Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q

被引：77

作者：

Ober, Carole ^{[1
,2
]}

Nord, Alex S. ^{[6
,7
]}

Thompson, Emma E. ^{[1
]}

Pan, Lin ^{[1
]}

Tan, Zheng ^{[1
]}

Cusanovich, Darren ^{[1
]}

Sun, Ying ^{[1
]}

Nicolae, Raluca ^{[1
]}

Edelstein, Celina ^{[3
]}

Schneider, Daniel H. ^{[1
]}

Billstrand, Christine ^{[1
]}

Pfaffinger, Ditta ^{[3
]}

Phillips, Natasha ^{[1
]}

Anderson, Rebecca L. ^{[1
]}

Philips, Binu ^{[4
]}

Rajagopalan, Ramakrishnan ^{[6
]}

Hatsukami, Thomas S. ^{[8
]}

Rieder, Mark J. ^{[8
]}

Heagerty, Patrick J. ^{[9
]}

Nickerson, Deborah A. ^{[7
]}

Abney, Mark ^{[1
]}

Marcovina, Santica ^{[8
]}

Jarvik, Gail P. ^{[6
,7
]}

Scanu, Angelo M. ^{[3
,4
]}

Nicolae, Dan L. ^{[1
,4
,5
]}

机构：

[1] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[2] Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA

[3] Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA

[4] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[5] Univ Chicago, Dept Stat, Chicago, IL 60637 USA

[6] Univ Washington, Med Ctr, Div Med Genet, Seattle, WA 98195 USA

[7] Univ Washington, Med Ctr, Dept Genom Sci, Seattle, WA 98195 USA

[8] Univ Washington, Med Ctr, Dept Vasc Surg, Seattle, WA 98195 USA

[9] Univ Washington, Med Ctr, Dept Biostat, Seattle, WA 98195 USA

来源：

JOURNAL OF LIPID RESEARCH | 2009年 / 50卷 / 05期

基金：

美国国家卫生研究院;

关键词：

genome-wide association study; LPA; carotid artery disease; kringle IV; APOLIPOPROTEIN(A) GENE; QUANTITATIVE TRAITS; FOUNDER POPULATION; COMPLEX PEDIGREES; DISEASE; NUMBER; POLYMORPHISM; CAUCASIANS; SEQUENCE; AFRICANS;

D O I：

10.1194/jlr.M800515-JLR200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 <= 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. jlr This study suggests a complex genetic architecture of Lp(a) levels that may involve multiple loci on chromosome 6q26-q27.-Ober, C., A. S. Nord, E. E. Thompson, L. Pan, Z. Tan, D. Cusanovich, Y. Sun, R. Nicolae, C. Edelstein, D. H. Schneider, C. Billstrand, D. Pfaffinger, N. Phillips, R. L. Anderson, B. Philips, R. Rajagopalan, T. S. Hatsukami, M. J. Rieder, P. J. Heagerty, D. A. Nickerson, M. Abney, S. Marcovina, G. P. Jarvik, A. M. Scanu, and D. L. Nicolae. Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q. J. Lipid Res. 2009. 50: 798-806.

引用

页码：798 / 806

页数：9

共 42 条

[1] Estimation of variance components of quantitative traits in inbred populations [J].

Abney, M ;

McPeek, MS ;

Ober, C .

AMERICAN JOURNAL OF HUMAN GENETICS, 2000, 66 (02) :629-650

[2] Quantitative-trait homozygosity and association mapping and empirical genomewide significance in large, complex pedigrees: Fasting serum-insulin level in the hutterites [J].

Abney, M ;

Ober, C ;

McPeek, MS .

AMERICAN JOURNAL OF HUMAN GENETICS, 2002, 70 (04) :920-934

[3] Broad and narrow heritabilities of quantitative traits in a founder population [J].

Abney, M ;

McPeek, MS ;

Ober, C .

AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 68 (05) :1302-1307

[4]

Anglés-Cano E, 1999, J LIPID RES, V40, P354

[5] Lipoprotein(a) An elusive cardiovascular risk factor [J].

Berglund, L ;

Ramakrishnan, R .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2004, 24 (12) :2219-2226

[6] APOLIPOPROTEIN(A) GENE ACCOUNTS FOR GREATER THAN 90-PERCENT OF THE VARIATION IN PLASMA LIPOPROTEIN(A) CONCENTRATIONS [J].

BOERWINKLE, E ;

LEFFERT, CC ;

LIN, JP ;

LACKNER, C ;

CHIESA, G ;

HOBBS, HH .

JOURNAL OF CLINICAL INVESTIGATION, 1992, 90 (01) :52-60

[7] Testing for Hardy-Weinberg equilibrium in samples with related indhiduals [J].

Bourgain, C ;

Abney, M ;

Schneider, D ;

Ober, C ;

McPeek, MS .

GENETICS, 2004, 168 (04) :2349-2361

[8] The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells [J].

Brunner, C ;

Lobentanz, EM ;

PethoSchramm, A ;

Ernst, A ;

Kang, C ;

Dieplinger, H ;

Muller, HJ ;

Utermann, G .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (50) :32403-32410

[9] TagSNP evaluation for the association of 42 inflammation loci and vascular disease:: evidence of IL6, FGB, ALOX5, NFKBIA, and IL4R loci effects [J].

Carlson, Christopher S. ;

Heagerty, Patrick J. ;

Nord, Alex S. ;

Pritchard, David K. ;

Ranchalis, Jane ;

Boguch, Joshua M. ;

Duan, Hangjun ;

Hatsukami, Thomas S. ;

Schwartz, Stephen M. ;

Rieder, Mark J. ;

Nickerson, Deborah A. ;

Jarvik, Gail P. .

HUMAN GENETICS, 2007, 121 (01) :65-75

[10] A multilocus genotyping assay for candidate markers of cardiovascular disease risk [J].

Cheng, S ;

Grow, MA ;

Pallaud, C ;

Klitz, W ;

Erlich, HA ;

Visvikis, S ;

Chen, JJ ;

Pullinger, CR ;

Malloy, MJ ;

Siest, G ;

Kane, JP .

GENOME RESEARCH, 1999, 9 (10) :936-949

← 1 2 3 4 5 →