Date of Award

2017

Document Type

Open Access Dissertation

Department

Epidemiology and Biostatistics

Sub-Department

The Norman J. Arnold School of Public Health

First Advisor

Wilfried Karmaus

Abstract

Background: Leptin, initially believed to simply be a satiety hormone responsible for obesity, is now recognized as a pleiotropic cytokine that is involved in many biological processes; including the body’s host inflammatory response. Clinically, leptin may affect lung function although research in this area is limited. It is also known that the leptin receptor is necessary for the activation of the leptin protein, making it an important protein to consider. Furthermore, single nucleotide polymorphisms (SNPs) and DNA methylations of the leptin and leptin receptor genes (LEP and LEPR respectively) may provide important insight on the relationship that leptin has with inflammation in the body.

Objectives: This dissertation focused on: 1) the association between leptin and leptin receptor gene polymorphisms and lung function (forced vital capacity, FVC; forced expiratory volume in 1 second, FEV1; and FEV1/FVC) at ages 10 and 18. 2a) The association between LEP SNPs and LEP DNA methylation. 2b) The association between LEP DNA methylation and serum leptin levels. 3) The association between leptin and FVC, FEV1, and FEV1/FVC controlling for body mass index (BMI).

Methods: The Isle of Wight (IOW) birth cohort, a population-based sample of 1,456 infants born between January 1989 and February 1990, was prospectively assessed at ages 1, 2, 4, 10, and 18 years. FVC, FEV1, and leptin were collected at 10 and 18-year follow-ups. SNP and DNA methylation data was analyzed from blood that was collected at birth and 18 years follow up respectively. Regarding associations between LEP and LEPR SNPs and FVC, FEV1, and FEV1, FVC, forty-two independent repeated measurement analyses were conducted to test their association. Linear regression analyses were used to test the links between LEP SNPs and LEP DNA methylation, as well as the association between LEP DNA methylation and serum leptin protein levels at age 18. Finally, linear regression analyses were applied to investigate the association between serum leptin levels at ages 10 and 18 and FVC, FEV1, and FEV1/FVC at ages 10 and 18.

Results: LEPR SNPs rs6669354, rs1137101, and rs3762274 were associated with decreased lung function from ages 10 to 18. Those with the AC genotype of rs6669354 had 0.092 L lower FVC and 0.10 L lower FEV1 than those with the AA genotype (Adjusted P-value=0.015 for both tests). A similar pattern was observed for SNPs rs1137101 and rs3762274 and the association with decreased FEV1/FVC (Adjusted P-values 0.04 and 0.02 respectively). LEP SNPs rs11763517 and rs4731429 were both found to be related with DNA methylation sites cg00666422 (5’UTR region) and cg24862443 (3’UTR region) and LEP SNP rs4731429 was associated with cg00840332 (TSS200 region). The results were replicated in the second-generation (F2) cohort. Regarding leptin in F1, increased methylation of cg00840332 interacting with rs11763517 and rs4731429 was associated with decreased leptin serum levels. Lastly, in boys, an increase in leptin levels from ages 10 to 18 was related to a 0.017 L decreased FVC at age 18 (STD=0.007, P-value=0.018), while in girls increased leptin between ages 10 to 18 was associated with FEV1 at age 18 decreasing by 0.013 L (STD=0.006, P-value=0.029). These associations were seen even after controlling for BMI.

Conclusions: LEPR SNPs are associated with decreased FVC, FEV1, and FEV1/FVC from ages 10 to 18. A possible mechanism for this association can be explained through the activity of leptin. First, LEP SNPs are associated with increased LEP DNA methylation at the start of the gene and decreased LEP DNA methylation at the 3’UTR region of the gene; DNA methylation is linked to circulating serum leptin protein levels. Second, an increase in leptin protein between the ages of 10 and 18 is associated with decreased FVC in boys and decreased FEV1 in girls at age 18.

Available for download on Wednesday, December 18, 2019

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