A Comprehensive Analysis of Genomics and Metagenomics in a Heterozygote Familial Hypercholesterolemia Family.

Honghong Liu,Chenhong Zhang,Shuyang Zhang,Ran Tian,Ye Jin,Siqin Feng

doi:10.3389/fcimb.2021.605954

Abstract

Familial hypercholesterolemia (FH) is an inherited rare disease leading to markedly elevated low-density lipoprotein cholesterol (LDL-C) levels and increased risk for cardiovascular event. Gut microbiota has been implicated as a pivotal contributing factor in hyperlipidemia, however, its role in FH remains elusive. We performed whole-exome and metagenomics sequencing on a family with 22 members in which myocardial infarctions occurred at a young age with unclear etiology. We confirmed the missense mutation of LDLR c.1723C>T accounted for the abnormal cholesterol metabolism in the family through co-segregation analysis. In addition, Prevotella dentalis was found elevated and strongly associated with LDL-C level in FH family members with mutation of LDLR c.1723C>T compared to unaffected members with hyperlipidemia. Overall, our work suggests that whole-exome sequencing can facilitate identification of disease-causing variants and enable preventive treatment of FH. Our metagenomics analysis provides early insights into potential contributions of host-microbe interactions in genetic and common hypercholesterolemia.

Highlights

Familial hypercholesterolemia (MIM#143890), an inherited rare disease mainly caused by the mutation of low-density lipoprotein receptor (LDLR) gene or apolipoprotein B (APOB) gene in autosomal dominant pattern, which is typically associated with premature coronary artery disease (CAD) (Defesche et al, 2017)
Since several members without mutation of LDLR c.1723C>T in this family were present with dyslipidemia, we investigated the changes in the gut microbiome in the Familial hypercholesterolemia (FH) members with mutation of LDLR c.1723C>T (n = 5, FM1, FM2, FM4, FM6, and FM11) and unaffected members with hyperlipidemia (HLP, n = 6, FM12, FM17, FM18, FM20, FM21, and FM22) by metagenomics sequencing, to further explore the contribution of microbial communities to cholesterol homeostasis
We unmasked the genetic cause of a young male patient with early-onset MI through detailed clinical assessment and diagnosed other nine family members with heterozygous familial hypercholesterolemia (HeFH) in the extended family through WES analysis

Summary

Introduction

Familial hypercholesterolemia (MIM#143890), an inherited rare disease mainly caused by the mutation of low-density lipoprotein receptor (LDLR) gene or apolipoprotein B (APOB) gene in autosomal dominant pattern, which is typically associated with premature coronary artery disease (CAD) (Defesche et al, 2017). HeFH Family, WES, and Metagenomics Analysis showed significant reductions in cardiovascular outcomes (Sabatine et al, 2015), FH remains underdiagnosed and undertreated in most countries, which need further effort to better manage (Nordestgaard et al, 2013). In recent years, emerged evidence shows that the gut microbiota, as an internalized environmental factor, plays an essential role in human cardiovascular disease (Brown and Hazen, 2018). Compelling evidence from animal and human studies suggests that genotype affects the composition of gut microbiome (Goodrich et al, 2014). The effect and interaction of the host genotype and gut microbiota in lipid metabolic phenotypes remain elusive, which might provide important information for treatment of hyperlipidemia and CAD

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