ABCMdb

PMID: 17383594

Mantaring M, Rhyne J, Ho Hong S, Miller M
Genotypic variation in ATP-binding cassette transporter-1 (ABCA1) as contributors to the high and low high-density lipoprotein-cholesterol (HDL-C) phenotype.
Transl Res. 2007 Apr;149(4):205-10., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp Carrier frequencies of common ABCA1 polymorphisms, R219K, V771M, V825I, I883M, E1172D, and R1587K were also assessed. Login to comment 8 ABCA1 p.Arg219Lys ABCA1 p.Glu1172Asp ABCA1 p.Glu1172Asp Of the 6 common ABCA1 polymorphisms, very high HDL-C was associated with a higher genotype frequency for R219K (Ptrend ‫؍‬ 0.04) and higher genotype and allelic frequency for E1172D (Ptrend ‫؍‬ 0.0004, Ptrend ‫؍‬ 0.0002, respectively) compared with lower HDL-C. Login to comment 10 ABCA1 p.Glu1172Asp However, at least 1 ABCA1 polymorphism (eg, E1172D) may contribute to the high HDL-C phenotype. Login to comment 16 ABCA1 p.Arg219Lys doi:10.1016/j.trsl.2006.11.007 itating the egress of cholesterol and phospholipids from interstitial macrophages.2 To date, numerous functional mutations or single nucleotide polymorphisms in ABCA1 have been associated with low HDL-C.3,4 Structural mutations causing ABCA1 deficiency have been implicated in Tangler disease, a co-dominant disorder characterized by yellowish-orange engorgement of tonsils, hepatosplenomegaly, and very low HDL.5 A milder clinical phenotype, familial hypoalphalipoproteinemia (FHA), results from a single defective ABCA1 allele and occurs in the general population at the lower end of the HDL-C spectrum.6,7 Alternatively, at least 1 common ABCA1 polymorphism (ie, R219K) has been associated with a modified risk of CVD without significantly impacting HDL-C levels.8-11 In contrast, fewer data are available evaluating the extent to which variation in ABCA1 contributes to the high HDL-C phenotype,7,12 as previously characterized by reduced CVD risk.13 Therefore, this study evaluated subjects at the upper and lower tails of the HDL-C spectrum to assess the relative impact of novel mutations and common polymorphisms in ABCA1 on the HDL-C phenotype. Login to comment 17 ABCA1 p.Arg219Lys doi:10.1016/j.trsl.2006.11.007 itating the egress of cholesterol and phospholipids from interstitial macrophages.2 To date, numerous functional mutations or single nucleotide polymorphisms in ABCA1 have been associated with low HDL-C.3,4 Structural mutations causing ABCA1 deficiency have been implicated in Tangler disease, a co-dominant disorder characterized by yellowish-orange engorgement of tonsils, hepatosplenomegaly, and very low HDL.5 A milder clinical phenotype, familial hypoalphalipoproteinemia (FHA), results from a single defective ABCA1 allele and occurs in the general population at the lower end of the HDL-C spectrum.6,7 Alternatively, at least 1 common ABCA1 polymorphism (ie, R219K) has been associated with a modified risk of CVD without significantly impacting HDL-C levels.8-11 In contrast, fewer data are available evaluating the extent to which variation in ABCA1 contributes to the high HDL-C phenotype,7,12 as previously characterized by reduced CVD risk.13 Therefore, this study evaluated subjects at the upper and lower tails of the HDL-C spectrum to assess the relative impact of novel mutations and common polymorphisms in ABCA1 on the HDL-C phenotype. Login to comment 35 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp DNA was PCR amplified and digested using standard methods and the frequency of the 6 common polymorphisms (R219K, V771M, V825I, I883M, E1172D, and R1587K) in ABCA1, which was determined as described by Clee et al.8 Sequencing of PCR-amplified DNA. Login to comment 36 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp DNA was PCR amplified and digested using standard methods and the frequency of the 6 common polymorphisms (R219K, V771M, V825I, I883M, E1172D, and R1587K) in ABCA1, which was determined as described by Clee et al.8 Sequencing of PCR-amplified DNA. Login to comment 53 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp The prevalence of 6 common ABCA1 polymorphisms, R219K, V771M, V825I, I883M, E1172D, and R1587K was also evaluated. Login to comment 54 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp The prevalence of 6 common ABCA1 polymorphisms, R219K, V771M, V825I, I883M, E1172D, and R1587K was also evaluated. Login to comment 56 ABCA1 p.Arg219Lys Very high HDL-C was associated with a higher genotype frequency of R219K (RK and KK, 68.2%; Ptrend afd; 0.04) although allele frequency was not materially different. Login to comment 57 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met Very high HDL-C was associated with a higher genotype frequency of R219K (RK and KK, 68.2%; Ptrend ϭ 0.04) although allele frequency was not materially different. Login to comment 58 ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp Mild differences in allele frequency were also identified between the highest and lowest HDL-C groups for V771M (23% vs 10%; Ptrend ϭ 0.04) and I883M (36% vs 20%; Ptrend ϭ 0.05). Login to comment 59 ABCA1 p.Glu1172Asp ABCA1 p.Glu1172Asp The least common variant, E1172D, was most prevalent in subjects with HDL-C Ͼ 100 mg/dL (2.6 mmol/L), and significant differences in both genotype and allele frequency were found between the HDL-C groups (Ptrend ϭ 0.0004 and Ptrend ϭ 0.0002, respectively). Login to comment 60 ABCA1 p.Glu1172Asp Overall, carriers of E1172D were more likely to have higher HDL-C and apoAI in association with lower TG levels (Table IV). Login to comment 61 ABCA1 p.Glu868Lys ABCA1 p.Gly1421* ABCA1 p.Tyr2178His ABCA1 p.Arg1925Gln ABCA1 p.Gln1279Lys According to the third National Health and Nutrition Examination Survey (NHANES III) (n afd; 17,000), the prevalence of HDL-C b0e; 100 mg/dL (0.85%) is similar to that of very low HDL-C (eg, b0d;20 mg/dL).20 Complete screening of ABCA1 disclosed 5 mutations (E868K, Q1279K, G1421X, R1925Q, and Y2178H) that, to the authors` knowledge,3,4 have not been previously reported. Login to comment 62 ABCA1 p.Glu868Lys ABCA1 p.Gly1421* ABCA1 p.Tyr2178His ABCA1 p.Arg1925Gln ABCA1 p.Gln1279Lys According to the third National Health and Nutrition Examination Survey (NHANES III) (n ϭ 17,000), the prevalence of HDL-C Ͼ 100 mg/dL (0.85%) is similar to that of very low HDL-C (eg, Ͻ20 mg/dL).20 Complete screening of ABCA1 disclosed 5 mutations (E868K, Q1279K, G1421X, R1925Q, and Y2178H) that, to the authors` knowledge,3,4 have not been previously reported. Login to comment 68 ABCA1 p.Glu868Lys ABCA1 p.Glu868Lys ABCA1 p.Gly1421* ABCA1 p.Gly1421* ABCA1 p.Tyr2178His ABCA1 p.Tyr2178His ABCA1 p.Arg1925Gln ABCA1 p.Arg1925Gln ABCA1 p.Gln1279Lys ABCA1 p.Gln1279Lys Novel ABCA1 mutations and associated clinical characteristics Mutation Gender YOB HDL-C† CVD Risk factors E868K Male* 1936 37 ϩ Diabetes Q1279K Male 1949 37 ϩ MetS G1421X Female 1942 32 ϩ Diabetes/Smoker R1925Q Male* 1931 23 ϩ MetS Y2178H Male 1955 36 ϩ Smoker Abbreviations: MetS, metabolic syndrome; YOB, year of birth. Login to comment 72 ABCA1 p.Glu1172Asp Although evaluation of 22 biologically unrelated subjects with extremely high HDL-C (mean, 139 mg/dL [6.2 mmol/L]) disclosed no mutations in ABCA1, the polymorphism E1172D was more commonly observed (allele frequency, 18%) compared with lower HDL groups (allele frequency, 0-0.03%). Login to comment 74 ABCA1 p.Glu1172Asp ABCA1 p.Glu1172Asp The authors are aware of only 1 other study that evaluated E1172D in subjects with high HDL-C and found significantly higher levels in female carriers compared with wild-type.7 Kinetic studies may resolve differences between E1172D and wild-type on HDL-apoA-I fractional catabolic rates. Login to comment 75 ABCA1 p.Glu1172Asp ABCA1 p.Glu1172Asp ABCA1 p.Glu1172Asp Previously, Clee et al had also observed that E1172D was found exclusively in carriers of R1587K.8 However, an individual with E1172D in the absence of R1587K (ie, R/R wild-type) was identified, confirmed by direct sequencing, suggesting that E1172D is not in complete linkage disequilibrium with R1587K. Login to comment 76 ABCA1 p.Arg219Lys Finally, although this small sample size did not permit assessment of CVD risk for the R219K variant, a higher prevalence of the K allele was found among subjects with very high HDL-C, suggesting that carriers Table III. Login to comment 77 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp ABCA1 p.Glu1172Asp Genotype and allele frequencies for 6 common ABCA1 polymorphisms in subgroups with HDL-C defined as very high (n ϭ 22), high (n ϭ 34), average (n ϭ 36), or low (n ϭ 32) R219K Genotype frequencies P value Allele frequencies P valueR/R R/K K/K R K Very high 31.8% 45.5% 22.7% 0.04 0.55 0.45 0.20 High 45.7% 51.4% 2.9% 0.71 0.29 Average 43.2% 56.8% 0.0% 0.72 0.28 Low 50.0% 40.0% 10.0% 0.70 0.30 V771M V/V V/M M/M V M Very high 59.0% 36.0% 4.5% 0.11 0.77 0.23 0.04 High 85.7% 14.3% 0.0% 0.93 0.07 Average 86.1% 13.9% 0.0% 0.93 0.07 Low 80.0% 20.0% 0.0% 0.90 0.10 V825I V/V V/I I/I V I Very high 77.3% 22.7% 0.0% 0.58 0.89 0.11 0.62 High 88.6% 11.4% 0.0% 0.94 0.06 Average 88.9% 11.1% 0.0% 0.94 0.06 Low 82.8% 17.2% 0.0% 0.92 0.08 I883M I/I I/M M/M I M Very high 40.9% 45.5% 13.6% 0.29 0.64 0.36 0.05 High 60.0% 34.3% 5.7% 0.78 0.22 Average 73.0% 24.3% 2.7% 0.85 0.15 Low 66.7% 26.7% 6.7% 0.80 0.20 E1172D E/E E/D D/D E D Very high 68.2% 31.8% 0.0% 0.0004 0.82 0.18 0.0002 High 94.3% 5.7% 0.0% 0.97 0.03 Average 94.6% 5.4% 0.0% 0.97 0.03 Low 100.00% 0.0% 0.0% 1.00 0.00 R1587K R/R R/K K/K R K Very high 31.8% 50.0% 18.2% 0.16 0.57 0.43 0.07 High 65.6% 25.0% 9.4% 0.78 0.22 Average 55.6% 41.7% 2.8% 0.76 0.24 Low 51.9% 33.3% 14.8% 0.69 0.31 of R219K may have a basis for reduced CVD risk as previously suggested.8-11,24 CONCLUSION The data extend previous findings that novel mutations in ABCA1 are associated with the low rather than the high HDL-C (FHA) phenotype. Login to comment 78 ABCA1 p.Glu1172Asp However, because the E1172D polymorphism may be associated with high HDL-C, further study is warranted to assess its potential clinical significance vis- à-vis CVD risk. Login to comment