Detection of genetic loci associated with plasma fetuin-A: a meta-analysis of genome-wide association studies from the CHARGE Consortium
Year: 2017
Type: review
Study design: Observational Study
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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddx091
Authors: Majken K. Jensen, Richard A. Jensen, Kenneth J. Mukamal, Xiuqing Guo, Jie Yao, Qi Sun, Marilyn Cornelis, Yongmei Liu, Ming-Huei Chen, Jorge R. Kizer, Luc Djoussé, David S. Siscovick, Bruce M. Psaty, Joseph M. Zmuda, Jerome I. Rotter, Melissa Garcia, Tamara Harris, Ida Chen, Mark O. Goodarzi, Michael A. Nalls, Margaux Keller, Alice M. Arnold, Anne B. Newman, Ron C. Hoogeveen, Kathryn M. Rexrode, Eric B. Rimm, Frank B. Hu, Vasan S. Ramachandran, Ronit Katz, James S. Pankow, Joachim H. Ix
Institutions: Brigham and Women's Hospital, Harvard University, University of Washington, Beth Israel Deaconess Medical Center, The Lundquist Institute, Harbor–UCLA Medical Center, Northwestern University, Wake Forest University Health Sciences, Boston University, Framingham Heart Study, Albert Einstein College of Medicine, VA Boston Healthcare System, New York Academy of Medicine, Group Health Cooperative, Kaiser Permanente Washington Health Research Institute, University of Pittsburgh, National Institutes of Health, National Institute on Aging, Cedars-Sinai Medical Center, Baylor College of Medicine, University of Minnesota, University of California San Diego, VA San Diego Healthcare System
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: American Diabetes Association, Framingham Heart Study, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, National Center for Advancing Translational Sciences, Niilo Helanderin Säätiö
Awards: G1023702118, G1052397333, Characterization of Normal Genomic Variability, G1135917780, G1220223050, G1243299691, G125972088, MESA, Genetic Determinants of Visceral Adiposity, CORONARY HEART DISEASE AND STROKE, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G1409423729, DYNAMICS OF HEALTH,AGING, AND BODY COMPOSITION, G1462415530, G1527150935, Inflammatory Precursors of Type 2 Diabetes, G1558303681, CORONARY HEART DISEASE AND STROKE, G1686417863, G1691174148, G173303992, G1941623656, G2024966744, Genome-wide case-only study of antihypertensive drug-gene interactions, G2070131968, DYNAMICS OF HEALTH, AGING, AND BODY COMPOSITION, G2193588257, G2194386449, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G2262782284, Determinants and Cardiovascular Consequences of Diabetes in Older Adults, G2391884931, MESA, Institute for Clinical and Translational Research (UL1), Exceptional Survival: Trajectories to Functional Aging (CHS All Stars), G2555954497, Biochemical Markers in the nurses' Health Study Cohort, CORONARY HEART DISEASE &STROKE IN THE ELDERLY, G270907595, G278200998, G2786044735, G2800149121, MESA, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, G3045517347, WGA Study to Identify Genetic Variants Associated with CV Events in CHS, G3075381221, G3114902838, HEALTH ABC--COORDINATING UNIT, G3220743633, UCLA Clinical and Translational Science Institute, G3342643523, G3405256882, G3410686264, G34347772, G3462919067, G3531780063, Dietary Etiologies of Heart Disease, G3647016462, G3687594596, G36937976, GWA for Gene-Environment Interaction Effects Influencing CHD, MESA, Dietary and Hormonal Determinants of Cancer in Women, G3991514562, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, G399481048, G423252844, TITLE: MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), G4512137732, G459566519, OPTION 3. 4/1/2014 - 3/31/2015. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) - READING CENTER, NHLBI, MESA, G5164707915, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY-ULTRASOUND, G5479317095, G5488312170, G567847597, G5709329001, G5787256936, G581887176, G5879129718, G5909482378, CHARGE consortium: omics discovery for CVD and aging phenotypes, CHS Events Follow-up Study, G6095866717, G6226795708, G6359107525, Institute for Clinical and Translational Research, The Framingham Heart Study, MESA, G6514094751, G6548750934, CHS-Transition Phase, SNP HEALTH ASSOCIATION RESOURCE (SHARE), G6822753503, Fetuin-A: A Novel Biomarker of Vascular Calcification and Diabetes Mellitus, G7169564462, G7176672723, Prospective Studies of Diet and Cancer in Men and Women, MESA, Long Term Multidisciplinary Study of Cancer in Women: The Nurses Health Study, G7622313283, Exceptional Survival: Trajectories to Functional Aging (CHS All Stars), Biochemical Markers in the Nurses? Health Study Cohort, G772621625, G777822606, CHS Events Follow-up Study, Cancer Epidemiology Cohort in Male Health Professionals, Clinical and Translational Science Award, G809473380, G8267674335, G8360006069, G870807107, G9000218235, Diabetes Research Center (DRC), RISK FACTORS FOR CVD IN WOMEN, Risk Factors for Ischemic Stroke in Women, Cancer Epidemiology Cohort in Male Health Professionals, G905887895, G945304896, G982388242
OpenAlex ID: W2604405910