Genome-wide association and Mendelian randomization study of fibroblast growth factor 21 reveals causal associations with hyperlipidemia and possibly NASH

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Larsson, Susanna C.Karolinska Institutet,Uppsala universitet,Medicinsk epidemiologi,Karolinska Inst, Unit Cardiovasc & Nutr Epidemiol, Inst Environm Med, Stockholm, Sweden. (författare)

Genome-wide association and Mendelian randomization study of fibroblast growth factor 21 reveals causal associations with hyperlipidemia and possibly NASH

Artikel/kapitelEngelska2022

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Elsevier,2022
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LIBRIS-ID:oai:DiVA.org:uu-487626
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-487626URI
https://doi.org/10.1016/j.metabol.2022.155329DOI
http://kipublications.ki.se/Default.aspx?queryparsed=id:150931986URI

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Sammanfattning på:engelska

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Correction in: Metabolism, Volume 143, June 2023, Pages 155555DOI: 10.1016/j.metabol.2023.155555
Background: Fibroblast growth factor 21 (FGF21) is a hepatokine that produces metabolic benefits, such as improvements of lipid profile. We performed a genome-wide association study (GWAS) to identify genetic variants associated with circulating FGF21 and investigated the causal effects of FGF21 on pertinent outcomes using Mendelian randomization (MR).Methods: We conducted a GWAS testing similar to 7.8 million DNA sequence variants with circulating FGF21 in a discovery cohort of 6259 Swedish adults with replication in 4483 Swedish women. We then performed two-sample MR analyses of genetically predicted circulating FGF21 in relation to alcohol and nutrient intake, cardiovascular and metabolic biomarkers and diseases, and liver function biomarkers using publicly available GWAS summary statistics data.Results: Our GWAS identified multiple single-nucleotide polymorphisms with genome-wide significant associations (P < 5 x 10(-8)) with circulating FGF21 on chromosomes 2 and 19 in or near the GCKR and FGF21 genes, respectively. The strongest signal at the FGF21 locus (rs2548957, beta = 0.181, P < 2.18 x 10(-42)) displayed in twosample MR analyses robust associations with lower alcohol intake, lower circulating low-density lipoprotein cholesterol, apolipoprotein B, C-reactive protein, gamma-glutamyl transferase, and galectin-3 concentrations, and higher circulating insulin-like growth factor-I and alkaline phosphatase concentrations after correcting for multiple testing (P < 0.0018) whereas associations with fat mass, type 2 diabetes, and cardiovascular disease were largely null.Conclusions: We identified robust associations of certain genetic variants in or near the GCKR and FGF21 genes with circulating FGF21 concentrations. Furthermore, our results support a strong causal effect of FGF21 on improved lipid profile, reduced alcohol consumption and C-reactive protein concentrations, and liver function biomarkers including fibrosis. We found largely null or weak positive associations with fat mass, diabetes, and cardiovascular disease as well as higher insulin-like growth factor-I concentrations, which could indicate a compensatory increase to regulate the above FGF21 resistant states in humans.

Ämnesord och genrebeteckningar

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Endokrinologi och diabetes hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Endocrinology and Diabetes hsv//eng
Fibroblast growth factor 21
Alkaline phosphatase
Genome-wide association study
Hepatokine
Mendelian randomization
Single-nucleotide polymorphisms

Biuppslag (personer, institutioner, konferenser, titlar ...)

Michaëlsson, Karl,1959-Uppsala universitet,Medicinsk epidemiologi(Swepub:uu)karlmich (författare)
Mola-Caminal, MarinaUppsala universitet,Medicinsk epidemiologi(Swepub:uu)marmo445 (författare)
Höijer, JonasUppsala universitet,Medicinsk epidemiologi(Swepub:uu)jonho616 (författare)
Mantzoros, Christos S.Harvard Med Sch, Dept Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA.;Harvard Med Sch, Sect Endocrinol, VA Boston Healthcare Syst, Boston, MA 02115 USA. (författare)
Uppsala universitetMedicinsk epidemiologi (creator_code:org_t)

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Ingår i:Metabolism: Elsevier1370026-04951532-8600

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Av författaren/redakt...: Larsson, Susanna ...; Michaëlsson, Kar ...; Mola-Caminal, Ma ...; Höijer, Jonas; Mantzoros, Chris ...

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Endokrinologi oc ...

Artiklar i publikationen: Metabolism

Av lärosätet: Uppsala universitet; Karolinska Institutet

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