title: Associations of Haplotypes Upstream of IRS1 with Insulin Resistance, Type 2 Diabetes, Dyslipidemia, Preclinical Atherosclerosis, and Skeletal Muscle LOC646736 mRNA Levels.
abstract: The genomic region ~500 kb upstream of IRS1 has been implicated in insulin resistance, type 2 diabetes, adverse lipid profile, and cardiovascular risk. To gain further insight into this chromosomal region, we typed four SNPs in a cross-sectional cohort and subjects with type 2 diabetes recruited from the same geographic region. From 16 possible haplotypes, 6 haplotypes with frequencies >0.01 were observed. We identified one haplotype that was protective against insulin resistance (determined by HOMA-IR and fasting plasma insulin levels), type 2 diabetes, an adverse lipid profile, increased C-reactive protein, and asymptomatic atherosclerotic disease (assessed by intima media thickness of the common carotid arteries). BMI and total adipose tissue mass as well as visceral and subcutaneous adipose tissue mass did not differ between the reference and protective haplotypes. In 92 subjects, we observed an association of the protective haplotype with higher skeletal muscle mRNA levels of LOC646736, which is located in the same haplotype block as the informative SNPs and is mainly expressed in skeletal muscle, but only at very low levels in liver or adipose tissues. These data suggest a role for LOC646736 in human insulin resistance and warrant further studies on the functional effects of this locus.
authors.affiliation: Institute of Pharmacology and Toxicology, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Selma M
authors.initials: SM
authors.lastname: Soyal
authors.affiliation: Department of Laboratory Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Felder
authors.affiliation: Department of Laboratory Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Simon
authors.initials: S
authors.lastname: Auer
authors.affiliation: Department of Laboratory Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Hannes
authors.initials: H
authors.lastname: Oberkofler
authors.affiliation: Department of Geriatric Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Iglseder
authors.affiliation: Department of Internal Medicine I, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Paulweber
authors.affiliation: Institute of Pharmacology and Toxicology, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Dossena
authors.affiliation: Institute of Pharmacology and Toxicology, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Charity
authors.initials: C
authors.lastname: Nofziger
authors.affiliation: Institute of Pharmacology and Toxicology, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Paulmichl
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
authors.affiliation: Department of Internal Medicine, Krankenhaus Hallein, 5400 Hallein, Austria.
authors.forename: Franz
authors.initials: F
authors.lastname: Krempler
authors.affiliation: Institute of Pharmacology and Toxicology, Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Patsch
mesh_terms: D020121:5' Untranslated Regions; D058070:Asymptomatic Diseases; D050197:Atherosclerosis / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001317:Austria; D016022:Case-Control Studies; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003925:Diabetic Angiopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D060467:Disease Resistance; D050171:Dyslipidemias / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D012333:RNA, Messenger