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Hum Mol Genet. 2017 Jun 1;26(11):2156-2163. doi: 10.1093/hmg/ddx091.

Detection of genetic loci associated with plasma fetuin-A: a meta-analysis of genome-wide association studies from the CHARGE Consortium.

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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.
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA 98101, USA.
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Wake Forest University Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
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.
Department of Medicine & Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Division of Aging, Brigham and Women's Hospital, Boston, MA 02115, USA, & Boston Veterans Affairs Healthcare System, Boston, MA 02130, USA.
New York Academy of Medicine, New York, NY, USA.
Group Health Research Institute and Group Health Cooperative, Seattle, WA 98101, USA.
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Laboratory of Epidemiology and Populations Sciences, National Institute on Aging, Bethesda, MD 20892, USA.
Division of Endocrinology, Diabetes & Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Department of Biostatistics, University of Washington School of Public Health and Community Medicine, Seattle, WA 98195, USA.
Division of Atherosclerosis & Vascular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
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.
Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN 55455, USA.
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.


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.

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