Physical activity modifies the effect of LPL, LIPC, and CETP polymorphisms on HDL-C levels and the risk of myocardial infarction in women of European ancestry.
BACKGROUND
Recent genome-wide association studies have identified common variants associated with high-density lipoprotein cholesterol (HDL-C). Whether these associations are modified by physical activity, which increases HDL-C levels and reduces the risk of cardiovascular disease, is uncertain.


RESULTS
In a prospective cohort study of 22 939 apparently healthy US women of European ancestry, we selected 58 single nucleotide polymorphisms (SNPs) in 9 genes that demonstrated genome-wide association (P<5×10(-8)) with HDL-C levels and sought evidence of effect modification according to levels of physical activity. Physical activity modified the effects on HDL-C of 7 SNPs at 3 loci, and the strongest evidence of effect was observed for rs10096633 at lipoprotein lipase (LPL), rs1800588 at hepatic lipase (LIPC), and rs1532624 at cholesteryl ester transfer protein (CETP) (each P-interaction<0.05). The per-minor-allele increase in HDL-C for rs1800588 at LIPC and rs1532624 at CETP was greater in active than inactive women, whereas the reverse was observed for rs10096633 at LPL. Minor-allele carrier status at the LPL SNP was associated with a reduced risk of myocardial infarction in active (hazard ratio, 0.51; 95% confidence interval 0.30-0.86) but not among inactive women (hazard ratio 1.13; 95% confidence interval 0.79 to 1.61; P-interaction=0.007). By contrast, carrier status at the CETP SNP was associated with a reduced risk of myocardial infarction regardless of activity level (hazard ratio, 0.72; 95% confidence interval, 0.57 to 0.92; P-interaction=0.71). No association between LIPC SNP carrier status and myocardial infarction risk was noted.


CONCLUSIONS
The effects of common variants in the LPL, LIPC, and CETP genes on HDL-C levels are modified by physical activity. For a common variant in LPL, the impact on myocardial infarction varied by activity level, whereas the effects of a common variant in CETP on myocardial infarction risk did not.
Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Tariq
T
Ahmad
Daniel I
DI
Chasman
Julie E
JE
Buring
I-Min
IM
Lee
Paul M
PM
Ridker
Brendan M
BM
Everett
D000483:Alleles; D016632:Apolipoprotein A-I / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007899:Leisure Activities; D008049:Lipase / Q000235:genetics*; D008071:Lipoprotein Lipase / Q000235:genetics*; D008875:Middle Aged; D009043:Motor Activity; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D044465:White People / Q000235:genetics*
D016632:Apolipoprotein A-I; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; C504173:LIPC protein, human; D008049:Lipase; C548261:LPL protein, human; D008071:Lipoprotein Lipase
Int J Sports Med. 2002 Jan;23(1):1-9
11774059
Clin Genet. 1999 Aug;56(2):158-63
10517255
J Atheroscler Thromb. 2010 Feb;17(1):21-9
20075597
Metabolism. 2002 Jun;51(6):774-8
12037734
PLoS Genet. 2009 Nov;5(11):e1000730
19936222
Clin Chem. 2008 Feb;54(2):249-55
18070814
Arterioscler Thromb. 1993 Sep;13(9):1359-67
8364020
Atherosclerosis. 2010 Feb;208(2):305-16
19596329
Curr Opin Lipidol. 1999 Jun;10(3):259-67
10431662
N Engl J Med. 2005 Mar 31;352(13):1293-304
15753114
Am J Clin Nutr. 2005 Jun;81(6):1429-35
15941898
JAMA. 2005 Jul 20;294(3):326-33
16030277
Nat Genet. 2009 Jan;41(1):47-55
19060911
Genet Epidemiol. 1985;2(3):227-54
4054601
N Engl J Med. 2002 Nov 7;347(19):1483-92
12421890
Atherosclerosis. 2006 Mar;185(1):65-9
16005460
Int J Epidemiol. 1994 Oct;23(5):991-9
7860180
Circ Cardiovasc Genet. 2009 Feb;2(1):26-33
20031564
Arterioscler Thromb Vasc Biol. 2002 Jan;22(1):133-40
11788473
JAMA. 2008 Jun 4;299(21):2524-32
18523221
J Am Coll Cardiol. 2003 Jun 4;41(11):1972-82
12798568
Atherosclerosis. 2005 Aug;181(2):363-9
16039291
Circulation. 1999 Jun 8;99(22):2901-7
10359734
Circulation. 2007 Nov 6;116(19):2110-8
17967770
Hum Genet. 2001 Oct;109(4):385-92
11702219
Atherosclerosis. 2007 Mar;191(1):40-7
16730014
Acta Physiol Scand. 1979 Nov;107(3):257-61
539455
Diabetes. 2005 Jul;54(7):2251-5
15983229
JAMA. 2008 Jun 18;299(23):2777-88
18560005
Metabolism. 1994 May;43(5):633-9
8177053
Am J Hum Genet. 2007 Sep;81(3):559-75
17701901
Atherosclerosis. 2009 Oct;206(2):500-4
19380136
Metabolism. 1987 Feb;36(2):165-71
3100910
N Engl J Med. 2008 Mar 20;358(12):1240-9
18354102
JAMA. 2004 Sep 8;292(10):1188-94
15353531
Am J Epidemiol. 2003 Nov 1;158(9):836-43
14585761
Circ Cardiovasc Genet. 2008 Oct;1(1):21-30
19802338
Arterioscler Thromb Vasc Biol. 1997 Mar;17(3):560-8
9102177
J Clin Endocrinol Metab. 2008 Jun;93(6):2294-9
18364377