1) and SNPs (modifying genetic variants; modGV) on airflow limitation and AR in 245 female participants of the Isle of Wight birth cohort. DNA-M was assessed using the Illumina Infinium HumanMethylation450 BeadChip.

Findings

Six CpG sites were analyzed in stage 1. DNA-M at cg13566430 was influenced by interaction of maternal smoking during pregnancy and rs20541. In stage 2, genotype at rs1800925 interacted with DNA-M at cg13566430 significantly affecting airflow limitation (P = 0.042) and AR (P = 0.01).

Conclusion

Both genetic variants and environment affect DNA-M. This study supports the proposed two-stage model (methQTL and modGV) to study genetic variants, environment and DNA-M interactions in asthma-related lung function.

【 授权许可】

   
2013 Patil et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Karmaus W, Dobai AL, Ogbuanu I, Arshard SH, Matthews S, Ewart S: Long-term effects of breastfeeding, maternal smoking during pregnancy, and recurrent lower respiratory tract infections on asthma in children. J Asthma 2008, 45:688-695.
• [2]Wang L, Pinkerton KE: Detrimental effects of tobacco smoke exposure during development on postnatal lung function and asthma. Birth Defects Res C Embryo Today 2008, 84:54-60.
• [3]Li X, Howard TD, Zheng SL, Haselkorn T, Peters SP, Meyers DA, Bleecker ER: Genome-wide association study of asthma identifies RAD50-IL13 and HLA-DR/DQ regions. J Allergy Clin Immunol 2010, 125:328-3354.
• [4]Holloway JW, Yang IA, Holgate ST: Genetics of allergic disease. J Allergy Clin Immunol 2010, 125(2 Suppl 2):S81-S94.
• [5]Nie W, Liu Y, Bian J, Li B, Xiu Q: Effects of polymorphisms -1112C/T and +2044A/G in interleukin-13 gene on asthma risk: a meta-analysis. PLoS One 2013, 8:e56065.
• [6]Cui L, Jia J, Ma CF, Li SY, Wang YP, Guo XM, Li Q, Yu HB, Liu WH, Gao LB: IL-13 polymorphisms contribute to the risk of asthma: a meta-analysis. Clin Biochem 2012, 45:285-288.
• [7]Beghe B, Hall IP, Parker SG, Moffatt MF, Wardlaw A, Connolly MJ, Fabbri LM, Ruse C, Sayers I: Polymorphisms in IL13 pathway genes in asthma and chronic obstructive pulmonary disease. Allergy 2010, 65:474-481.
• [8]Park H-W, Lee J-E, Kim S-H, Kim Y-K, Min K-U, Kim Y-Y, Cho S-H: Genetic variation of IL13 as a risk factor of reduced lung function in children and adolescents: a cross-sectional population-based study in Korea. Respir Med 2009, 103:284-288.
• [9]Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, Harris JM, Scheerens H, Wu LC, Su Z, Mosesova S, Eisner MD, Bohen SP, Matthews JG: Lebrikizumab treatment in adults with asthma. N Engl J Med 2011, 365:1088-1098.
• [10]Yang G, Volk A, Petley T, Emmell E, Giles-Komar J, Shang X, Li J, Das AM, Shealy D, Griswold DE, Li L: Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling. Cytokine 2004, 28:224-232.
• [11]Kabesch M, Michel S, Tost J: Epigenetic mechanisms and the relationship to childhood asthma. Eur Respir J 2010, 36:950-961.
• [12]Joubert BR, Haberg SE, Nilsen RM, Wang X, Vollset SE, Murphy SK, Huang Z, Hoyo C, Midttun O, Cupul-Uicab LA, Ueland PM, Wu MC, Nystad W, Bell DA, Peddada SD, London SJ: 450 K Epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy. Environ Health Perspect 2012, 120:1425-1431.
• [13]Bell CG, Finer S, Lindgren CM, Wilson GA, Rakyan VK, Teschendorff AE, Akan P, Stupka E, Down TA, Prokopenko I, Morison IM, Mill J, Pidsley R, Deloukas P, Frayling TM, Hattersley AT, McCarthy MI, Beck S, Hitman GA, International Type 2 Diabetes 1q C: Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS One 2010, 5:e14040.
• [14]Sadeghnejad A, Karmaus W, Arshad SH, Kurukulaaratchy R, Huebner M, Ewart S: IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study. Respir Res 2008, 9:2. BioMed Central Full Text
• [15]Soto-Ramirez N, Arshad SH, Holloway JW, Zhang H, Schauberger E, Ewart S, Patil V, Karmaus W: The interaction of genetic variants and DNA methylation of the interleukin-4 receptor gene increase the risk of asthma at age 18 years. Clin Epigenetics 2013, 5:1. BioMed Central Full Text
• [16]Karmaus W, Ziyab AH, Everson T, Holloway JW: Epigenetic mechanisms and models in the origins of asthma. Curr Opin Allergy Clin Immunol 2013, 13:63-69.
• [17]Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, MacIntyre NR, McKay RT, Wanger JS, Anderson SD, Cockcroft DW, Fish JE, Sterk PJ: Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS board of directors, July 1999. Am J Respir Crit Care Med 2000, 161:309-329.
• [18]Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J: Standardisation of spirometry. Eur Respir J 2005, 26:319-338.
• [19]Raza A, Kurukulaaratchy RJ, Grundy JD, Clayton CB, Mitchell FA, Roberts G, Ewart S, Sadeghnejad A, Arshad SH: What does adolescent undiagnosed wheeze represent? Findings from the Isle of Wight cohort. Eur Respir J 2012, 40:580-588.
• [20]Kuan PF, Wang S, Zhou X, Chu H: A statistical framework for Illumina DNA methylation arrays. Bioinformatics 2010, 26:2849-2855.
• [21]Wang D, Yan L, Hu Q, Sucheston LE, Higgins MJ, Ambrosone CB, Johnson CS, Smiraglia DJ, Liu S: IMA: an R package for high-throughput analysis of Illumina’s 450K Infinium methylation data. Bioinformatics 2012, 28:729-730.
• [22]Michel S, Busato F, Genuneit J, Pekkanen J, Dalphin JC, Riedler J, Mazaleyrat N, Weber J, Karvonen AM, Hirvonen MR, Braun-Fahrlander C, Lauener R, von Mutius E, Kabesch M, Tost J, group Ps: Farm exposure and time trends in early childhood may influence DNA methylation in genes related to asthma and allergy. Allergy 2013, 68:355-364.
• [23]Bell JT, Tsai PC, Yang TP, Pidsley R, Nisbet J, Glass D, Mangino M, Zhai G, Zhang F, Valdes A, Shin SY, Dempster EL, Murray RM, Grundberg E, Hedman AK, Nica A, Small KS, Mu TC, Dermitzakis ET, McCarthy MI, Mill J, Spector TD, Deloukas P: Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLoS Genet 2012, 8:e1002629.
• [24]Bibikova M, Barnes B, Tsan C, Ho V, Klotzle B, Le JM, Delano D, Zhang L, Schroth GP, Gunderson KL, Fan J-B, Shen R: High density DNA methylation array with single CpG site resolution. Genomics 2011, 98:288-295.
• [25]Razin A: CpG methylation, chromatin structure and gene silencing-a three-way connection. EMBO J 1998, 17:4905-4908.