title: Detection of genetic loci associated with plasma fetuin-A: a meta-analysis of genome-wide association studies from the CHARGE Consortium.
abstract: Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin-A concentrations by a genome-wide association study in six population-based studies. We examined the association of fetuin-A levels with ∼ 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, the strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (P < 0.05 × 10-8) SNPs near the AHSG locus, the top SNP was rs4917 (P =1.27 × 10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/l (∼13%) lower fetuin-A level. This variant alone explained 14% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.
authors.affiliation: Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA & Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Majken K
authors.initials: MK
authors.lastname: Jensen
authors.affiliation: Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA 98101, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Jensen
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Mukamal
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA & Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Cornelis
authors.affiliation: Wake Forest University Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.|The Boston University and the National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA.
authors.forename: Ming-Huei
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Department of Medicine & Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Kizer
authors.affiliation: Division of Aging, Brigham and Women's Hospital, Boston, MA 02115, USA, & Boston Veterans Affairs Healthcare System, Boston, MA 02130, USA.
authors.forename: Luc
authors.initials: L
authors.lastname: Djoussé
authors.affiliation: New York Academy of Medicine, New York, NY, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
authors.affiliation: Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA 98101, USA.|Group Health Research Institute and Group Health Cooperative, Seattle, WA 98101, USA.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Zmuda
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Laboratory of Epidemiology and Populations Sciences, National Institute on Aging, Bethesda, MD 20892, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Harris
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors.forename: Ida
authors.initials: I
authors.lastname: Chen
authors.affiliation: Division of Endocrinology, Diabetes & Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Margaux
authors.initials: M
authors.lastname: Keller
authors.affiliation: Department of Biostatistics, University of Washington School of Public Health and Community Medicine, Seattle, WA 98195, USA.
authors.forename: Alice M
authors.initials: AM
authors.lastname: Arnold
authors.affiliation: Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Newman
authors.affiliation: Division of Atherosclerosis & Vascular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ron C
authors.initials: RC
authors.lastname: Hoogeveen
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Rexrode
authors.affiliation: Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA & Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Rimm
authors.affiliation: Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA & Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Hu
authors.affiliation: Sections of Preventive Medicine and Epidemiology, and Cardiology & Department of Medicine, Boston University School of Medicine, Boston, MA 02118, Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA.|The Boston University and the National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA.
authors.forename: Vasan S
authors.initials: VS
authors.lastname: Ramachandran
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors.forename: Ronit
authors.initials: R
authors.lastname: Katz
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN 55455, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.affiliation: Nephrology Section, Veterans Affairs San Diego Healthcare System, University of California San Diego, San Diego, CA 92161, USA & Divisions of Nephrology and Preventive Medicine, Department of Medicine, University of California San Diego School of Medicine, San Diego, CA 92161, USA.
authors.forename: Joachim H
authors.initials: JH
authors.lastname: Ix
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044465:White People / Q000235:genetics; D060749:alpha-2-HS-Glycoprotein / Q000032:analysis* / Q000235:genetics* / Q000378:metabolism
chemical_list: C556354:AHSG protein, human; D060749:alpha-2-HS-Glycoprotein