title: Evaluating the role of LPIN1 variation in insulin resistance, body weight, and human lipodystrophy in U.K. Populations.
abstract: OBJECTIVE
  Loss of lipin 1 activity causes lipodystrophy and insulin resistance in the fld mouse, and LPIN1 expression and common genetic variation were recently suggested to influence adiposity and insulin sensitivity in humans. We aimed to conduct a comprehensive association study to clarify the influence of common LPIN1 variation on adiposity and insulin sensitivity in U.K. populations and to examine the role of LPIN1 mutations in insulin resistance syndromes.
  
  
  METHODS
  Twenty-two single nucleotide polymorphisms tagging common LPIN1 variation were genotyped in Medical Research Council (MRC) Ely (n = 1,709) and Hertfordshire (n = 2,901) population-based cohorts. LPIN1 exons, exon/intron boundaries, and 3' untranslated region were sequenced in 158 patients with idiopathic severe insulin resistance (including 23 lipodystrophic patients) and 48 control subjects.
  
  
  RESULTS
  We found no association between LPIN1 single nucleotide polymorphisms and fasting insulin but report a nominal association between rs13412852 and BMI (P = 0.042) in a meta-analysis of 8,504 samples from in-house and publicly available studies. Three rare nonsynonymous variants (A353T, R552K, and G582R) were detected in severely insulin-resistant patients. However, these did not cosegregate with disease in affected families, and Lipin1 protein expression and phosphorylation in patients with variants were indistinguishable from those in control subjects.
  
  
  CONCLUSIONS
  Our data do not support a major effect of common LPIN1 variation on metabolic traits and suggest that mutations in LPIN1 are not a common cause of lipodystrophy in humans. The nominal associations with BMI and other metabolic traits in U.K. cohorts require replication in larger cohorts.
authors.affiliation: Metabolic Disease Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, U.K.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fawcett
authors.forename: Neil
authors.initials: N
authors.lastname: Grimsey
authors.forename: Ruth J F
authors.initials: RJ
authors.lastname: Loos
authors.forename: Eleanor
authors.initials: E
authors.lastname: Wheeler
authors.forename: Allan
authors.initials: A
authors.lastname: Daly
authors.forename: Maria
authors.initials: M
authors.lastname: Soos
authors.forename: Robert
authors.initials: R
authors.lastname: Semple
authors.forename: Holly
authors.initials: H
authors.lastname: Syddall
authors.forename: Cyrus
authors.initials: C
authors.lastname: Cooper
authors.forename: Symeon
authors.initials: S
authors.lastname: Siniossoglou
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
mesh_terms: D000328:Adult; D000368:Aged; D001835:Body Weight / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008060:Lipodystrophy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D010375:Pedigree; D010711:Phosphatidate Phosphatase; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom
chemical_list: D009687:Nuclear Proteins; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase