Date on Master's Thesis/Doctoral Dissertation

12-2020

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Epidemiology and Population Health

Degree Program

Public Health Sciences with a specialization in Epidemiology, PhD

Committee Chair

Taylor, Kira

Committee Member

North, Kira

Committee Member

Baumgartner, Richard

Committee Member

Little, Bertis

Committee Member

Dupre, Natalie

Author's Keywords

Pleiotropy; adiposity; inflammation; genetic; hispanic; cardiovascular

Abstract

The observed overlap between genetic variants associated with both adiposity and inflammatory markers suggests that changes in both adiposity and inflammation could be partially mediated by common pathways. The pervasive but sparsely characterized “pleiotropic” genetic variants associated with both adiposity and inflammation have been hypothesized to provide insight into the shared biology. This study explored and characterized the genetic pleiotropy underpinning adiposity and inflammation using genetic and phenotypic observations from the Cameron County Hispanic Cohort (CCHC). A total of 3,313 samples and >9 million single nucleotide polymorphisms (SNPs) were examined in this study. Mixed model genome-wide association studies (GWAS) were performed for 9 phenotypes including C-reactive protein (CRP), Interleukin (IL)-6, IL-8, fibrinogen, body mass index (BMI), waist circumference (WC) in males and females, and waist to hip ratio (WHR) in males and females (separately). GWAS for WHR and WC were meta-analyzed to obtain sex-combined results. Pleiotropy assessment was completed using adaptive Sum of Powered Score (aSPU) test. Three genetic loci with evidence of pleiotropy on chromosome 3, 12 and 18 were fine-mapped to distinguish the set of likely vi causal variants. Causal mediation analysis was used to assess whether likely causal variants were independently associated with both inflammation and adiposity. At least 3 signals, on chromosomes 3, 12, and 12, were identified that suggested the presence of SNPs with strong pleiotropic p-values (< 5 × 10−6 ). The fine-mapping of these three suspected pleiotropic regions distinguished 22 variants with posterior causality probabilities greater than 50%. The mediation analysis indicated that rs60505812, on chromosome 3, was independently associated with both an inflammatory marker (IL-6) and an adiposity measure (BMI). For the variant rs73093474, on chromosome 12, results indicated both a direct association with CRP and an indirect association (via WHR). The identification of likely pleiotropic variants indicated that 1) a considerable degree of overlapping genetic pleiotropy exists between adiposity and inflammation, and 2) evidence exists to support both the direct and indirect pleiotropy. The results showed the potential of these genetic variants to provide biological insight, intended to improve the cardiovascular health of the Hispanics, and by extension all populations.

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