title: Genetic variation in NR1H4 encoding the bile acid receptor FXR determines fasting glucose and free fatty acid levels in humans.
abstract: BACKGROUND
  Bile acid signaling via farnesoid X receptor (FXR) regulates glucose and lipid levels, fat mass, and hepatic steatosis in animal models.
  
  
  OBJECTIVE
  To understand the role of FXR in human metabolism, we investigated associations of common single-nucleotide polymorphisms (SNPs) in the FXR-encoding gene NR1H4 with glucose and lipid metabolism, body fat mass, and liver fat content.
  
  
  METHODS
  We genotyped 2166 healthy German subjects for 7 tagging SNPs within NR1H4 (rs35735, rs1030454, rs11110415, rs11610264, rs17030285, rs4764980, and rs11110390) covering 100% of common genetic variation (minor allele frequency > 10%).
  
  
  METHODS
  Subjects were metabolically characterized by an oral glucose tolerance test. In subgroups, hyperinsulinemic-euglycemic clamp and liver fat quantification by (1)H-magnetic resonance spectroscopy were performed.
  
  
  RESULTS
  SNP rs4764980 was significantly associated with fasting glycemia (P = .0043) and nominally associated with fasting and postglucose load free fatty acid (FFA) levels (P = .01). Upon interrogation of publicly available Meta-Analyses of Glucose and Insulin-related traits Consortium data, the association of rs4764980 with fasting glycemia was replicated (Meta-Analyses of Glucose and Insulin-related traits Consortium, P = .005). Additionally, SNP rs11110390 showed significant associations with fasting (P = .0054) and postload (P = .0051) FFA levels. For none of the investigated SNPs, associations with insulin secretion or sensitivity, body fat mass, or liver fat content were detected.
  
  
  CONCLUSIONS
  We conclude that FXR contributes to fasting glucose and FFA levels in humans independent of unhealthy body fat accumulation. The receptor represents an interesting target to influence lipid and glucose metabolism.
authors: Department of Internal Medicine, Division of Endocrinology, University Hospital, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
authors: Martin
authors: M
authors: Heni
authors: Robert
authors: R
authors: Wagner
authors: Caroline
authors: C
authors: Ketterer
authors: Anja
authors: A
authors: Böhm
authors: Katarzyna
authors: K
authors: Linder
authors: Fausto
authors: F
authors: Machicao
authors: Jürgen
authors: J
authors: Machann
authors: Fritz
authors: F
authors: Schick
authors: Anita M
authors: AM
authors: Hennige
authors: Norbert
authors: N
authors: Stefan
authors: Hans-Ulrich
authors: HU
authors: Häring
authors: Andreas
authors: A
authors: Fritsche
authors: Harald
authors: H
authors: Staiger
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D050154:Adiposity; D000328:Adult; D001647:Bile Acids and Salts / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis*; D015992:Body Mass Index; D005215:Fasting; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005858:Germany; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D006949:Hyperlipidemias / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D050177:Overweight / Q000473:pathology / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated