Genome-wide association study for circulating fibroblast growth factor 21 and 23

Abstract

Fibroblast growth factors (FGFs) 21 and 23 are recently identified hormones regulating metabolism of glucose, lipid, phosphate and vitamin D. Here we conducted a genome-wide association study (GWAS) for circulating FGF21 and FGF23 concentrations to identify their genetic determinants. We enrolled 5,000 participants from Taiwan Biobank for this GWAS. After excluding participants with diabetes mellitus and quality control, association of single nucleotide polymorphisms (SNPs) with log-transformed FGF21 and FGF23 serum concentrations adjusted for age, sex and principal components of ancestry were analyzed. A second model additionally adjusted for body mass index (BMI) and a third model additionally adjusted for BMI and estimated glomerular filtration rate (eGFR) were used. A total of 4,201 participants underwent GWAS analysis. rs67327215, located within RGS6 (a gene involved in fatty acid synthesis), and two other SNPs (rs12565114 and rs9520257, located between PHC2-ZSCAN20 and ARGLU1-FAM155A respectively) showed suggestive associations with serum FGF21 level (P = 6.66 × 10-7 , 6.00 × 10-7 and 6.11 × 10-7 respectively). The SNPs rs17111495 and rs17843626 were significantly associated with FGF23 level, with the former near PCSK9 gene and the latter near HLA-DQA1 gene (P = 1.04 × 10-10 and 1.80 × 10-8 respectively). SNP rs2798631, located within the TGFB2 gene, was suggestively associated with serum FGF23 level (P = 4.97 × 10-7). Additional adjustment for BMI yielded similar results. For FGF23, further adjustment for eGFR had similar results. We conducted the first GWAS of circulating FGF21 levels to date. Novel candidate genetic loci associated with circulating FGF21 or FGF23 levels were found. Further replication and functional studies are needed to support our findings. Fibroblast growth factor (FGF) superfamily includes 22 family members. Except for the endocrine FGF19, FGF21, and FGF23, other family members act as autocrine or paracrine factors 1. Recent evidence showed that FGF21 exerts metabolic effects by acting both centrally and peripherally, mostly in the liver, adipose tissue and pancreas. In prolonged starvation, FGF21 is secreted by the liver to promote gluconeogenesis, increases hepatic

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

“…We are not aware of any previous GWAS for circulating FGF21 in populations of European ancestry, as done herein, but there is a GWAS for this hormone conducted in Taiwanese adults [18]. That GWAS found no genome-wide significant associations with circulating FGF21 which may be related to insufficient power due to the small sample size (n = 4201 participants).…”

“…In addition to nutritional and hormonal regulation of FGF21 production [4], circulating FGF21 concentration may be genetically modified. However, a genome-wide association study (GWAS) in 4201 participants of the Taiwan Biobank identified no significant associations with circulating FGF21 [18]. Other GWAS analyses with a focus on macronutrient intake found that genetic variants in or near the FGF21 locus (rs838133 and rs838145) were associated with increased relative carbohydrate intake but decreased relative protein and fat intake [8,19,20].…”

The role of FGF21 and its analogs on liver associated diseases

“…Previously a Genome-Wide Association Study (GWAS) reported the most important SNPs which regulate FGF21 serum levels. These SNPs were rs12565114, rs9520257 and rs67327215 ( 56 ). Investigations on the role of these SNPs and the susceptibility of people to having liver diseases may help to personalized the cure of these diseases.…”

New insights into the pathological development of dyslipidemia in patients with hypothyroidism

“…Among different members, FGF21 is a novel discovered cytokine which is significantly increased under the status of multiple lipid disorder diseases, such as dyslipidemia, obesity, and coronary artery diseases (CAD) [38]. Recently, emerging evidence demonstrated that FGF-21 plays an important role in regulating carbohydrate, lipid and phosphate metabolism, and consequently modulating the pathological progression of lipid metabolic disorder diseases [39]. Consistently, treatment with FGF-21 has been confirmed to improve the energy metabolism in hepatocytes in both rodents and non-human primates, supporting that FGF21 could be considered as a potential therapeutic method for dyslipidemia [40].…”