TY - JOUR
T1 - Population-Based Genome-wide Association Studies Reveal Six Loci Influencing Plasma Levels of Liver Enzymes
AU - Yuan, Xin
AU - Waterworth, Dawn
AU - Perry, John R B
AU - Lim, Noha
AU - Song, Kijoung
AU - Chambers, John C.
AU - Zhang, Weihua
AU - Vollenweider, Peter
AU - Stirnadel, Heide
AU - Johnson, Toby
AU - Bergmann, Sven
AU - Beckmann, Noam D.
AU - Li, Yun
AU - Ferrucci, Luigi
AU - Melzer, David
AU - Hernandez, Dena
AU - Singleton, Andrew
AU - Scott, James
AU - Elliott, Paul
AU - Waeber, Gerard
AU - Cardon, Lon
AU - Frayling, Timothy M.
AU - Kooner, Jaspal S.
AU - Mooser, Vincent
PY - 2008/10/10
Y1 - 2008/10/10
N2 - Plasma liver-enzyme tests are widely used in the clinic for the diagnosis of liver diseases and for monitoring the response to drug treatment. There is considerable evidence that human genetic variation influences plasma levels of liver enzymes. However, such genetic variation has not been systematically assessed. In the present study, we performed a genome-wide association study of plasma liver-enzyme levels in three populations (total n = 7715) with replication in three additional cohorts (total n = 4704). We identified two loci influencing plasma levels of alanine-aminotransferase (ALT) (CPN1-ERLIN1-CHUK on chromosome 10 and PNPLA3-SAMM50 on chromosome 22), one locus influencing gamma-glutamyl transferase (GGT) levels (HNF1A on chromosome 12), and three loci for alkaline phosphatase (ALP) levels (ALPL on chromosome 1, GPLD1 on chromosome 6, and JMJD1C-REEP3 on chromosome 10). In addition, we confirmed the associations between the GGT1 locus and GGT levels and between the ABO locus and ALP levels. None of the ALP-associated SNPs were associated with other liver tests, suggesting intestine and/or bone specificity. The mechanisms underlying the associations may involve cis- or trans-transcriptional effects (some of the identified variants were associated with mRNA transcription in human liver or lymphoblastoid cells), dysfunction of the encoded proteins (caused by missense variations at the functional domains), or other unknown pathways. These findings may help in the interpretation of liver-enzyme tests and provide candidate genes for liver diseases of viral, metabolic, autoimmune, or toxic origin. The specific associations with ALP levels may point to genes for bone or intestinal diseases.
AB - Plasma liver-enzyme tests are widely used in the clinic for the diagnosis of liver diseases and for monitoring the response to drug treatment. There is considerable evidence that human genetic variation influences plasma levels of liver enzymes. However, such genetic variation has not been systematically assessed. In the present study, we performed a genome-wide association study of plasma liver-enzyme levels in three populations (total n = 7715) with replication in three additional cohorts (total n = 4704). We identified two loci influencing plasma levels of alanine-aminotransferase (ALT) (CPN1-ERLIN1-CHUK on chromosome 10 and PNPLA3-SAMM50 on chromosome 22), one locus influencing gamma-glutamyl transferase (GGT) levels (HNF1A on chromosome 12), and three loci for alkaline phosphatase (ALP) levels (ALPL on chromosome 1, GPLD1 on chromosome 6, and JMJD1C-REEP3 on chromosome 10). In addition, we confirmed the associations between the GGT1 locus and GGT levels and between the ABO locus and ALP levels. None of the ALP-associated SNPs were associated with other liver tests, suggesting intestine and/or bone specificity. The mechanisms underlying the associations may involve cis- or trans-transcriptional effects (some of the identified variants were associated with mRNA transcription in human liver or lymphoblastoid cells), dysfunction of the encoded proteins (caused by missense variations at the functional domains), or other unknown pathways. These findings may help in the interpretation of liver-enzyme tests and provide candidate genes for liver diseases of viral, metabolic, autoimmune, or toxic origin. The specific associations with ALP levels may point to genes for bone or intestinal diseases.
UR - http://www.scopus.com/inward/record.url?scp=53049090077&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=53049090077&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2008.09.012
DO - 10.1016/j.ajhg.2008.09.012
M3 - Article
C2 - 18940312
AN - SCOPUS:53049090077
SN - 0002-9297
VL - 83
SP - 520
EP - 528
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -