Date of Award

9-27-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Bioinformatics

First Advisor

Barbara Fuhrman

Abstract

Introduction Early menarche has been associated with greater risks of cardiovascular disease (CVD) and CVD-related mortality but the mechanisms remain unclear. We hypothesized that early menarche and CVD may share as a common cause, changes in the natural history of the gut microbiome. Methods We obtained data on 2,400 adult female twins from the TwinsUK registry. Participants reported their age at menarche retrospectively and underwent anthropometric and clinical laboratory measures in 1992-2014. They provided fecal samples in 2007-2012. Microbial DNA sequences represent the V4 region of the 16S rRNA gene. OTU-picking was done using open-reference strategy in QIIME and the Green Genes database. Alpha diversity was measured in samples rarefied to depth of 8,136. PICRUStT was used to impute measures of metabolic potential. SAS proc MIXED was used to model CVD risk factors and measures of gut microbial composition, diversity, and metabolic potential, as functions of the age at menarche while accounting for twinned subjects. Models adjusted for birth year and BMI. Menarche was categorized into five groups (15 y). Associations with menarche were modeled first as a linear trend and then simultaneously as a category (12 y) and an independent linear trend across remaining categories. SAS proc CAUSALMED was used to assess mediation of menarche-CVD associations by anthropometric and microbial measures. Results Compared to women who experienced menarche at the median age of 12 y, those reporting earlier menarche were more likely to be obese (Prevalence Ratio (PR) =1.90, 95%CI:1.24-2.91, Ptrend=9E-6), to have metabolic syndrome or diabetes (PR=1.53, 95%CI:0.85-2.77, Ptrend=0.42), high triglycerides (PR=1.87, 95%CI:1.08-3.23, Ptrend=0.08), and elevated lipid accumulation product (LAP>31.6 cm*mmol/L, PR=1.80, 95%CI:1.11-2.92, Ptrend=0.34). Associations of early menarche with CVD-risk factors were U-shaped and only partially mediated by BMI. Some microbial measures showed similar non-linear patterns of association with menarche. Substantial overlap was observed between metabolic measures associated with early menarche and with LAP. Conclusion Findings suggest that early menarche influences cardiovascular risks through its effects on disposition of lipids and metabolic activities of gut microbiome. Prospective studies should be carried out to identify causes of early menarche and pathways mediating associations with CVD.

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