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

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

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

Michaëlsson, Karl, 1959- (author): Uppsala universitet,Medicinsk epidemiologi

Mola-Caminal, Marina (author): Uppsala universitet,Medicinsk epidemiologi

Höijer, Jonas (author): Uppsala universitet,Medicinsk epidemiologi

Mantzoros, Christos S. (author): 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.

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Elsevier, 2022
2022
English.
In: Metabolism. - : Elsevier. - 0026-0495 .- 1532-8600. ; 137

Related links:: https://doi.org/10.1...; show more...; https://uu.diva-port... (primary) (Raw object); https://urn.kb.se/re...; https://doi.org/10.1...; http://kipublication...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Keyword

Fibroblast growth factor 21
Alkaline phosphatase
Genome-wide association study
Hepatokine
Mendelian randomization
Single-nucleotide polymorphisms

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

Articles in the publication: Metabolism

By the university: Uppsala University; Karolinska Institutet

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