**2. Genetic variants in lipid metabolism and HDL-C levels**

As mentioned above, HDL-C is important for "reverse cholesterol transport" or the shuttling of cholesterol from peripheral cells to the liver. Many of the genetic variants associated with HDL-C levels have been summarized nicely in a recent comprehensive review by Boes et al. (Boes et al., 2009). In Table 1, we include common SNPs tabulated in Boes et al. (2009) review of large studies (ethnic group sample sizes ≥500) as well as common SNPs in large studies that have been identified since their review.


Dyslipidemia: Genetics and Role in the Metabolic Syndrome 97

HoCo

(GP)

(Ho Co, P)

(Ho Co)

(GP)

HoCo

HoCo

(GP)

(GP)

(P)

APOB rs11902417 0.78 (G) E 17723 p= 3.7x10-7 (Waterworth

rs2072560 Ma 707 (P) -0.4 /9.3 mg/dl


p=0.26




> (1/2 copies); p=0.02

carriers; p=0.008


(1/2 copies) ; p=0.004

carriers; p<0.01




(1/2 copies) ; p<0.05

F: +0.1/-4.2 mg/dl 1/2 copies;p=0.029

M: -1.8 mg/dl for carriers; p=0.04.

> heteroz.; p=0.0014

(Yamada et al. 2007)

> (Klos et al. 2006a)

(Lai et al. 2003)

(Yamada et al. 2007)

(Yamada et al. 2008)

(Talmud et al. 2002a)

(Lai et al. 2004)

(Lai et al. 2003)

(Qi et al. 2007)

(Hubacek 2005)

(Yamada et al. 2007)

(Yamada et al. 2008)

(Lai et al. 2003)

et al. 2010)

(Lahiry et al. 2007)

(Kamboh et al. 1999)

(Russo et al. 2001)

(Hegele et al. 1995)

APOA5 - 1131T > C rs662799 0.34 (C) A 521

APOA5 -3A > G rs651821 0.18 (G) C 2711

APOA5 -3A > G rs651821 0.34 (C) A 5207

APOA5 -3A > G rs651821 0.36 (G) A 2417

APOA5 rs2072560 0.16 (A) C 2711

APOA5 +553 rs2075291 0.07 (T) A 5206

APOA5 Gly185Cys rs2075291 0.08 (T) A 2417

APOA5 1259T>C rs2266788 0.18 (C) C 2711

APOC3 PvuIl rs618354 0.49 A F:291

APOC3 Sst1 RFLP rs5128 0.09 (S2) W M:1219

APOA5 IVS3+476

G>A

APOA5 -3A > G rs651821 0.07 W 2056 (P) M; p=0.30; F;

APOA5 S19W rs3135506 0.06 (W) UK 1660 (P) -1.9 /+1.2 mg/dl

APOA5 56C>G rs3135506 0.06 (G) W 2347 (P) -2.0 mg/dl for

APOA5 V153M rs3135507 W 2557 F:- 3.5 mg/dl for

APOC3 C455T rs2854116 0.41 (C) In 1308 (P) -3.1/-5.4 mg/dl

APOC3 3'-utr/Sac I rs5128 0.09 (+) Hu 713 (P) -5.0 mg/dl for


CVD 834 (Co)

(GP)

(GP)

W 1543 (P) -2.2 mg/dl for

(CVD)

(GP)

rs5069 0.31 (C) B 3831 (P) M/F; p=n.s/0.022 (Brown et al.

rs41474449 . W 1543 (P) +1.6 mg/dl for

ABCA1 rs3890182 0.12 (A) EA 25,167 p= 4.53E-07 (Dumitrescu et

APOA1 rs28927680 0.93 (G) EA 25,167 p= 8.61E-09 (Dumitrescu et

APOA1 rs964184 0.86 (C) EA 25,167 p= 6.08E-10 (Dumitrescu et

rs662799 0.06 (C) UK 1696 (P) -1.5 mg/dl /-5.4

C, Ma 2711 (C) 707 (M)

PHIR)

F; p<0.001

0.2 /+2.8 mg/dl (1/2 copies); p=0.02

carriers; p=0.02

M: +2.0 mg/dl for heterozygotes; p<0.01

F: +3.1 mg/dl for carriers; p=0.0005

p=0.05

carriers ; p=0.0040

heterozygotes; p=0.008


carriers; p=0.043

+1.9 /+5.4 mg/dl (1/2copies); p=0.0005

mg/dl (1/2 copies) ; p=0.04



(Klos et al. 2006a)

(Whiting et al. 2005)

(Frikke-Schmidt et al. 2004)

(Hodoglugil et al. 2005)

(Hodoglugil et al. 2005)

(Frikke-Schmidt et al. 2004)

(Costanza et al. 2005)

(Frikke-Schmidt et al. 2004)

> (Clee et al. 2001)

(Costanza et al. 2005)

al. 2011)

(Shioji et al. 2004a)

2006)

al. 2011)

al. 2011)

(Talmud et al. 2002a)

(Grallert et al. 2007)

(Lai et al. 2003)

ABCA1 rs2515602 0.27 B 1943 (P) M; p=0.034;

ABCA1 2310G>A rs2066718 0.03 (A) W 9123 (P) F: higher levels in

rs2066718 0.06 (A) Tu 2105

ABCA1 1883M rs4149313 0.12 (G) W 9123 (P) F: + heterozygotes;

ABCA1 R1587K rs2230808 0.24 (A) W 9123 (P) M: - 1.5 mg/dl for

rs5070 0.23 (C) A 1637

rs662799 0.07 (C) W 1596(SA

0.30 (C)

rs662799 0.23–

ABCA1 G596A rs2853578 0.28 (A) W 2468

ABCA1 G2706A rs2066718 0.05 (A) Tu 2458

ABCA1 4759G > A rs2230808 0.26 (K) W 779

ABCA1 2472G>A

ABCA1 32b.+30,

ABCA1 50b.3038,

APOA1 T84C

APOA1 MspI

APOA5 - 1131T >

APOA5 - 1131T >

APOA5 - 1131T >

G2868A

ABC32

ABC50

(HaeIII)

RFLP

C

C

C


Dyslipidemia: Genetics and Role in the Metabolic Syndrome 99

(Meta)

2056 1943 (P)

(GP)

(GP)

556 CVd

cvd 827 Co

CVD

571 (Co)

CVD 1105 Co

(CVD)

+4.6 mg/dl for homoz.; p<0.00001

> (1/2 copies) ; p<0.001

> (1/2 copies) ; p<0.001

> > p<0.01; p<0.02

(1/2 copies) ; p<0.001 +3.8/9.8 mg/dl (1/2 copies) ; p<0.001

(1/2 copies) ; p<0.001

+2.5/4.4 mg/dl (1/2 copies ; p=1.25x10-10

M: +1.2/3.5 mg/dl (1/2 copies); p=0.096 F: +1.9/6.2 mg/dl (1/2 copies); p<0.001

+2.7 mg/dl per copy; p<0.001

+1.7/3.6 mg/dl (1/2 copies) ; p<0.001

+2.1/3.0 mg/dl (1/2 copies) ; p=0.003

+2.6 /+4.3 mg/dl (1/2 copies) ; p<0.02

+2.1/3.6 mg/dl (1/2 copies) ; p<0.001

+1.2/3.5 mg/dl (1/2 copies) ; p=0.0009

8764 (P) +2.3/5.8 mg/dl

(Boekholdt & Thompson 2003)

(Borggreve et al. 2005b)

(Ordovas et al. 2000)

> (Klos et al. 2006b)

(Nettleton et al. 2007)

(Sandhofer et al. 2008)

> (Tai et al. 2003b)

(Tsujita et al. 2007)

(McCaskie et al. 2007)

(Whiting et al. 2005)

(Carlquist & Anderson 2007)

(Blankenberg et al. 2004)

(Freeman et al. 2003)

(Klerkx et al. 2003)

CETP Taq1B rs708272 >10,000

CETP Taq1B rs708272 0.43

CETP Taq1B rs708272 0.44

CETP Taq1B rs708272 0.42 (B2) W 7083 (P) +2.7/5.0 mg/dl

CETP Taq1B rs708272 0.44 (B2) W 2916 (P) +2.5/4.7 mg/dl

W B

W

B

0.26 (A)

0.27 (A)

CETP Taq1B rs708272 0.41 (A) W 1503 (P) +2 /+5 mg/dl

CETP Taq1B rs708272 0.33 (A) A 4207

CETP Taq1B rs708272 0.40 (A) A 1729

CETP Taq1B rs708272 0.42 (A) W 2683 GP

CETP Taq1B rs708272 0.42 (A) W 2392

CETP Taq1B rs708272 0.40 (A) W 1464

CETP Taq1B rs708272 0.41 (A) W 1200 CV

CETP Taq1B rs708272 0.44 (A) W 499

CETP +784CCC rs34145065 0.39 (A) W 709


APOE Cys112Arg rs429358 0.16 (A) N 3575 p=0.001 (Povel et al.

556 Cvd

(CVD)

(CVD)

873 F (P)

(GP)

(GP)

556 Cvd

(CVD) 574 (Co)

(CVD)

757 (Co)

(cvd) 1107(Co)

(Meta)

carriers; p=0.079

+1.9 mg/dl per copy; p<0.001

+1.5 /+3.5 mg/dl (1/2 copies) ;p=0.0016

p=4.3x10-14

+1.2/+1.9 mg/dl (1/2 copies) ; p=0.09

> (1/2 copies); p<0.001

+4.2 mg/dl for homoz.; p<0.002

+3 /+5 mg/dl (1/2 copies) ; p= 2x10-29

+2.2/+3.4 mg/dl 1/2 copies; p=3.28x10-9

+2.7 mg/dl per copy; p<0.001

CVD: +2.0/3.5mg/dl (1/2 copies) ; p=0.02 Co: +3.3/6.1 mg/dl (1/2 copies) ; p=0.05

+0.8/3.9 mg/dl (1/2 copies) ; p<0.0001

+1.9/6.1 mg/dl (1/2 copies) ; p<0.0001

+2.9/4.4 mg/dl (1/2 copies) ; p<0.001

+1.2 /+3.8 mg/dl 1/2 copies; p<0.0001

(Corella et al. 2002)

2011)

(McCaskie et al. 2007)

(Klerkx et al. 2003)

> (Liu et al. 2011)

(Klerkx et al. 2003)

(Borggreve et al. 2005a)

(Bernstein et al. 2003)

(Kathiresan et al. 2008)

> (Tai et al. 2003b)

(McCaskie et al. 2007)

(Blankenberg et al. 2004)

(Klerkx et al. 2003)

(Eiriksdottir et al. 2001)

(Freeman et al. 2003)

(Boekholdt et al. 2005)

APOC3 3238C > G rs5128 0.07 (S2) W 906 (GP) +1.9 mg/dl for

CETP rs3764261 0.14 (T) C 4192 +0.07 mg/dl;

CETP C629A rs1800775 0.48 (A) W 7083 (P) +2.7 /+5.4 mg/dl

CETP G2708A rs12149545 0.30 (A) W 2683 GP

CETP G2708A rs12149545 0.31 (A) W 709

CETP G971A rs4783961 0.49 (A) W 709

CETP C629A rs1800775 0.51 (A) W 847 M,

CETP C629A rs1800775 0.49 (A) W 5287

CETP C629A rs1800775 0.42 A A 4050

CETP C629A rs1800775 0.48 (A) W 2683 GP

CETP C629A rs1800775 0.40 (A) W 1214

CETP C629A rs1800775 0.44 (A) W 709

CETP C629A rs1800775 0.50 (A) W 309 (MI)

CETP C629A rs1800775 0.48 (A) W 498

CETP Taq1B rs708272 0.40 (B2) 13,677


Dyslipidemia: Genetics and Role in the Metabolic Syndrome 101

(Ho Co)

0.39 (+) Hu 713 (P) 2.3 / 4.3 mg/dl

HoCo

(Meta)

8897 (P) 2909 (P)

(GP)

(GP)

1385 Co

Ho Co

(CVD)

LIPC rs2070895 0.32 (A) W 514 (P) M; p=0.001 (de Andrade

0.12 (T) A 2417

0.17 (C) A 2417

W B

carriers; p=0.0056

+1.5 /+8.5 mg/dl (1/2 copies) ; p=0.0155

> (1/2 copies) ; p=0.047

+1.2/+5.4 (1/2 copies) ; p=0.043

p<0.001

+1.5 /+3.5 mg/dl (1/2 copies); p<0.001

W: +2.2/+3.8 mg/dl (1/2 copies); p<0.001 B: +1.6/+4.0 mg/dl (1/2 copies); p<0.001

> (1/2 copies); p<0.001

> (1/2 copies); p=0.001

+1 /+4 mg/dl (1/2 copies) ; p=4x 10 -10

+1.5 mg/dl per copy; p=0.04

+1.0 /+3.8 mg/dl (1/2 copies); p=0.001

+2.5 mg/dl per copy; p<0.001

+2.0–2.5 mg/dl per copy; p<0.001

p<0.001

carriers; p=0.020

(Costanza et al. 2005)

(Yamada et al. 2008)

(Hegele et al. 1995)

(Yamada et al. 2008)

(Andersen et al. 2003)

(Isaacs et al. 2004)

(Nettleton et al. 2007)

(Isaacs et al. 2007)

> (Tai et al. 2003a)

(Kathiresan et al. 2008)

(Talmud et al. 2002b)

(Whiting et al. 2005)

(Yamada et al. 2007)

(McCaskie et al. 2006)

(Andersen et al. 2003)

(Costanza et al. 2005)

et al. 2004)

LDLR Exon 2 rs2228671 W 1543 (P) +3.8 mg/dl for

LIPC T-710C rs1077834 0.22 (C) W 9121 (P) +3–4% per copy;

0.53 (T)

LIPC rs1800588 0.21 (T) W 6239 (P) +1.3/+4.3 mg/dl

LIPC rs1800588 0.38 (T) A 2170 (P) +2.3 /+2.7 mg/dl

LIPC G -250A rs2070895 0.22 (A) W 9121 (P) +3–4% per copy;

LIPC rs2070895 W 1543 (P) +1.5 mg/dl for

rs688 = rs57911429

rs688 = rs57911429

rs57369606

LIPC Pos.-480T rs1800588 0.21 (T)

LIPC C-514Ta rs1800588 0.25 (T) Va >24,000

LIPC rs1800588 0.21 (T) W 5287

LIPC rs1800588 0.25 (T) W 2773

LIPC rs1800588 0.24 (T) W 3319 CV

LIPC rs1800588 0.51 (T) A 5207

LIPC rs1800588 0.21 (T) W 6412

LDLR 1866C > T

LDLR Exon

Asn591As n

12/HincII

LDLR 2052T >C rs5925 =


1636 CV

(Meta)

(CVD) 572 (Co)

> (CVD) 1108 (Co)

(He Ex)

1636 (CVD)

532 Co

EA 25,167

EA 25,167

W 156 low 160 high

(CVD)

122 Co

CVD,Co

A 190 CVD 209 (Co)

rs61212082 0.32 (A) W 6421 (P) M: +1.5/2.3 mg/dl

5.4 mg/dl for heteroz.; p<0.0001

+1.9 mg/dl for homoz. ; p<0.00001

(1/2 copies); p=0.002 F: +0.0/+2.3 mg/dl (1/2 copies); p=0.007

+1.4 /+3.1 mg/dl (1/2 copies) ; p=0.08 +0.3 /+8.4 mg/dl (1/2 copies); p=0.003

+1.2 /+3.5 mg/dl (1/2 copies); p<0.05 +1.5 /+1.5 mg/dl (1/2 copies); p<0.05

+4.9 mg/dl for heteroz.; p<0.001

5.4 mg/dl for heterozygotes ; p<0.001

3.6 /5.2 mg/dl for heteroz.; p=0.06/0.07

p=1.18E-05

p=1.71E-53

Variant sig. only in low HDL group

Increase in HDL; p=0.015

Lower HDL-C in heteroz.; p<0.05

Association with low HDLC; p<0.01

Increases HDLC; p=2 x 10 -5

(Agerholm-Larsen et al. 2000)

(Boekholdt & Thompson 2003)

(Isaacs et al. 2007)

(Blankenberg et al. 2004)

(Freeman et al. 2003)

(Zhong et al. 1996)

(Agerholm-Larsen et al. 2000)

(Blankenberg et al. 2004)

(Dumitrescu et al. 2011)

(Dumitrescu et al. 2011)

(Miettinen et al. 1998)

(Zhang et al. 2003)

(Zhu et al. 2006)

(Zhang et al. 2004)

(Pare et al. 2007)

CETP A373P rs5880 0.05 (A) W 8467 P

CETP Ile405Val rs5882 >10,000

CETP rs61212082 0.30 (A) W 1208

CETP rs61212082 0.30 (A) W 498

CETP D442G rs2303790b 0.03 (A) A 3469

CETP R451Q rs1800777 0.04 (A) W 8467 (P)

LCAT 608C/T rs5922 . A 203

LCAT rs5922 A 150 Str

LCAT rs2292318 0.12 (A) W 1442

rs1800777 0.03 (A) W 1071 CV

CETP A +

CETP G +

LCAT Gly230Ar

LCAT P143L

82A/Ex15

g

+511C>T

CETP rs12596776 0.90 (C)

CETP rs9989419 0.39 (A)

16G/Ex.14


Dyslipidemia: Genetics and Role in the Metabolic Syndrome 103

(HDL)

(Kids)

(Meta)

(Meta)

(Meta)

rs320 0.30 (H) W 520 (P) +5.5 mg/dl in H –

rs320 0.32 (H) W 906 (GP) +1.9 mg/dl;

(NGT) 465 (DM)

615(W); 579(H)

(Meta)

rs328 0.10 (G) W 8968 (P) +2.8 /+4.0 mg/dl

rs328 0.07 (G) B 2677 (P) +3.1 /+12.6 mg/dl

LPL rs328 25,167 P=5.6E-22 (Dumitrescu et

(GP)

Decreases HDLC; p=0.004

4.0 mg/dl /-4.3 mg/dl (1/2 copies) ; p=0.011




H- vs. H+H+; p=0.025

heteroz. ; p=0.0018 F : +4.2 mg/dl for heteroz. ; p=0.0212

p=0.003

NGT: +3.0 mg/dl for carriers; p<0.05 DM: +1.0 mg/dl for carriers; p<0.05

F; p=0.004

+1.5 mg/dl for heteroz.; p<0.001

> (1/2 copies); p<0.001

> (1/2 copies); p<0.001

> > p<0.001

p=0.0017

+3 /+5 mg/dl (1/2 copies); p=3 x 10-12

W 1361 (P) M: +3.5 mg/dl for

(Mank-Seymour et al. 2004)

(Yamakawa-Kobayashi et al. 2003)

(Wittrup et al. 1999)

(Wittrup et al. 1999)

(Wittrup et al. 1999)

> (Senti et al. 2001)

(Holmer et al. 2000)

(Corella et al. 2002)

(Radha et al. 2006)

1993)

(Klos et al. 2006a)

(Wittrup et al. 1999)

(Nettleton et al. 2007)

> (Lee et al. 2004)

(Costanza et al. 2005)

al. 2011)

(Kathiresan et al. 2008)

p=0.005 (Ahn et al.

rs6507931 0.42 (C) W 594

rs1801177 – 5067

LIPG 2237G > A rs3744841 0.36 (A) A 340

LPL Gly188Glu – 10,434

LPL N291S rs268 – 14,912

rs320 0.26

rs320 0.27-

(H1)

rs320 A 550

NHW , H

0.31

LPL rs326 0.44 B 1943 (P) M; p=0.013;

LPL S447X rs328 0.11 (X) A 4058 (P) +3.1 mg/dl;

LPL rs328 W 1543 (P) +2.7 mg/dl;

LPL rs328 0.09 (G) W 5287

rs328 4388

LIPG T+2864C/l

LPL D9N;

LPL HindIll;

LPL HindIll;

LPL HindIll;

LPL HindIll;

LPL HindIll;

LPL S447X

LPL S447X

LPL S447X

n8

Asp9Asn

Int8

Int8

Int8

Int8

Int8

Ser447Ter

Ser447Ter

Ser447Ter


HoCo

HeEx

(GP)

(GP)

(Kids)

CVD 265 Co

372 (CVD)

(HDL)

LIPC rs4775041 0.29C EA 25,167 p=1.03E-16 (Dumitrescu et

LIPC rs261332 0.20 (A) EA 25,167 p=1.99E-13 (Dumitrescu et

LPC rs261334 0.20 (T) E 17723 p= 4.9×10-22 (Waterworth

rs2000813 0.32 (I) W 495 (GP) M: 1.2 /+2.7

(1/2 copies); p=8x10-10

+2.7 mg/dl per copy; p<0.001

+2.1 mg/dl for carriers; p=0.026

heterozygotes; p<0.05

(1/2 copies) ; p=0.021

+0.7/+9.8 (1/2 copies) ; p=0.0086

mg/dl (1/2 copies) ; p=0.82 F: 0.4 /+1.9 mg/dl (1/2 copies) ; p=0.09

> (1/2 copies) ; p=0.048

+3.7 for carries;

+1.6 /+6.0 mg/dl (1/2 copies) ; p=0.035

Decreases HDLC; p=0.007

(Grarup et al. 2008)

(Yamada et al. 2007)

(Ko et al. 2004)

2008)

2008)

(Fang & Liu 2002)

al. 2011)

al. 2011)

et al. 2010)

(Hutter et al. 2006)

(Yamakawa-Kobayashi et al. 2003)

(Paradis et al. 2003)

(Hutter et al. 2006)

2008)

(Ma et al. 2003)

(Mank-Seymour et al. 2004)

p=<0.02 (Tang et al.

p=0.00003 (Iijima et al.

p=0.0001 (Iijima et al.

LIPC rs2070895 0.23 (A) W 5585 (P) +3.9/3.9 mg/dl

LIPC +1075C rs3829462 0.05 (C) A 823 +8.0 mg/dl for

LIPG -384A > C rs3813082 0.12 (C) A 541 (Co) +1.3/+10.2 mg/dl

LIPG rs2000813 0.24 (T) A 541 (Co) +0.5/+6.1 mg/dl

rs2276269 0.44 (T) W 594

90%

LIPC rs2070895 0.51 (A) A 5213

LIPC rs2070895 0.39 (A) A 716

LIPC rs12594375 0.37 (A) A 2970

LIPC rs8023503 0.38 (T) A 2970

LIPG rs3813082 0.12 (C) A 340

LIPG rs2000813 0.30 (T) A 265

LIPG rs2000813 0.29 (T) W

LIPG 584 C/T

LIPG C+42T/ln

5

T111l


Dyslipidemia: Genetics and Role in the Metabolic Syndrome 105

629C>A (rs1800775); Ile405Val (rs5882)) can all modestly inhibit CETP activity and have been consistently associated with higher HDL-C levels (Bernstein et al., 2003; Blankenberg et al., 2004; Boekholdt et al., 2005; Boekholdt and Thompson, 2003; Borggreve et al., 2005; Eiriksdottir et al., 2001; Freeman et al., 2003; Kathiresan et al., 2008a; Klerkx et al., 2003; Tai et al., 2003b; Thompson et al., 2008). The CETP gene is located on chromosome 16 (16q21). Lipoprotein lipase (LPL) is an enzyme involved in lipolysis of TG-containing lipoproteins such as VLDL and chlyomicrons (Miller and Zhan, 2004), which generate free fatty acids (FFA) that can be taken up by the liver, muscle and adipose tissues (Kwan et al., 2007). Thus, LPL affects LDL levels directly (see Section 3.2) may only affect HDL-C levels indirectly (Lewis and Rader, 2005). The human LPL gene is located on chromosome 8 (8p22). Several LPL SNPs have been associated with HDL-C (Table 1) (Ahn et al., 1993; Corella et al., 2002; Holmer et al., 2000; Klos and Kullo, 2007; Klos et al., 2006; Komurcu-Bayrak et al., 2007; Lee et al., 2004; Nettleton et al., 2007; Senti et al., 2001; Wittrup et al., 1999); however, many of them are in strong linkage disequilibrium with each other (e.g., rs320, rs326, rs13702,

Hepatic lipase (HL; LIPC) is a glycoprotein that is synthesized by liver cells (hepatocytes) and catalyzes the hydrolysis of TG and phospholipids (Miller et al., 2003). For example, after hydrolysis of TG by LPL, VLDL particles are reduced to IDL particles and can be further hydrolyzed by HL/LIPC to LDL or taken up by the liver (Kwan et al., 2007). The human HL/LIPC gene is located on chromosome 15 (15q21). Several HL/LIPC SNPs have been associated with HDL-C levels (Table 1) (Andersen et al., 2003; Costanza et al., 2005; de Andrade et al., 2004; Fang and Liu, 2002; Grarup et al., 2008; Iijima et al., 2008; Isaacs et al., 2007; Kathiresan et al., 2008b; Ko et al., 2004; McCaskie et al., 2006; Nettleton et al., 2007; Tai et al., 2003a; Talmud et al., 2002b; Whiting et al., 2005; Yamada et al., 2007). However, the most consistent associations have been observed for rs1800588 and rs2070895 and, several

Endothelial lipase (EL; LIPG) is an enzyme expressed in endothelial cells that, in the presence of HL/LIPC, metabolizes larger (HDL3) to smaller (HDL2) HDL-C particles and increases the catabolism of APOA-I (see Section 2.3) (Jaye and Krawiec, 2004). EL/LIPG plays a role in the dyslipidemia component and, possibly, the yet to be established, proinflammatrory component of MetSyn (Lamarche and Paradis, 2007) (see Section 5.0). The human EL/LIPG gene is located on chromosome 18 (18q21.1). Several polymorphisms in EL/LPIG have been associated with HDL-C levels (Table 1) (Hutter et al., 2006; Ma et al., 2003; Mank-Seymour et al., 2004; Paradis et al., 2003; Tang et al., 2008; Yamakawa-Kobayashi et al., 2003). However, most of these SNPs have not been as well studied as those in CETP, LPL and EL; and, only the nonsynonymous SNP, rs2000813, has been consistently associated with HDL-C levels in African-American populations (Hutter et al., 2006; Tang et

In the presence of cofactor, APOA-I (see Section 2.3), lecithin-cholesteryl acyltransferase (LCAT), catalyzes the esterification of free cholesterol and, can metabolize larger HDL-C particles to smaller HDL-C particles (Klos and Kullo, 2007; Miller and Zhan, 2004). The human LCAT is located on chromosome 16 (16q22.1). Although mutations leading to complete loss of LCAT and marked (5-10%) reduction in HDL-C levels are rare and can cause cornea opacifications (fish eye disease) and renal disease (Garg and Simha, 2007), several common polymorphisms in LCAT have been associated, albeit inconsistently, with much more modest changes in HDL-C levels (Table 1) (Boekholdt et al., 2006; Miettinen et

rs10105606) (Boes et al., 2009; Heid et al., 2008).

al., 2008; Yamakawa-Kobayashi et al., 2003).

SNPs in the promoter region are in strong LD (Boes et al., 2009).

al., 1998; Pare et al., 2007; Zhang et al., 2004; Zhu et al., 2006).


Table 1. Genetic Polymorphisms Associated With HDL-C. MAF=Minor Allele Frequency; Ethn.: A=Asians; AA=African Americans; Am=Amish; A-I=Asian Indian; B=Blacks; C=Chinese; CH=Caribbean Hispanics; In=Inuit; Ma= Malays; N=Netherlands; NHW=Non-Hispanic Whites; H=Hispanics; Hu=Hutteries; Tu=Turks; UK=United Kingdom; W-Bra=Caucasian Brazilians; W= Whites; Va=Various; Non-DM C0=Non diabetic control subjects; MI=Myocardial infarction; NGT=Normal glucose tolerance; DM= Diabetes mellitus; Ho Sta= Hospital staff; HBP= Hypertensive patients; He Ex=Health examination; Cor Ang=coronary angiography; hyperCH=hypercholesterolemia patients; CVD= Cardiovascular Disease; Co=Controls; Ho Co=Hospital based controls; GP=General Population; Meta= Meta Analysis; P=Population based; M= Males; F= females; + =increase; - = decrease; n.s.=not significant; see text for full gene names. Adapted from Boes et al. (2009) with permission from Elsevier.
