Germline Mutations in
            <i>CIDEB</i>
            and Protection against Liver Disease

Verweij, Niek; Haas, Mary E.; Nielsen, Jonas B.; Sosina, Olukayode A.; Kim, Minhee; Akbari, Parsa; De, Tanima; Hindy, George; Bovijn, Jonas; Persaud, Trikaldarshi; Miloscio, Lawrence; Germino, Mary; Panagis, Lampros; Watanabe, Kyoko; Mbatchou, Joelle; Jones, Marcus B.; LeBlanc, Michelle G.; Balasubramanian, Suganthi; Lammert, Craig; Enhörning, Sofia; Melander, Olle; Carey, David J.; Still, Christopher D.; Mirshahi, Tooraj; Rader, Daniel J.; Parasoglou, Prodromos; Walls, Johnathon R.; Overton, John D.; Reid, Jeffrey G.; Economides, Aris N.; Cantor, Michael; Zambrowicz, Brian; Murphy, Andrew; Abecasis, Gonçalo R.; Ferreira, Manuel A. R.; Šmagris, Ēriks; Gusarova, Viktoria; Sleeman, Mark W.; Yancopouloš, George D.; Marchini, Jonathan; Kang, Hyun Min; Karalis, Katia; Shuldiner, Alan R.; Gatta, Giusy Della; Locke, Adam E.; Baras, Aris; Lotta, Luca A.

doi:10.1056/nejmoa2117872

Cited by 61 publications

(75 citation statements)

References 48 publications

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“…Multiple attributes of this association made it of particular interest. Associations of naturally occurring pLOF alleles with protection from human disease have helped define new therapeutic targets in a growing number of examples 24 , 25 and this was a newly identified, large-effect association (0.17 SD units; Table 1 ) with a favorable phenotype (lower BMI-adjusted WHR) for pLOF alleles. Also, in contrast with the exome-wide enrichment for adipose genes, INHBE was the only identified gene with strong and specific expression in hepatocytes, but no expression in visceral or subcutaneous adipose tissues (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…These findings may have therapeutic implications. The identification of naturally ccurring loss-of-function variants associated with protection from human disease has helped identify a growing number of new targets for pharmacological inhibition across multiple indications 22 – 25 , 42 , 43 . Human genetic support is associated with higher odds of successful drug development 44 and hepatocyte-expressed genes that encode circulating proteins like INHBE can be effectively inhibited via liver-directed oligonucleotide therapeutics or by monoclonal antibodies targeting the circulating protein product, as shown in several clinical trials 45 – 51 .…”

Section: Discussionmentioning

confidence: 99%

“…Here, we tackled these outstanding questions with human genetic studies centered around the exome sequencing of 618,375 individuals across five ancestries. This approach may identify naturally occurring loss-of-function (LOF) alleles that protect from disease 22 , 23 , a type of genetic association which has informed therapeutic target identification in a growing number of examples 24 , 25 . We also combined exome sequencing with common-variant polygenic scores and with refined measures of liver fat and inflammation, to study the role of liver health in fat distribution-associated cardiometabolic disease (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes

Akbari

Sosina²,

Bovijn³

et al. 2022

Nat Commun

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Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10−09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin βE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes

Akbari

Sosina²,

Bovijn³

et al. 2022

Nat Commun

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“…Despite their proven efficacy and wide usage 5 , smoking remains a global health hazard, warranting advancements in smoking related drug discovery efforts that make use of recent innovations in therapeutic design and delivery 6 . Large scale rare variant association studies have the potential to advance drug discovery [7][8][9][10] . Drug designs inspired by naturally occurring genetic variants that protect humans against diseases have been successful in the past, for example, PCSK9 inhibitors for the treatment of hypercholesterolemia [11][12][13] .…”

Section: Mainmentioning

confidence: 99%

Rare coding variants inCHRNB2reduce the likelihood of smoking

Rajagopal

Watanabe

Mbatchou

et al. 2022

Preprint

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Human genetic studies of smoking behavior have been so far largely limited to common variations. Studying rare coding variants has potential to identify new drug targets and refine our understanding of the mechanisms of known targets. We performed an exome-wide association study (ExWAS) of smoking phenotypes in up to 749,459 individuals across multiple ancestries and discovered a protective association signal in CHRNB2 that encodes the β2 subunit of α4β2 nicotine acetylcholine receptor (nAChR). Rare predicted loss-of-function (pLOF) and likely deleterious missense variants in CHRNB2 in aggregate were associated with a 35% decreased odds for smoking more than 10 cigarettes per day (OR=0.65, CI=0.56-0.76, P=1.9e-8). An independent common variant association in the protective direction (rs2072659; OR=0.96; CI=0.94-0.98; P=5.3e-6) was also evident, suggesting an allelic series. The protective effects of both rare and common variants were detectable to some extent on phenotypes downstream of smoking including lung function, emphysema, chronic obstructive pulmonary disease (COPD) and lung cancer. α4β2 is the predominant nAChR in human brain and is one of the targets of varenicline, a partial nAChR agonist/antagonist used to aid smoking cessation. Our findings in humans align with decades-old experimental observations in mice that β2 loss abolishes nicotine mediated neuronal responses and attenuates nicotine self-administration. Our genetic discovery will inspire future drug designs targeting CHRNB2 in the brain for the treatment of nicotine addiction.

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“…Whereas variants in ALB , ACVR2A , FOXO1 and TNRC6B do not reach genome‐wide significance either as individual variants or on burden testing for rare variants. As highlighted in this study there is a trend towards association with ALT on gene burden testing 6 and common variants in or near these genes are also associated with related metabolic traits, for example, serum lipid profile 15 …”

Section: Figurementioning

confidence: 71%

Lipid droplets as the genetic nexus of fatty liver

Mann

Romeo

Valenti

2022

Liver International

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Lipid droplets as the genetic nexus of fatty liverNon-alcoholic fatty liver disease (NAFLD) has become the leading cause of liver damage worldwide and is rapidly becoming the leading cause of end-stage liver disease in the USA. The main trigger of fatty liver is metabolic dysfunction, but dietary factors, alcohol intake and genetic predisposition modulate the risk of onset and progression to severe liver disease. A range of exome-wide and genome-wide association studies (GWAS) have identified common variants (>1% prevalence) implicated in all stages of NAFLD. 1Approximately 10 genes have been robustly implicated in fatty liver at genome-wide significance. The majority bind to hepatic lipid droplets (e.g. PNPLA3, HSD17B13) or are involved in their biogenesis (e.g. TM6SF2, APOB) and/or turnover 1,2 (Figure 1). These are liver specific and are not known to be associated with lipodystrophies. Despite the strong bidirectional association between insulin resistance and NAFLD there is a notable absence of genes directly implicated in modulation of circulating glucose levels and the development of type 2 diabetes (aside from the highly pleiotropic GCKR that also controls de novo lipogenesis). Similarly, no genes directly related to immune regulation have yet been robustly validated at genome-wide significance.These findings, and the observation that the impact of these variants on the development of complications of liver disease is directly proportional to that on hepatic fat, strongly support the notion that liver fat accumulation in lipid droplets plays a causal role in liver disease. [3][4][5]

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Germline Mutations in CIDEB and Protection against Liver Disease

Cited by 61 publications

References 48 publications

Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes

Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes

Rare coding variants inCHRNB2reduce the likelihood of smoking

Lipid droplets as the genetic nexus of fatty liver

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