title: Genetic Variation in the 11β-hydroxysteroid-dehydrogenase 1 Gene Determines NAFLD and Visceral Obesity.
abstract: Acute pharmacological inhibition of 11β-hydroxysteroid-dehydrogenase 1 (11β-HSD1), which converts cortisone into the much more potent cortisol in peripheral tissues, results in reduction of total, visceral, and liver fat but not insulin resistance. We now investigated whether lifelong alterations of 11β-HSD1 activity similarly affect these cardiometabolic risk parameters by studying single-nucleotide polymorphisms (SNPs) in the 11β-HSD1-coding gene (HSD11B1).
  
  
  
  Liver fat content was measured by1H-magnetic resonance spectroscopy and total and visceral fat mass by1H-magnetic resonance tomography in 327 subjects. Insulin sensitivity (IS) was estimated during an oral glucose tolerance test and the euglycemic, hyperinsulinemic clamp (n = 219). Nine SNPs covering the whole HSD11B1 gene were genotyped.
  
  
  
  After correction for multiple testing, liver fat content strongly correlated with three SNPs, rs2235543, rs12565406, and rs4844880 (P = .0002, P = .001, and P = .0009, respectively), independently of gender and age. There was a nominal association of these SNPs with hepatic IS but only of rs4844880 with whole-body IS. Subjects homozygous for the major allele had an adjusted odds ratio of 2.16 (95% confidence interval [CI] 1.23-3.90) for rs2235543, 2.06 (95% CI 1.08-4.13) for rs12565406, and 1.95 (95% CI 1.13-3.49) for rs4844880 for having nonalcoholic fatty liver disease compared with carriers of the minor allele. Less strong associations of these SNPs with visceral fat mass were observed. In liver biopsies, carriers of the minor alleles of rs2235543 and rs12565406 had significantly lower HSD11B1 mRNA expression (n = 105, P = .034 and P = .0086, respectively).
  
  
  
  11β-HSD1 may be an important enzyme in the pathogenesis of fatty liver and visceral obesity and a promising target for their treatment.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry (S.Z.L., A.P., F.M., A.L., A.F., H.-U.H., N.S., K.K.), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), Section on Experimental Radiology (J.M., F.S.), Department of General, Visceral, and Transplant Surgery (I.K., A.K.), and Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry (H.S.), University of Tübingen, D-72076 Tübingen, Germany; German Center for Diabetes Research (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), 85764 München-Neuherberg, Germany.
authors.forename: Stefan Z
authors.initials: SZ
authors.lastname: Lutz
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry (S.Z.L., A.P., F.M., A.L., A.F., H.-U.H., N.S., K.K.), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), Section on Experimental Radiology (J.M., F.S.), Department of General, Visceral, and Transplant Surgery (I.K., A.K.), and Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry (H.S.), University of Tübingen, D-72076 Tübingen, Germany; German Center for Diabetes Research (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), 85764 München-Neuherberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Peter
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry (S.Z.L., A.P., F.M., A.L., A.F., H.-U.H., N.S., K.K.), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), Section on Experimental Radiology (J.M., F.S.), Department of General, Visceral, and Transplant Surgery (I.K., A.K.), and Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry (H.S.), University of Tübingen, D-72076 Tübingen, Germany; German Center for Diabetes Research (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), 85764 München-Neuherberg, Germany.
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry (S.Z.L., A.P., F.M., A.L., A.F., H.-U.H., N.S., K.K.), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), Section on Experimental Radiology (J.M., F.S.), Department of General, Visceral, and Transplant Surgery (I.K., A.K.), and Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry (H.S.), University of Tübingen, D-72076 Tübingen, Germany; German Center for Diabetes Research (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), 85764 München-Neuherberg, Germany.
authors.forename: Apostolia
authors.initials: A
authors.lastname: Lamprinou
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry (S.Z.L., A.P., F.M., A.L., A.F., H.-U.H., N.S., K.K.), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), Section on Experimental Radiology (J.M., F.S.), Department of General, Visceral, and Transplant Surgery (I.K., A.K.), and Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry (H.S.), University of Tübingen, D-72076 Tübingen, Germany; German Center for Diabetes Research (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), 85764 München-Neuherberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Machann
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry (S.Z.L., A.P., F.M., A.L., A.F., H.-U.H., N.S., K.K.), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), Section on Experimental Radiology (J.M., F.S.), Department of General, Visceral, and Transplant Surgery (I.K., A.K.), and Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry (H.S.), University of Tübingen, D-72076 Tübingen, Germany; German Center for Diabetes Research (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), 85764 München-Neuherberg, Germany.
authors.forename: Fritz
authors.initials: F
authors.lastname: Schick
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry (S.Z.L., A.P., F.M., A.L., A.F., H.-U.H., N.S., K.K.), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), Section on Experimental Radiology (J.M., F.S.), Department of General, Visceral, and Transplant Surgery (I.K., A.K.), and Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry (H.S.), University of Tübingen, D-72076 Tübingen, Germany; German Center for Diabetes Research (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), 85764 München-Neuherberg, Germany.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Königsrainer
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry (S.Z.L., A.P., F.M., A.L., A.F., H.-U.H., N.S., K.K.), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), Section on Experimental Radiology (J.M., F.S.), Department of General, Visceral, and Transplant Surgery (I.K., A.K.), and Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry (H.S.), University of Tübingen, D-72076 Tübingen, Germany; German Center for Diabetes Research (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), 85764 München-Neuherberg, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Königsrainer
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry (S.Z.L., A.P., F.M., A.L., A.F., H.-U.H., N.S., K.K.), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), Section on Experimental Radiology (J.M., F.S.), Department of General, Visceral, and Transplant Surgery (I.K., A.K.), and Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry (H.S.), University of Tübingen, D-72076 Tübingen, Germany; German Center for Diabetes Research (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), 85764 München-Neuherberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry (S.Z.L., A.P., F.M., A.L., A.F., H.-U.H., N.S., K.K.), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), Section on Experimental Radiology (J.M., F.S.), Department of General, Visceral, and Transplant Surgery (I.K., A.K.), and Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry (H.S.), University of Tübingen, D-72076 Tübingen, Germany; German Center for Diabetes Research (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), 85764 München-Neuherberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry (S.Z.L., A.P., F.M., A.L., A.F., H.-U.H., N.S., K.K.), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), Section on Experimental Radiology (J.M., F.S.), Department of General, Visceral, and Transplant Surgery (I.K., A.K.), and Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry (H.S.), University of Tübingen, D-72076 Tübingen, Germany; German Center for Diabetes Research (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), 85764 München-Neuherberg, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry (S.Z.L., A.P., F.M., A.L., A.F., H.-U.H., N.S., K.K.), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), Section on Experimental Radiology (J.M., F.S.), Department of General, Visceral, and Transplant Surgery (I.K., A.K.), and Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry (H.S.), University of Tübingen, D-72076 Tübingen, Germany; German Center for Diabetes Research (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), 85764 München-Neuherberg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology, and Clinical Chemistry (S.Z.L., A.P., F.M., A.L., A.F., H.-U.H., N.S., K.K.), Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), Section on Experimental Radiology (J.M., F.S.), Department of General, Visceral, and Transplant Surgery (I.K., A.K.), and Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry (H.S.), University of Tübingen, D-72076 Tübingen, Germany; German Center for Diabetes Research (S.Z.L., A.P., F.M., A.L., J.M., F.S., A.F., H.S., H.-U.H., N.S., K.K.), 85764 München-Neuherberg, Germany.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kantartzis
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics*; D050154:Adiposity; D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D005858:Germany; D006801:Humans; D007333:Insulin Resistance; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics; D056128:Obesity, Abdominal / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D066244:Proton Magnetic Resonance Spectroscopy; D055815:Young Adult
chemical_list: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human