Page 29 - L. Genetics and genomics

An Integrative Systems Genetic Analysis of
Atherosclerosis and Gut Microbiota

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Myungsuk Kim 1,2 , M. Nazmul Huda , Excel Que , Erik R. Gertz , Brian J. Bennett 1,2
1 Department of Nutrition, University of California, Davis 95616,
2 Western Human Nutrition Research Center, Davis, CA 95616
BACKGROUNDS & AIMS STUDY DESIGN & METHODS
BACKGROUNDS We collected offspring (238 female and 234
Atherosclerosis is a precipitating event in the development of male mice) from a cross between
cardiovascular disease. Recent studies report that gut transgenic male C57BL/6J mice, which
microbiota contributes to the pathogenesis of cardiovascular were made susceptible to atherosclerosis
by microinjection of human apolipoprotein
disease, including metabolic syndrome. While host genetic E-Leiden and cholesterol ester transfer
variants are known factors that affect atherosclerosis protein genes, and ~200 female DO mice,
development and gut microbiota composition, the a population derived from 8 inbred strains.
mechanisms underlying genetic variations are not yet clear. We fed the offspring a high fat/cholesterol
diet for 12 weeks. We then examined over
AIMS 30 cardio-metabolic traits, fecal microbiota
Here, we interrogated atherosclerosis regulatory networks in compositions using 16S rRNA gene
.
hyperlipidemic Diversity Outbred mice to reveal key insights sequencing, and global liver gene
into control of atherosclerosis using system genetic expression using RNA-sequencing. To
approaches of cardio-metabolic traits, microbiome and liver elucidate the association of genetic factors
and phenotype, we performed quantitative
transcriptome. trait locus (QTL) analysis.
RESULTS

Fig.1. Genetic architecture of quantitative trait loci (QTL) for A B
cardio-metabolic traits and microbial taxa abundance in Diversity
Outbred (DO)-F1 mice. (A) Genetic architecture of QTL for cardio-
metabolic traits, microbial taxa abundance, and microbial amplicon
sequence variants (ASVs). The outer layer shows the chromosome location.
LOD range is shown for each track. Each dot represents a QTL on each
chromosome of the mouse genome for a given trait. Grey dots denote
QTLs with LOD < 7. Co-mapped loci between (B) aortic lesion area QTL
and (C) Lactococcus QTL is denoted.

Fig.2. Correlation between Lactococcus abundance and A B C
atherosclerotic traits in DO-F1 mice. (A) Lactococcus abundance is
significantly associated with aortic lesion area in females (R = 0.14, p =
0.026) and males (R = 0.22, p = 0.00031). (B) Lactococcus abundance is
significantly associated with plasma total cholesterol in females (R = 0.17,
-5
p = 0.012) and males (R = 0.26, p = 7.3×10 ). (C) Lactococcus
abundance is significantly associated with hepatic total cholesterol in
-6
females (R = 0.23, p = 0.000047) and males (R = 0.26, p = 3.7×10 ).
Fig.3. Co-mapping of aortic lesion area and Lactococcus QTL on A B
chromosome 10 in DO-F1 female mice. (A) Change in LOD score of
aortic lesion area when adjusting for Lactococcus abundance. Inset on
above summarizes proposed causal model that Lactococcus abundance
mediates changes in the levels of aortic lesion area. (B) Change in LOD
score of Lactococcus abundance when adjusting for aortic lesion area.
Inset on above summarizes proposed causal model that levels of aortic
lesion area mediates the alteration in Lactococcus abundance. Dashed lines
correspond to p < 0.9 (significant) or p < 0.63 (suggestive) thresholds..
Fig.4. Identification of Ptprk gene associated with both aortic A B C
lesion area and Lactococcus abundance in DO-F1 female mice. (A-
C) Association between a SNP (rs243273871) in Ptprk gene and aortic
lesion area (A), Lactococcus abundance (B), and Ptprk gene (C).
Heterozygous SNP (A/C) is from wild-type inbred strains (CAST or PWK
strains) and homozygous SNP (C/C) is from laboratory inbred strains (A/J,
129, NOD, NZO, or WSB strains).

CONCLUSION REFERENCES ACKNOWLEDGEMENT

Our study shows the power of systems genetics to Afshari, N.A., et al. (2017). Genome-wide 2032-51530-022-00D Improving Public Health by
identify novel interactions between cardio-metabolic association study identifies three novel loci in Fuchs Understanding Diversity in Diet, Body, and Brain
traits and gut microbial taxa, and trans-omics datasets endothelial corneal dystrophy. Nat Commun 8, Interactions. USDA 1R01H: 128572 Systems
and methodologies may help complement and validate 14898. Genetic Studies of TMAO regulation and
existing and future discovery resources. Bennett, B.J., et al. (2015). Genetic Architecture of Atherosclerosis. NIH/NHLBI
Atherosclerosis in Mice: A Systems Genetics Analysis
of Common Inbred Strains. PLOS Genetics 11. Contact Information
Benson, A.K., et al. (2010). Individuality in gut
microbiota composition is a complex polygenic trait
shaped by multiple environmental and host genetic Email: kmskim@ucdavis.edu
factors. Proc Natl Acad Sci U S A 107, 18933-18938.