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.
Bibliographical noteFunding Information:
The authors thank the staffand participants of the individual studies for their important contributions, and acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in the development and support of this manuscript. The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN 268201100006C, HHSN268201100007C, HHSN268201100008C, HH SN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding for fetuin-A measurements was provided by R01-DK56918. The authors thank the staffand participants of the ARIC study for their important contributions. NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086 supported CHS research; and NHLBI grants HL080295, HL087652, HL105756, R01HL094555 & HL085251 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). A full list of CHS investigators and institutions can be found at http://chs-nhlbi.org/. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195, HHSN268201500001 & HL25195) supported the Framingham Heart Study, and its contract with Affymetrix, Inc., for genotyping services (contract number N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. NIA contracts N01AG62101, N01AG62103, and N01AG62106 supported the Health, Aging, and Body Composition (Health ABC) Study. Fetuin-A was measured with support from American Diabetes Association: 1-08-IG-01. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Mike Nalls' participation was supported in part by the Intramural Research Program of the NIH, National Institute on Aging NIA contract Z01-AG000932-03 and utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov). National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators supported the Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SHARe project. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. Fetuin-A was measured with support from NHLBI R21HL091217. UM1 CA186107, HL34594, CA87969, CA49449, HL35464, CA55075, R01 HL088521 and CA167552 from the National Institutes of Health, Bethesda, MD, with additional support for genotyping from Merck Research Laboratories, North Wales, PA supported the Nurses' Health Study (NHS).