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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Detection of genetic loci associated with plasma fetuin-A : A meta-analysis of genome-wide association studies from the CHARGE Consortium. / Jensen, Majken K.; Jensen, Richard A.; Mukamal, Kenneth J.; Guo, Xiuqing; Yao, Jie; Sun, Qi; Cornelis, Marilyn; Liu, Yongmei; Chen, Ming Huei; Kizer, Jorge R.; Djoussé, Luc; Siscovick, David S.; Psaty, Bruce M.; Zmuda, Joseph M.; Rotter, Jerome I.; Garcia, Melissa; Harris, Tamara; Chen, Ida; Goodarzi, Mark O.; Nalls, Michael A.; Keller, Margaux; Arnold, Alice M.; Newman, Anne B.; Hoogeveen, Ron C.; Rexrode, Kathryn M.; Rimm, Eric B.; Hu, Frank B.; Ramachandran, Vasan S.; Katz, Ronit; Pankow, James S.; Ix, Joachim H.
I: Human Molecular Genetics, Bind 26, Nr. 11, 01.01.2017, s. 2156-2163.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Detection of genetic loci associated with plasma fetuin-A
T2 - A meta-analysis of genome-wide association studies from the CHARGE Consortium
AU - Jensen, Majken K.
AU - Jensen, Richard A.
AU - Mukamal, Kenneth J.
AU - Guo, Xiuqing
AU - Yao, Jie
AU - Sun, Qi
AU - Cornelis, Marilyn
AU - Liu, Yongmei
AU - Chen, Ming Huei
AU - Kizer, Jorge R.
AU - Djoussé, Luc
AU - Siscovick, David S.
AU - Psaty, Bruce M.
AU - Zmuda, Joseph M.
AU - Rotter, Jerome I.
AU - Garcia, Melissa
AU - Harris, Tamara
AU - Chen, Ida
AU - Goodarzi, Mark O.
AU - Nalls, Michael A.
AU - Keller, Margaux
AU - Arnold, Alice M.
AU - Newman, Anne B.
AU - Hoogeveen, Ron C.
AU - Rexrode, Kathryn M.
AU - Rimm, Eric B.
AU - Hu, Frank B.
AU - Ramachandran, Vasan S.
AU - Katz, Ronit
AU - Pankow, James S.
AU - Ix, Joachim H.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
U2 - 10.1093/hmg/ddx091
DO - 10.1093/hmg/ddx091
M3 - Journal article
C2 - 28379451
AN - SCOPUS:85027369881
VL - 26
SP - 2156
EP - 2163
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 11
ER -
ID: 244626716