Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.
Blood concentrations of lipoproteins and lipids are heritable risk factors for cardiovascular disease. Using genome-wide association data from three studies (n = 8,816 that included 2,758 individuals from the Diabetes Genetics Initiative specific to the current paper as well as 1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables reported in a companion paper in this issue) and targeted replication association analyses in up to 18,554 independent participants, we show that common SNPs at 18 loci are reproducibly associated with concentrations of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and/or triglycerides. Six of these loci are new (P < 5 x 10(-8) for each new locus). Of the six newly identified chromosomal regions, two were associated with LDL cholesterol (1p13 near CELSR2, PSRC1 and SORT1 and 19p13 near CILP2 and PBX4), one with HDL cholesterol (1q42 in GALNT2) and five with triglycerides (7q11 near TBL2 and MLXIPL, 8q24 near TRIB1, 1q42 in GALNT2, 19p13 near CILP2 and PBX4 and 1p31 near ANGPTL3). At 1p13, the LDL-associated SNP was also strongly correlated with CELSR2, PSRC1, and SORT1 transcript levels in human liver, and a proxy for this SNP was recently shown to affect risk for coronary artery disease. Understanding the molecular, cellular and clinical consequences of the newly identified loci may inform therapy and clinical care.
Kathiresan
Sekar
S
Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. skathiresan@partners.org
Melander
Olle
O
Guiducci
Candace
C
Surti
Aarti
A
Burtt
Noël P
NP
Rieder
Mark J
MJ
Cooper
Gregory M
GM
Roos
Charlotta
C
Voight
Benjamin F
BF
Havulinna
Aki S
AS
Wahlstrand
Björn
B
Hedner
Thomas
T
Corella
Dolores
D
Tai
E Shyong
ES
Ordovas
Jose M
JM
Berglund
Göran
G
Vartiainen
Erkki
E
Jousilahti
Pekka
P
Hedblad
Bo
B
Taskinen
Marja-Riitta
MR
Newton-Cheh
Christopher
C
Salomaa
Veikko
V
Peltonen
Leena
L
Groop
Leif
L
Altshuler
David M
DM
Orho-Melander
Marju
M
D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000097:blood* / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood* / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1; D002888:Chromosomes, Human, Pair 19; D002897:Chromosomes, Human, Pair 7; D002898:Chromosomes, Human, Pair 8; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D015810:Linkage Disequilibrium; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011336:Probability; D011446:Prospective Studies; D012333:RNA, Messenger / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D017422:Sequence Analysis, DNA; D014280:Triglycerides / Q000097:blood* / Q000235:genetics*
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005819:Genetic Markers; D012333:RNA, Messenger; D014280:Triglycerides