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. 2016 Mar 23;7(1):1-17.
eCollection 2016.

DNA methylation and genetic polymorphisms of the Leptin gene interact to influence lung function outcomes and asthma at 18 years of age

Nandini Mukherjee  1 , Gabrielle A Lockett  2 , Simon K Merid  3 , Erik Melén  3 , Göran Pershagen  3 , John W Holloway  4 , Syed Hasan Arshad  5 , Susan Ewart  6 , Hongmei Zhang  1 , Wilfried Karmaus  1
Affiliations

DNA methylation and genetic polymorphisms of the Leptin gene interact to influence lung function outcomes and asthma at 18 years of age

Nandini Mukherjee et al. Int J Mol Epidemiol Genet. .

Abstract

The leptin gene (LEP) plays a regulatory role in satiety, inflammation, and allergy. Prior findings linking leptin to asthma motivated us to investigate whether DNA methylation (DNA-M) of CpG (cytosine-phosphate-guanine) sites in concert with single nucleotide polymorphisms (SNPs) of LEP can explain the risk of asthma and lung function. Methylation of CpG sites was assessed using the Illumina Infinium Human Methylation 450 beadchip in blood samples collected from 10- and 18-year-old boys and girls from the Isle of Wight (IOW) birth cohort (UK). Four LEP SNPs were genotyped. Linear and log linear models were used for the analysis, adjusting for false discovery rate (FDR). The analyses were repeated in the BAMSE cohort (Sweden). In the IOW study, the interaction of cg00666422 and rs11763517 (CT vs TT and CC) was associated with FEV1 (FDR-adjusted p-value: 0.03), FEV1/FVC ratio (FDR-adjusted p-value: 0.0096), and FEF25-75% (FDR-adjusted p-value: 0.00048) such that they decreased with increasing DNA-M. The interaction of the same CpG-SNP pair was also associated with increased risk of asthma at age 18. We replicated the findings for FEV1/FVC and FEF25-75% in a smaller sample of 34 participants at age 10. Regarding the BAMSE cohort, although, the interaction of cg00666422 and rs11763517 on lung function were not significant, the direction of the effect was the same as in IOW cohort. Thus, penetrance of LEP genotype seems to be modified by methylation at cg00666422 and is linked to airway obstruction and asthma.

Keywords: CpGs; Epigenetics; FEF25-75%; FEV1; FEV1/FVC ratio; SNPs; asthma; spirometry.

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Figures

Figure 1
Figure 1
Linkage disequilibrium plot of LEP SNPs, standard (D’/LOD) color scheme; D’ LD values are displayed.
Figure 4
Figure 4
The positions of CpG sites and SNPs included in this study, relative to the LEP gene. CDS=coding sequence, UTR=untranslated region.
Figure 2
Figure 2
Comparison of rs11763517 genotypes in interaction with categorized methylation levels of cg00666422 on (A) FEV1 (B) FEV1/FVC and (C) FEF25-75% at age 18. The horizontal axis represents the bins of DNA methylation, and the green bars represent the frequency for the DNA methylation bins. For example, 34 individuals have a DNA methylation level of 39%-41%. The CT genotype (red dots) and the TT and CC (combined) genotype (black diamonds) are plotted against (A) FEV1 (B) FEV1/FVC and (C) FEF25-75%. The reference genotype was TT and CC combined.
Figure 3
Figure 3
Risk ratio of asthma at age 18 versus methylation of the LEP CpG site cg00666422, for rs11763517 genotype CT relative to TT or CC (combined). The horizontal axis represents bins of DNA methylation and the green bars represent the frequency for those DNA methylation bins. The CT genotype (red dots) is plotted against asthma relative risk. The reference genotype was TT and CC combined.
Figure 5
Figure 5
Methylation levels (β values) of the LEP CpG sites.
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