Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q.
Plasma lipoprotein(a) (Lp[a]) level is an independent risk factor of cardiovascular disease that is under strong genetic control. We conducted a genome-wide association study of plasma Lp(a) in 386 members of a founder population that adheres to a communal lifestyle, proscribes cigarette smoking, and prepares and eats meals communally. We identified associations with 77 single nucleotide polymorphisms (SNPs) spanning 12.5 Mb on chromosome 6q26-q27 that met criteria for genome-wide significance (P <or= 1.3 x 10(-7)) and were within or flanking nine genes, including LPA. We show that variation in at least six genes in addition to LPA are significantly associated with Lp(a) levels independent of each other and of the kringle IV repeat polymorphism in the LPA gene. One novel SNP in intron 37 of the LPA gene was also associated with Lp(a) levels and carotid artery disease number in unrelated Caucasians (P = 7.3 x 10(-12) and 0.024, respectively), also independent of kringle IV number. This study suggests a complex genetic architecture of Lp(a) levels that may involve multiple loci on chromosome 6q26-q27.
Ober
Carole
C
Department of Human Genetics, University of Chicago, Chicago, IL, USA. c-ober@genetics.uchicago.edu
Nord
Alex S
AS
Thompson
Emma E
EE
Pan
Lin
L
Tan
Zheng
Z
Cusanovich
Darren
D
Sun
Ying
Y
Nicolae
Raluca
R
Edelstein
Celina
C
Schneider
Daniel H
DH
Billstrand
Christine
C
Pfaffinger
Ditta
D
Phillips
Natasha
N
Anderson
Rebecca L
RL
Philips
Binu
B
Rajagopalan
Ramakrishnan
R
Hatsukami
Thomas S
TS
Rieder
Mark J
MJ
Heagerty
Patrick J
PJ
Nickerson
Deborah A
DA
Abney
Mark
M
Marcovina
Santica
S
Jarvik
Gail P
GP
Scanu
Angelo M
AM
Nicolae
Dan L
DL
D000818:Animals; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D018082:Kringles / Q000235:genetics; D015810:Linkage Disequilibrium; D017270:Lipoprotein(a) / Q000097:blood / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000097:blood / Q000235:genetics; D012067:Religion; D013023:South Dakota; D044465:White People / Q000235:genetics
D017270:Lipoprotein(a); D020033:Protein Isoforms