ABCMdb

PMID: 15935359

Hodoglugil U, Williamson DW, Huang Y, Mahley RW
Common polymorphisms of ATP binding cassette transporter A1, including a functional promoter polymorphism, associated with plasma high density lipoprotein cholesterol levels in Turks.
Atherosclerosis. 2005 Dec;183(2):199-212. Epub 2005 Jun 2., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met The rare alleles of C-14T and V771M polymorphisms were associated with higher HDL-C levels in men and, in combination with the rare alleles of R219K and I883M, respectively, with higher HDL-C in both sexes. Login to comment 4 ABCA1 p.Val771Met Rare alleles of the C-14T and V771M polymorphisms were more frequent in the high HDL-C (≥40 mg/dl) than in the low HDL-C group (≤30 mg/dl) in men (P < 0.05). Login to comment 8 ABCA1 p.Arg219Lys The C-14T and R219K polymorphisms were on different haplotype blocks. Login to comment 9 ABCA1 p.Val771Met Analysis of the coding region structure revealed that the rare M allele of V771M was distributed predominantly among three common haplotypes, but the sum of their frequencies comprise only two-thirds of the frequency of the M allele. Login to comment 10 ABCA1 p.Ile883Met ABCA1 p.Val771Met The rare alleles of the V771M and the I883M polymorphisms do not exist together on any of the common haplotypes. Login to comment 11 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met In conclusion, we describe a functional promoter polymorphism (C-14T) and a coding sequence variant (V771M) of ABCA1 and their interactions with two other variants (R219K and I883M) on plasma HDL-C levels in Turks. Login to comment 21 ABCA1 p.Arg219Lys Some common polymorphisms of ABCA1, including R219K 0021-9150/$ - see front matter (c) 2005 Elsevier Ireland Ltd. All rights reserved. Login to comment 22 ABCA1 p.Ile883Met doi:10.1016/j.atherosclerosis.2005.03.004 [9] and I883M [9-11], are associated with elevated HDL-C levels, although not in all studies [10,12-17]. Login to comment 24 ABCA1 p.Val825Ile ABCA1 p.Val771Met Recently, it was shown that some polymorphisms of ABCA1 were associated with increases (V771M and V825I) or decreases (R1587K) in HDL-C in women and with some consistent trends in men in a large random Danish population [17]. Login to comment 31 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys In onestudy,wheremalesandfemaleswereanalyzedseparately, R219K and I883M were associated with elevated HDL-C levels in females only [9]. Login to comment 103 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp ABCA1 p.Val1773Met ABCA1 p.Gln1328Arg ABCA1 p.Tyr1767His The G-803A Table 2 ABCA1 polymorphisms Nucleotide changea Carrier of rare allele (%) Rare allele (%) nb Referencesc Frequency in 5 and promoter regions G-803A ~10 92/141 [19] T-564C 72.7 47.7 728/1268 [18] G-407C 62.5 40.7 220/233 [18] G-99C 42.2 24.2 875/1130 [46] C-14T 61.2 37.7 916/1416 [46] InsG 319 26.6 14.2 848/1288 [46] Nucleotide changed Amino acid change Exon Carrier of rare allele (%) Rare allele (%) nb Referencesc Frequency in coding sequence Nonsynonymous G(70943)A R219K 7 62.3 38.5 996/1466 db 2230806 G(102555)A V771M 16 10.0 5.1 981/1477 db 2066718 G(103777)A V825I 17 12.3 6.2 960/1145 db 4149312 A(105057)G I883M 18 38.1 21.8 1084/1448 db 4149313 G(112177)C E1172D 24 9.0 4.6 1001/1237 [12,13] A(116887)G Q1328R 28 0.003e 0.0015 172/156 NR G(129004)A R1587K 35 55.1 33.0 937/1351 db 2230808 T(133402)C Y1767H 39 ~1.0e 40/55 NR G(133420)A V1773M 39 ~1.0e 40/55 NR Synonymous C(100538)A I620I 15 ~4.0 40/55 NR C(109469)T V990V 21 ~3.0 87/90 [17] T(109861)G V1053V 22 ~1.0 90/90 [12] C(109868)T L1056L 22 ~5.0 90/90 NR C(109906)T R1068R 22 ~3.0 90/90 NR A(113280)G E1211E 25 ~4.0 40/55 [17] A(116879)G T1325T 28 ~1.0 40/55 NR T(137043)C Y1921Y 43 ~1.0 40/55 NR Nucleotide changed Intron Carrier of rare allele (%) Intronic location nb Referencesc Frequency in noncoding sequence G(23816)A 1 ~1.0 11 bp 5 exon 1b 94 NR G(23819)C 1 42 8 bp 5 exon 1b 94 NR A(22997)T 1 46 90 bp 5 exon 1d 91 NR A(23004)G 1 ~1.0 83 bp 5 exon 1d 91 NR G(23058)C 1 46 29 bp 5 exon 1d 91 NR G(40504)A 3 2.6 26 bp 3 of exon 3 192 NR C(45217)T 4 0.7 64 bp 3 of exon 4 142 NR T(98628)A 14 35-40 24 bp 3 of exon 14 190 db 4743763 C(100332)T 14 4.3 59 bp 5 of exon 15 90 db 2066717 C(108020)T 19 0.7 3 bp 5 of exon 20 144 NR DelTTT(134503-6) 39 7.0 20-23 bp 5 of exon 40 90 NR C(142026)T 46 8.6 34 bp 5 of exon 47 116 NR A(142751)G 48 15.9 13 bp 3 of exon 48 107 NR a Relative to transcriptional start. Login to comment 104 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp ABCA1 p.Val1773Met ABCA1 p.Gln1328Arg ABCA1 p.Tyr1767His The G-803A Table 2 ABCA1 polymorphisms Nucleotide changea Carrier of rare allele (%) Rare allele (%) nb Referencesc Frequency in 5 and promoter regions G-803A ~10 92/141 [19] T-564C 72.7 47.7 728/1268 [18] G-407C 62.5 40.7 220/233 [18] G-99C 42.2 24.2 875/1130 [46] C-14T 61.2 37.7 916/1416 [46] InsG 319 26.6 14.2 848/1288 [46] Nucleotide changed Amino acid change Exon Carrier of rare allele (%) Rare allele (%) nb Referencesc Frequency in coding sequence Nonsynonymous G(70943)A R219K 7 62.3 38.5 996/1466 db 2230806 G(102555)A V771M 16 10.0 5.1 981/1477 db 2066718 G(103777)A V825I 17 12.3 6.2 960/1145 db 4149312 A(105057)G I883M 18 38.1 21.8 1084/1448 db 4149313 G(112177)C E1172D 24 9.0 4.6 1001/1237 [12,13] A(116887)G Q1328R 28 0.003e 0.0015 172/156 NR G(129004)A R1587K 35 55.1 33.0 937/1351 db 2230808 T(133402)C Y1767H 39 ~1.0e 40/55 NR G(133420)A V1773M 39 ~1.0e 40/55 NR Synonymous C(100538)A I620I 15 ~4.0 40/55 NR C(109469)T V990V 21 ~3.0 87/90 [17] T(109861)G V1053V 22 ~1.0 90/90 [12] C(109868)T L1056L 22 ~5.0 90/90 NR C(109906)T R1068R 22 ~3.0 90/90 NR A(113280)G E1211E 25 ~4.0 40/55 [17] A(116879)G T1325T 28 ~1.0 40/55 NR T(137043)C Y1921Y 43 ~1.0 40/55 NR Nucleotide changed Intron Carrier of rare allele (%) Intronic location nb Referencesc Frequency in noncoding sequence G(23816)A 1 ~1.0 11 bp 5 exon 1b 94 NR G(23819)C 1 42 8 bp 5 exon 1b 94 NR A(22997)T 1 46 90 bp 5 exon 1d 91 NR A(23004)G 1 ~1.0 83 bp 5 exon 1d 91 NR G(23058)C 1 46 29 bp 5 exon 1d 91 NR G(40504)A 3 2.6 26 bp 3 of exon 3 192 NR C(45217)T 4 0.7 64 bp 3 of exon 4 142 NR T(98628)A 14 35-40 24 bp 3 of exon 14 190 db 4743763 C(100332)T 14 4.3 59 bp 5 of exon 15 90 db 2066717 C(108020)T 19 0.7 3 bp 5 of exon 20 144 NR DelTTT(134503-6) 39 7.0 20-23 bp 5 of exon 40 90 NR C(142026)T 46 8.6 34 bp 5 of exon 47 116 NR A(142751)G 48 15.9 13 bp 3 of exon 48 107 NR a Relative to transcriptional start. Login to comment 108 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp Table 3 ABCA1 polymorphisms and mean plasma HDL-C levels (mg/dl &#b1; S.D.) in a random Turkish population Females Males AAa AB BB AAa AB BB Promoter and 5 region T-564C 40.4 &#b1; 8.4 (205) 41.0 &#b1; 7.9 (365) 39.9 &#b1; 7.6 (158) 35.6 &#b1; 7.4 (339) 35.5 &#b1; 6.5 (635) 34.9 &#b1; 6.5 (294) G-407C 41.3 &#b1; 11.2 (82) 40.7 &#b1; 7.7 (101) 40.7 &#b1; 12.2 (37) 35.7 &#b1; 6.9 (88) 35.3 &#b1; 6.7 (96) 35.4 &#b1; 7.4 (49) G-99C 40.7 &#b1; 7.5 (505) 41.0 &#b1; 7.2 (317) 41.3 &#b1; 8.4 (53) 35.1 &#b1; 6.5 (654) 35.0 &#b1; 6.3 (405) 34.9 &#b1; 6.5 (71) C-14T 41.3 &#b1; 9.0 (361) 41.0 &#b1; 9.0 (417) 41.0 &#b1; 9.4 (138) 34.8 &#b1; 7.0b (547) 35.5 &#b1; 7.5 (675) 36.7 &#b1; 8.1b (194) InsG 319 41.3 &#b1; 8.1 (641) 40.5 &#b1; 7.7 (193) 43.1 &#b1; 8.0 (14) 35.3 &#b1; 6.4 (933) 34.7 &#b1; 6.4 (332) 34.5 &#b1; 6.5 (23) Nonsynonymous R219K 41.2 &#b1; 9.4 (364) 40.8 &#b1; 8.6 (480) 41.2 &#b1; 10 (152) 35.2 &#b1; 7.3 (574) 35.3 &#b1; 7.3 (688) 35.2 &#b1; 7.6 (204) V771M 40.9 &#b1; 9.2 (896) 42.8 &#b1; 9.3 (82) 38.7 &#b1; 10 (3) 35.1 &#b1; 7.2c (1330) 37.1 &#b1; 8.0c (144) 45.7 &#b1; 10.7 (3) V825I 40.6 &#b1; 9.4 (842) 38.9 &#b1; 8.5 (117) 42 (1) 35.8 &#b1; 8.7 (1005) 37.1 &#b1; 9.5 (140) (-) I883M 41.1 &#b1; 9.5 (643) 40.8 &#b1; 8.4 (372) 41.4 &#b1; 9.1 (69) 35.0 &#b1; 7.0 (922) 35.7 &#b1; 8.0 (457) 35.6 &#b1; 7.4 (69) E1172D 40.5 &#b1; 8.8 (907) 40.5 &#b1; 7.6 (93) 29 (1) 34.6 &#b1; 7.3 (1129) 35.4 &#b1; 7.6 (105) 30.7 &#b1; 8.7 (3) R1587K 41.1 &#b1; 9.4 (410) 40.8 &#b1; 9.6 (433) 41.0 &#b1; 10.1 (94) 35.9 &#b1; 8.1 (617) 35.1 &#b1; 7.6 (579) 35.3 &#b1; 8.6 (155) Numbers of subjects are shown in parenthesis. Login to comment 109 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp Table 3 ABCA1 polymorphisms and mean plasma HDL-C levels (mg/dl ± S.D.) in a random Turkish population Females Males AAa AB BB AAa AB BB Promoter and 5 region T-564C 40.4 ± 8.4 (205) 41.0 ± 7.9 (365) 39.9 ± 7.6 (158) 35.6 ± 7.4 (339) 35.5 ± 6.5 (635) 34.9 ± 6.5 (294) G-407C 41.3 ± 11.2 (82) 40.7 ± 7.7 (101) 40.7 ± 12.2 (37) 35.7 ± 6.9 (88) 35.3 ± 6.7 (96) 35.4 ± 7.4 (49) G-99C 40.7 ± 7.5 (505) 41.0 ± 7.2 (317) 41.3 ± 8.4 (53) 35.1 ± 6.5 (654) 35.0 ± 6.3 (405) 34.9 ± 6.5 (71) C-14T 41.3 ± 9.0 (361) 41.0 ± 9.0 (417) 41.0 ± 9.4 (138) 34.8 ± 7.0b (547) 35.5 ± 7.5 (675) 36.7 ± 8.1b (194) InsG 319 41.3 ± 8.1 (641) 40.5 ± 7.7 (193) 43.1 ± 8.0 (14) 35.3 ± 6.4 (933) 34.7 ± 6.4 (332) 34.5 ± 6.5 (23) Nonsynonymous R219K 41.2 ± 9.4 (364) 40.8 ± 8.6 (480) 41.2 ± 10 (152) 35.2 ± 7.3 (574) 35.3 ± 7.3 (688) 35.2 ± 7.6 (204) V771M 40.9 ± 9.2 (896) 42.8 ± 9.3 (82) 38.7 ± 10 (3) 35.1 ± 7.2c (1330) 37.1 ± 8.0c (144) 45.7 ± 10.7 (3) V825I 40.6 ± 9.4 (842) 38.9 ± 8.5 (117) 42 (1) 35.8 ± 8.7 (1005) 37.1 ± 9.5 (140) (-) I883M 41.1 ± 9.5 (643) 40.8 ± 8.4 (372) 41.4 ± 9.1 (69) 35.0 ± 7.0 (922) 35.7 ± 8.0 (457) 35.6 ± 7.4 (69) E1172D 40.5 ± 8.8 (907) 40.5 ± 7.6 (93) 29 (1) 34.6 ± 7.3 (1129) 35.4 ± 7.6 (105) 30.7 ± 8.7 (3) R1587K 41.1 ± 9.4 (410) 40.8 ± 9.6 (433) 41.0 ± 10.1 (94) 35.9 ± 8.1 (617) 35.1 ± 7.6 (579) 35.3 ± 8.6 (155) Numbers of subjects are shown in parenthesis. Login to comment 115 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met Informative associations between HDL-C levels and the R219K, V771M, and I883M polymorphisms will be discussed. Login to comment 116 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met Informative associations between HDL-C levels and the R219K, V771M, and I883M polymorphisms will be discussed. Login to comment 148 ABCA1 p.Val771Met Of these, only the V771M polymorphism appeared to be associated with altered HDL-C levels in males (Table 3). Login to comment 149 ABCA1 p.Val771Met ABCA1 p.Val771Met Of these, only the V771M polymorphism appeared to be associated with altered HDL-C levels in males (Table 3). Login to comment 150 ABCA1 p.Val771Met Since the V771M polymorphism was present in the Turkish population with an allelic frequency of 5.1% (n = 2458), the rare 771MM homozygous genotype (BB) occurred infrequently (three males and three females). Login to comment 151 ABCA1 p.Val771Met Analysis of covariance revealed that the V771M polymorphism was primarily associated with plasma HDL-C, not with triglycerides, in Turkish males (P < 0.05). Login to comment 152 ABCA1 p.Val771Met Analysis of covariance revealed that the V771M polymorphism was primarily associated with plasma HDL-C, not with triglycerides, in Turkish males (P < 0.05). Login to comment 153 ABCA1 p.Val771Met The V771M polymorphism had no significant effect on HDL-C levels in females (Table 3). Login to comment 154 ABCA1 p.Val771Met ABCA1 p.Val771Met The V771M polymorphism had no significant effect on HDL-C levels in females (Table 3). Login to comment 155 ABCA1 p.Val771Met ABCA1 p.Val771Met Further stratification of the V771M polymorphism by age, BMI, smoking, alcohol consumption, and apoE genotype yielded no additional information. Login to comment 156 ABCA1 p.Val771Met The association of the V771M polymorphism with HDL-C levels was confirmed in the randomly divided subpopulations of Turkish males (Supplemental Table II). Login to comment 162 ABCA1 p.Val771Met Genotypic (left) and allelic (right) frequencies of the ABCA1 V771M polymorphism in males with low (ࣘ30 mg/dl), moderate (30-40 mg/dl), or high (ࣙ40 mg/dl) levels of HDL-C. Login to comment 163 ABCA1 p.Val771Met Genotypic (left) and allelic (right) frequencies of the ABCA1 V771M polymorphism in males with low (≤30 mg/dl), moderate (30-40 mg/dl), or high (≥40 mg/dl) levels of HDL-C. Login to comment 167 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Effect of combined ABCA1 polymorphisms on HDL-C levels in a random Turkish population The R219K and I883M polymorphisms have been shown to affect lipid metabolism or CAD risk [9,10,12,15,43]. Login to comment 168 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Effect of combined ABCA1 polymorphisms on HDL-C levels in a random Turkish population The R219K and I883M polymorphisms have been shown to affect lipid metabolism or CAD risk [9,10,12,15,43]. Login to comment 169 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met In contrast, the combinations of C-14T with R219K and of V771M with I883M were associated with altered HDL-C levels. Login to comment 170 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val771Met In contrast, the combinations of C-14T with R219K and of V771M with I883M were associated with altered HDL-C levels. Login to comment 171 ABCA1 p.Arg219Lys As shown in Table 4, subjects were stratified according to their R219K genotype (RR, RK, or KK) versus C-14T (CC, CT, or TT). Login to comment 176 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Val771Met To assess the combined effect of the V771M and I883M polymorphisms on HDL-C levels, subjects were stratified by the I883M genotype (II, IM, or MM) versus V771M. Login to comment 177 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Val771Met To assess the combined effect of the V771M and I883M polymorphisms on HDL-C levels, subjects were stratified by the I883M genotype (II, IM, or MM) versus V771M. Login to comment 180 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met Separate haplotype blocks of ABCA1 In order to assess whether the length of the ABCA1 locus could be treated as a single haplotype block, haplotypes were constructed and significant LDs between polymorphisms were calculated using 10 common ABCA1 polymorphisms Table 4 Interactive effects of ABCA1 polymorphisms on mean plasma HDL-C levels (mg/dl &#b1; S.D.) R219K C-14T Females Males RR CC 41.4 &#b1; 8.5 (128) 34.7 &#b1; 6.7 (207) CT 41.6 &#b1; 9.8 (150) 35.7 &#b1; 7.6 (253) TT 41.3 &#b1; 8.9 (55) 36.3 &#b1; 7.8 (84) RK CC 41.8 &#b1; 8.3 (169) 34.8 &#b1; 7.4 (261) CT 39.9 &#b1; 8.3 (203) 35.5 &#b1; 6.8 (309) TT 39.5 &#b1; 9.0 (60) 36.8 &#b1; 8.5 (84) KK CC 39.8 &#b1; 11.2 (60) 34.0 &#b1; 6.2 (69) CT 41.1 &#b1; 9.0 (60) 35.7 &#b1; 8.4 (102) TT 44.7 &#b1; 9.8a (22) 37.1 &#b1; 7.8a (22) I883M V771M II VV 40.9 &#b1; 9.8 (499) 34.8 &#b1; 6.8 (797) VM 41.4 &#b1; 8.3 (74) 36.7 &#b1; 8.3b (112) IM VV 40.3 &#b1; 8.0 (313) 35.1 &#b1; 8.1 (427) VM 44.2 &#b1; 11.5b (17) 37.3 &#b1; 7.4b (26) MM VV 41.6 &#b1; 9.2 (60) 35.6 &#b1; 7.5 (67) Numbers of subjects are shown in parenthesis. Login to comment 181 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met Separate haplotype blocks of ABCA1 In order to assess whether the length of the ABCA1 locus could be treated as a single haplotype block, haplotypes were constructed and significant LDs between polymorphisms were calculated using 10 common ABCA1 polymorphisms Table 4 Interactive effects of ABCA1 polymorphisms on mean plasma HDL-C levels (mg/dl ± S.D.) R219K C-14T Females Males RR CC 41.4 ± 8.5 (128) 34.7 ± 6.7 (207) CT 41.6 ± 9.8 (150) 35.7 ± 7.6 (253) TT 41.3 ± 8.9 (55) 36.3 ± 7.8 (84) RK CC 41.8 ± 8.3 (169) 34.8 ± 7.4 (261) CT 39.9 ± 8.3 (203) 35.5 ± 6.8 (309) TT 39.5 ± 9.0 (60) 36.8 ± 8.5 (84) KK CC 39.8 ± 11.2 (60) 34.0 ± 6.2 (69) CT 41.1 ± 9.0 (60) 35.7 ± 8.4 (102) TT 44.7 ± 9.8a (22) 37.1 ± 7.8a (22) I883M V771M II VV 40.9 ± 9.8 (499) 34.8 ± 6.8 (797) VM 41.4 ± 8.3 (74) 36.7 ± 8.3b (112) IM VV 40.3 ± 8.0 (313) 35.1 ± 8.1 (427) VM 44.2 ± 11.5b (17) 37.3 ± 7.4b (26) MM VV 41.6 ± 9.2 (60) 35.6 ± 7.5 (67) Numbers of subjects are shown in parenthesis. Login to comment 189 ABCA1 p.Val771Met Many of the rare single nucleotide polymorphisms, such as V771M, were not well represented on the 26 common haplotypes and therefore existed only on the remaining rare haplotypes. Login to comment 190 ABCA1 p.Val771Met Many of the rare single nucleotide polymorphisms, such as V771M, were not well represented on the 26 common haplotypes and therefore existed only on the remaining rare haplotypes. Login to comment 203 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val825Ile ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp ABCA1 p.Glu1172Asp ABCA1 p.Glu1172Asp However, further analysis Table 5 Allele frequency and significant (P < 0.01) pair-wise linkage disequilibrium coefficients between the ABCA1 polymorphisms in a random Turkish population Position Allele % T-564C G-99C C-14T InsG 319 R219K V771M V825I I883M E1172D R1587K T-564C 52.3/47.7 - G-99C 75.8/24.2 0.36 - C-14T 62.3/37.7 -0.96 -0.98 - InsG 319 85.8/14.2 - - - - R219K 61.5/38.5 - - - - V771M 94.9/5.1 - - - 0.99 - V825I 93.8/6.2 -0.40 -0.69 - - -0.76 - - I883M 78.2/21.8 - -0.42 - - 0.20 -0.79 0.91 - E1172D 95.4/4.6 - - - - - 0.34 - - - R1587K 67.0/33.0 - - -0.23 - - 0.56 - - 0.87 - Table 6 Common haplotypes of promoter and coding regions of ABCA1 gene in a random Turkish population Promoter region haplotypes % T-564C G-99C C-14T InsG 319 1 31.7 0 0 1 0 2 20.1 1 1 0 0 3 19.9 1 0 0 0 4 12.7 0 0 0 0 5 4.6 0 0 1 1 6 4.2 1 1 0 1 7 3.2 1 0 0 1 8 2.5 0 0 0 1 Sum 98.9 Coding region haplotypes % R219K V771M V825I I883M E1172D R1587K 1 39.3 0 0 0 0 0 0 2 12.6 1 0 0 0 0 0 3 12.0 0 0 0 0 0 1 4 8.7 1 0 0 1 0 0 5 8.3 1 0 0 0 0 1 6 4.0 0 0 1 1 0 0 7 3.4 0 0 0 0 1 1 8 1.6 1 0 0 1 0 1 9 1.3 1 1 0 0 0 0 10 1.3 0 1 0 0 1 1 11 1.3 0 0 1 1 0 1 12 1.1 1 1 0 0 0 1 Sum 95.1 0: common allele; 1: rare allele. Login to comment 204 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val825Ile ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp ABCA1 p.Glu1172Asp ABCA1 p.Glu1172Asp However, further analysis Table 5 Allele frequency and significant (P < 0.01) pair-wise linkage disequilibrium coefficients between the ABCA1 polymorphisms in a random Turkish population Position Allele % T-564C G-99C C-14T InsG 319 R219K V771M V825I I883M E1172D R1587K T-564C 52.3/47.7 - G-99C 75.8/24.2 0.36 - C-14T 62.3/37.7 -0.96 -0.98 - InsG 319 85.8/14.2 - - - - R219K 61.5/38.5 - - - - V771M 94.9/5.1 - - - 0.99 - V825I 93.8/6.2 -0.40 -0.69 - - -0.76 - - I883M 78.2/21.8 - -0.42 - - 0.20 -0.79 0.91 - E1172D 95.4/4.6 - - - - - 0.34 - - - R1587K 67.0/33.0 - - -0.23 - - 0.56 - - 0.87 - Table 6 Common haplotypes of promoter and coding regions of ABCA1 gene in a random Turkish population Promoter region haplotypes % T-564C G-99C C-14T InsG 319 1 31.7 0 0 1 0 2 20.1 1 1 0 0 3 19.9 1 0 0 0 4 12.7 0 0 0 0 5 4.6 0 0 1 1 6 4.2 1 1 0 1 7 3.2 1 0 0 1 8 2.5 0 0 0 1 Sum 98.9 Coding region haplotypes % R219K V771M V825I I883M E1172D R1587K 1 39.3 0 0 0 0 0 0 2 12.6 1 0 0 0 0 0 3 12.0 0 0 0 0 0 1 4 8.7 1 0 0 1 0 0 5 8.3 1 0 0 0 0 1 6 4.0 0 0 1 1 0 0 7 3.4 0 0 0 0 1 1 8 1.6 1 0 0 1 0 1 9 1.3 1 1 0 0 0 0 10 1.3 0 1 0 0 1 1 11 1.3 0 0 1 1 0 1 12 1.1 1 1 0 0 0 1 Sum 95.1 0: common allele; 1: rare allele. Login to comment 208 ABCA1 p.Arg219Lys We observed an interaction between the C-14T and R219K polymorphisms (Table 4). Login to comment 209 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys We observed an interaction between the C-14T and R219K polymorphisms (Table 4). Login to comment 210 ABCA1 p.Arg219Lys In an effort to construct haplotypes including these two polymorphisms, a haplotype block including five polymorphisms (T-564C, G-99C, C-14T, InsG 319, and R219K) was used for mapping. Login to comment 212 ABCA1 p.Arg219Lys Therefore, haplotype-to-phenotype associations containing the C-14T and R219K polymorphisms within the same block could not be conducted. Login to comment 213 ABCA1 p.Arg219Lys Therefore, haplotype-to-phenotype associations containing the C-14T and R219K polymorphisms within the same block could not be conducted. Login to comment 214 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp Haplotype structure and haplotype-phenotype association of polymorphisms in the coding region of ABCA1 When the haplotype structure of the coding region was constructed using six polymorphisms (R219K, V771M, V825I, I883M, E1172D, and R1587K; Table 6), 12 haplotypes with a frequency >1% accounted for 95.1% of all haplotypes. Login to comment 215 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp Haplotype structure and haplotype-phenotype association of polymorphisms in the coding region of ABCA1 When the haplotype structure of the coding region was constructed using six polymorphisms (R219K, V771M, V825I, I883M, E1172D, and R1587K; Table 6), 12 haplotypes with a frequency >1% accounted for 95.1% of all haplotypes. Login to comment 218 ABCA1 p.Val771Met The rare allele frequency of the V771M polymorphism, which was associated with high HDL-C in males, was 5.1% (Table 2). Login to comment 219 ABCA1 p.Val771Met The rare allele frequency of the V771M polymorphism, which was associated with high HDL-C in males, was 5.1% (Table 2). Login to comment 220 ABCA1 p.Val771Met Those remaining must be distributed among the rare (<1%) haplotypes, and this distribution may explain the lack of association for the V771M on haplotype analysis. Login to comment 221 ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Val771Met Those remaining must be distributed among the rare (<1%) haplotypes, and this distribution may explain the lack of association for the V771M on haplotype analysis. Login to comment 222 ABCA1 p.Ile883Met ABCA1 p.Val771Met We observed an interaction between the V771M and I883M polymorphisms (Table 4). Login to comment 229 ABCA1 p.Ile883Met ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp (rare allele in LD with rare allele) was observed between pairs of V771M and InsG 319, V825I and I883M, and R1587K and E1172D. Login to comment 230 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp (rare allele in LD with rare allele) was observed between pairs of V771M and InsG 319, V825I and I883M, and R1587K and E1172D. Login to comment 231 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Val771Met There was negative LD (rare allele to common allele) between I883M and V771M as seen in Table 4. Login to comment 232 ABCA1 p.Arg219Lys ABCA1 p.Val771Met The R219K, C-14T, and V771M polymorphisms were not in LD in the Turkish population. Login to comment 278 ABCA1 p.Val771Met In the analysis of covariance, where the sources of variance on plasma HDL-C levels were examined, introduction of interaction variables (smoking or alcohol consumption) &#d7; (C-14T or V771M) to the model showed that neither parameter modulated (P > 0.05) the effect of polymorphisms on HDL-C levels in males or females or when data for both genders were pooled. Login to comment 279 ABCA1 p.Arg219Lys ABCA1 p.Val771Met In the analysis of covariance, where the sources of variance on plasma HDL-C levels were examined, introduction of interaction variables (smoking or alcohol consumption) × (C-14T or V771M) to the model showed that neither parameter modulated (P > 0.05) the effect of polymorphisms on HDL-C levels in males or females or when data for both genders were pooled. Login to comment 280 ABCA1 p.Arg219Lys However, we are able to see an association with elevated HDL-C in females through the combined effect between C-14T and R219K. Login to comment 281 ABCA1 p.Arg219Lys We tried to examine the combined effect of the C-14T and R219K polymorphisms by examining the haplotypes that contain these two rare allele genotypes; unfortunately, haplotype construction was complicated by an inability to predict a unique set of diplotypes. Login to comment 282 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys We tried to examine the combined effect of the C-14T and R219K polymorphisms by examining the haplotypes that contain these two rare allele genotypes; unfortunately, haplotype construction was complicated by an inability to predict a unique set of diplotypes. Login to comment 283 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys This prevented further statistical association of haplotypes that include both the C-14T and the R219K polymorphisms in the same haplotype block. Login to comment 284 ABCA1 p.Arg219Lys R219K by itself did not affect plasma lipid levels in Turks and Danes [17]. Login to comment 287 ABCA1 p.Arg219Lys On the other hand, the R219K polymorphism did not affect the severity of coronary atherosclerosis in the Veterans Administration HDL Cholesterol Intervention Trial [13] or in Japanese CAD patients [14]. Login to comment 288 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys On the other hand, the R219K polymorphism did not affect the severity of coronary atherosclerosis in the Veterans Administration HDL Cholesterol Intervention Trial [13] or in Japanese CAD patients [14]. Login to comment 289 ABCA1 p.Arg219Lys ABCA1 p.Val771Met In Turks, the interaction of C-14T and R219K may play a role in altering plasma HDL-C levels and possibly CAD risk. Login to comment 290 ABCA1 p.Ile883Met ABCA1 p.Val771Met In Turkish males but not females, the M allele of the V771M polymorphism was associated with high plasma HDL-C levels. After stratification by HDL-C levels, the M allele was significantly more frequent in the high than in the low HDL-C group, further supporting an association with high plasma HDL-C levels. Login to comment 291 ABCA1 p.Ile883Met The 771VM genotype was associated with high HDL-C in both males and females when it occurred in combination with the IM genotype of the I883M polymorphism. Login to comment 294 ABCA1 p.Val771Met The V771M polymorphism was associated with high HDL-C in females and consistent trends in males [17], whereas male subjects with the 771M allele had decreased focal atherosclerosis without alterations in plasma lipid levels [12]. Login to comment 295 ABCA1 p.Ile883Met ABCA1 p.Val771Met The V771M polymorphism was associated with high HDL-C in females and consistent trends in males [17], whereas male subjects with the 771M allele had decreased focal atherosclerosis without alterations in plasma lipid levels [12]. Login to comment 296 ABCA1 p.Ile883Met The I883M polymorphism alone did not appear to alter HDL-C levels in Turks. Login to comment 298 ABCA1 p.Ile883Met In contrast, the M allele of the I883M polymorphism was associated with increased progression of atherosclerosis [12]. Login to comment 299 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Val771Met In contrast, the M allele of the I883M polymorphism was associated with increased progression of atherosclerosis [12]. Login to comment 300 ABCA1 p.Ile883Met ABCA1 p.Val771Met The combination of V771M and I883M alone or with other factors may modulate plasma HDL-C levels and CAD risk. Login to comment 301 ABCA1 p.Val825Ile The association with V825I and R1587K on plasma HDL-C levels were found in a large general Danish population [17]; however, it was not observed in Dutch men with CAD [18] or in our population. Login to comment 302 ABCA1 p.Val825Ile The association with V825I and R1587K on plasma HDL-C levels were found in a large general Danish population [17]; however, it was not observed in Dutch men with CAD [18] or in our population. Login to comment 303 ABCA1 p.Val771Met A functional promoter polymorphism, C-14T, and a coding sequence polymorphism, V771M, in the ABCA1 gene appeared to affect HDL-C levels in Turks and these results could be replicated when our entire data set was randomly divided in two different subsets (Supplemental Table II). Login to comment 304 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Val771Met A functional promoter polymorphism, C-14T, and a coding sequence polymorphism, V771M, in the ABCA1 gene appeared to affect HDL-C levels in Turks and these results could be replicated when our entire data set was randomly divided in two different subsets (Supplemental Table II). Login to comment 305 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met Two combinations of rare alleles-C-14T with R219K and V771M with I883M-were associated with high HDL-C in both males and females. Login to comment