ABCMdb

PMID: 20427018

Flores-Dorantes T, Arellano-Campos O, Posadas-Sanchez R, Villarreal-Molina T, Medina-Urrutia A, Romero-Hidalgo S, Yescas-Gomez P, Perez-Mendez O, Jorge-Galarza E, Tusie-Luna T, Villalobos-Comparan M, Jacobo-Albavera L, Villamil-Ramirez H, Lopez-Contreras BE, Aguilar-Salinas CA, Posadas-Romero C, Canizales-Quinteros S
Association of R230C ABCA1 gene variant with low HDL-C levels and abnormal HDL subclass distribution in Mexican school-aged children.
Clin Chim Acta. 2010 Sep 6;411(17-18):1214-7. Epub 2010 Apr 26., [PubMed]

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0 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys Association of R230C ABCA1 gene variant with low HDL-C levels and abnormal HDL subclass distribution in Mexican school-aged children Teresa Flores-Dorantes a , Olimpia Arellano-Campos b , Rosalinda Posadas-Sánchez c , Teresa Villarreal-Molina a , Aida Medina-Urrutia c , Sandra Romero-Hidalgo d , Petra Yescas-Gómez e , Oscar Pérez-Méndez f , Esteban Jorge-Galarza c , Teresa Tusié-Luna a , Marisela Villalobos-Comparán a , Leonor Jacobo-Albavera a , Hugo Villamil-Ramírez a , Blanca E. López-Contreras a , Carlos A. Aguilar-Salinas b , Carlos Posadas-Romero c , Samuel Canizales-Quinteros a, ⁎ a Unit of Molecular Biology and Genomic Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico b Department of Endocrinology and Metabolism, INCMNSZ, Mexico City, Mexico c Department of Endocrinology, Instituto Nacional de Cardiología Ignacio Chávez (INCICh), Mexico City, Mexico d Department of Computational Genomics, Instituto Nacional de Medicina Genómica, Mexico City, Mexico e Deparment of Neurogenetics, Instituto Nacional de Neurología, Mexico City, Mexico f Department of Molecular Biology, INCICh, Mexico City, Mexico a b s t r a c ta r t i c l e i n f o Article history: Received 26 October 2009 Received in revised form 20 April 2010 Accepted 21 April 2010 Available online 26 April 2010 Keywords: ABCA1 R230C variant HDL-cholesterol HDL subclasses Mexican children Background: The effect of ABCA1 genetic variation on HDL-C levels has been widely documented, although studies in children are scarce. Login to comment 1 ABCA1 p.Arg230Cys We recently found a frequent non-synonymous ABCA1 variant (R230C) exclusive to populations with Native American ancestry, associated with low HDL-C levels and other metabolic traits in adults. Login to comment 2 ABCA1 p.Arg230Cys Methods: We genotyped R230C variant in 1253 healthy unrelated Mexican school-aged children aged 6-15 years (595 boys and 658 girls) to seek associations with HDL-C levels and other metabolic traits. Login to comment 5 ABCA1 p.Arg230Cys HDL size was smaller in R230C heterozygotes as compared to R230R homozygotes (Pb0.05). Login to comment 6 ABCA1 p.Arg230Cys Moreover, the proportion of HDL2b was lower, while the proportion of HDL3a and HDL3b particles was higher in R230C heterozygous and/or C230C homozygous individuals as compared to R230R homozygotes (Pb0.05). Login to comment 7 ABCA1 p.Arg230Cys Conclusions: Our data suggest that the R230C ABCA1 gene variant plays an important role in HDL-C level regulation and HDL subclass distribution in healthy Mexican school-aged children. Login to comment 19 ABCA1 p.Arg230Cys We recently found a frequent non-synonymous ABCA1 variant (R230C, rs9282541) exclusive to populations with Native American ancestry, associated with low HDL-C levels, and Clinica Chimica Acta 411 (2010) 1214-1217 ⁎ Corresponding author. Login to comment 25 ABCA1 p.Arg230Cys We thus analyzed the possible effect of the R230C ABCA1 gene variant on HDL-C levels, HDL subclasses and other metabolic traits in healthy Mexican school-aged children. Login to comment 48 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys HDL subclass distribution analysis HDL subclass distribution was analyzed as described by Medina-Urrutia et al. [26] and compared in different R230C genotypes in a subgroup of 81 school-aged children matched by age, gender and BMI (32 R230R homozygotes, 32 R230C heterozygotes and the 17 available C230C homozygotes). Login to comment 56 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys R230C genotyping The R230C variant (rs9282541) was genotyped using TaqMan assays (ABI Prism 7900HT Sequence Detection System; Applied Biosystems, Foster City, CA). Login to comment 62 ABCA1 p.Arg230Cys Differences in anthropometric and biochemical parameters according to R230C genotype were analyzed by multiple linear regression analyses, and logistic regression analysis was used to test for association with hypoalphalipoproteinemia, adjusting for age, sex, BMI and Tanner score when appropriate (SPSS ver10.0, Chicago, IL). Login to comment 70 ABCA1 p.Arg230Cys Moreover, C230C and R230C genotypes were significantly more frequent in individuals with hypoalphalipoproteinemia (35 and 24.9%, respectively) than in those with HDL-C levels N35 mg/dl (12.6%, OR 2.19, 95% CI 1.60-2.99, P=9.4×10-7 ). Login to comment 71 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys Analysis according to gender showed that the effect of R230C on HDL-C levels and hypoalphalipoproteinemia was highly significant in both boys and girls. Login to comment 72 ABCA1 p.Arg230Cys Analysis according to gender showed that the effect of R230C on HDL-C levels and hypoalphalipoproteinemia was highly significant in both boys and girls. Login to comment 75 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys The R230C allele was associated with significantly lower HDL-C levels in pubertal children (45.6±10.9 vs. 41.3±10.9 mg/dl for R230R and R230C/C230C genotypes respectively; P=3.7×10-6 ). Login to comment 76 ABCA1 p.Arg230Cys The same tendency was observed in prepubertal children with marginal significance (48.3±10.6 vs. 45.8±10.4 mg/dl for R230R and R230C/C230C genotypes respectively; P=0.077). Login to comment 77 ABCA1 p.Arg230Cys HDL subclass distribution differed according to R230C genotypes in 81 school-aged children matched by age, gender and BMI (Table 3). Login to comment 78 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys The R230C allele was associated with significantly lower HDL-C levels in pubertal children (45.6&#b1;10.9 vs. 41.3&#b1;10.9 mg/dl for R230R and R230C/C230C genotypes respectively; P=3.7&#d7;10-6 ). Login to comment 79 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys HDL-C levels were significantly lower in individuals with heterozygous R230C and homozygous C230C genotypes as compared to those with the R230R homozygous genotype (Pb0.05 for both comparisons). Login to comment 80 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys Moreover, significant differences were observed between the proportion of HDL2b, HDL3a and HDL3b particles and the R230C variant (P=0.002, 0.004 and 0.029, respectively). Login to comment 81 ABCA1 p.Arg230Cys Overall, the proportion of large HDL particles decreased while the proportion of small HDL particles increased in individuals with R230C heterozygous and C230C homozygous genotypes as compared to those with the R230R homozygous genotype (Table 3). Login to comment 82 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys In addition, the R230C variant was associated with the mean HDL particle size (P=0.014). Login to comment 83 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys In agreement with the shift toward small HDL particles, mean HDL particle size was significantly smaller in R230C heterozygotes as compared to R230R homozygotes (Pb0.05), and although homozygous C230C subjects showed smaller HDL particles, the difference with R230R homozygotes did not reach statistical significance. Login to comment 84 ABCA1 p.Arg230Cys Overall, the proportion of large HDL particles decreased while the proportion of small HDL particles increased in individuals with R230C heterozygous and C230C homozygous genotypes as compared to those with the R230R homozygous genotype (Table 3). Login to comment 85 ABCA1 p.Arg230Cys In addition, the R230C variant was associated with the mean HDL particle size (P=0.014). Login to comment 86 ABCA1 p.Arg230Cys In agreement with the shift toward small HDL particles, mean HDL particle size was significantly smaller in R230C heterozygotes as compared to R230R homozygotes (Pb0.05), and although homozygous C230C subjects showed smaller HDL particles, the difference with R230R homozygotes did not reach statistical significance. Login to comment 93 ABCA1 p.Arg230Cys The only currently identified functional gene variant exclusive and common to Native American populations throughout the Americas is R230C/ABCA1 [35]. Login to comment 94 ABCA1 p.Arg230Cys The association of R230C with low HDL-C levels and hypoalphalipoproteinemia was highly significant while its association with BMI was marginal,inagreementwithpreviousobservationsinMexicanadults[21]. Login to comment 95 ABCA1 p.Arg230Cys However, although a differential effect of some ABCA1 gene polymorphisms according to gender has been previously reported in adults [36], the effect of R230C was independent of gender in Mexican school-aged children. Login to comment 96 ABCA1 p.Arg230Cys The only currently identified functional gene variant exclusive and common to Native American populations throughout the Americas is R230C/ABCA1 [35]. Login to comment 97 ABCA1 p.Arg230Cys The association of R230C with low HDL-C levels and hypoalphalipoproteinemia was highly significant while its association with BMI was marginal,inagreementwithpreviousobservationsinMexicanadults[21]. Login to comment 98 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys R230C was associated with lower HDL-C levels in both pubertal and prepubertal children, although only with marginal significance in the latter group probably because of the reduced sample size. Login to comment 99 ABCA1 p.Arg230Cys Thus, the effect of R230C on HDL-C levels is observed since childhood both in boys and girls. Login to comment 100 ABCA1 p.Arg230Cys R230C affected HDL particle size distribution independently of age, gender and BMI, as the proportion of large HDL particles decreased and the proportion of small HDL particles increased in C230 carriers. Login to comment 101 ABCA1 p.Arg230Cys R230C was associated with lower HDL-C levels in both pubertal and prepubertal children, although only with marginal significance in the latter group probably because of the reduced sample size. Login to comment 102 ABCA1 p.Arg230Cys Thus, the effect of R230C on HDL-C levels is observed since childhood both in boys and girls. Login to comment 103 ABCA1 p.Arg230Cys R230C affected HDL particle size distribution independently of age, gender and BMI, as the proportion of large HDL particles decreased and the proportion of small HDL particles increased in C230 carriers. Login to comment 104 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys Although Table 2 Clinical and biochemical parameters according to R230C ABCA1 genotypes in Mexican school-aged children, and stratified by gender. Characteristic R230R R230C C230C Pa Total subjects (%) n=1012 (80.8) n=221 (17.6) n=20 (1.6) Age (years) 11.5±2.4 11.2±2.4 11.6±2.0 NS BMI (kg/m2 ) 21.4±4.4 21.8±4.9 22.5±4.5 0.049 BMI z-score 0.88±0.95 1.02 ± 0.88 1.10±0.98 0.032 FM (%) (n=596) 30.6±10.8 32.1±11.7 35.9±12.9 0.039 TC (mg/dl) 160.5±31.1 157.6±28.1 149.1±36.5 0.019 TG (mg/dl) 114.9±77.6 108.6±52.9 95.1±36.7 NS HDL-C (mg/dl) 46.4±10.9 42.9±11.0 38.2±9.4 2.9×10-8 TC/HDL-C ratio 3.62±1.05 3.87±1.08 4.19±1.12 0.001 HA (%) 12.6 24.9 35.0 9.4×10-7b Boys (%) n=471 (79.2) n=112 (18.8) n=12 (2.0) Age (years) 11.5±2.4 11.2±2.3 11.6±2.3 NS BMI (kg/m2 ) 21.3±4.7 22.1±5.6 21.7±3.8 NS BMI z-score 0.87±1.02 1.05±0.96 1.0±0.98 NS FM (%) (n=287) 29.1±11.9 31.9±13.7 35.2±14.2 0.024 TC (mg/dl) 158.5±30.5 157.9±30.2 150.1±3.8 NS TG (mg/dl) 111.8±85.0 111.5±58.4 92.8±42.2 NS HDL-C (mg/dl) 46.1±11.0 42.8±10.7 38.3±10.9 6.9×10-5 TC/HDL-C ratio 3.61±1.07 3.87±1.09 4.33±1.26 0.007 HA (%) 12.5 22.3 33.3 0.001b Girls (%) n=541 (82.2) n=109 (16.6) n=8 (1.2) Age (years) 11.6±2.4 11.3±2.4 11.7±1.5 NS BMI (kg/m2 ) 21.6±4.4 21.7±4.0 24.5±5.7 NS BMI z-score 0.89±0.88 0.99±0.78 1.30±1.04 NS FM (%) (n=309) 32.0±9.6 32.3±9.4 37.2±11.6 NS TC (mg/dl) 162.2±31.6 157.3±25.9 146.8±25.3 0.020 TG (mg/dl) 117.9±70.7 105.8±47.0 100.5±20.6 NS HDL-C (mg/dl) 46.6±10.8 43.1±11.5 37.8±4.7 1.1×10-4 TC/HDL-C ratio 3.64±1.03 3.87±1.07 3.93±0.816 NS HA (%) 12.6 27.5 37.5 1.8×10-4b Data are the means±SD or n (%). Login to comment 107 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys Table 3 HDL size and subclass distribution according to R230C ABCA1 genotype groups. Login to comment 108 ABCA1 p.Arg230Cys R230R n=32 R230C n=32 C230C n=17 P-value Age (years) 12.2±1.5 12.2±1.6 11.8±2.0 NS BMI (kg/m²) 23.8±5.5 24.2±6.3 23.0±4.6 NS BMI z-score 1.17±1.01 1.18±0.98 1.15±1.00 NS HDL-C (mg/dl) 48.6±11.0 42.2±11.8 39.4±9.2 0.011a,b HDL2b (%) 13.0±3.6 10.9±2.8 9.8±2.8 0.002a,b HDL2a (%) 21.1±3.5 19.7±3.3 19.9±3.2 NS HDL3a (%) 27.2±1.9 28.3±2.0 29.2±2.1 0.004b HDL3b (%) 23.4±2.6 24.8±2.5 25.0±2.0 0.029 HDL3c (%) 15.2±3.7 16.3±3.8 16.2±4.8 NS HDL size (nm) 8.77±0.17 8.65±0.16 8.64±0.16 0.014a Data are the means±SD or n (%). Login to comment 110 ABCA1 p.Arg230Cys Table 3 HDL size and subclass distribution according to R230C ABCA1 genotype groups. Login to comment 111 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys a Pb0.05 after Scheffé post hoc test comparing R230R vs. R230C. Login to comment 114 ABCA1 p.Arg230Cys a Pb0.05 after Scheff&#e9; post hoc test comparing R230R vs. R230C. Login to comment 115 ABCA1 p.Arg230Cys Although the association of obesity and insulin resistance with smaller HDL particles has been attributed to increased fractional clearance of HDL secondary to depletion of its cholesterol [44,45], in the present study the association of R230C with smaller HDL particles was independent of BMI. Login to comment 118 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys In conclusion, our data suggest that the R230C ABCA1 gene variant plays an important role in HDL-C level regulation and HDL subclass distribution in healthy Mexican school-aged children. Login to comment 121 ABCA1 p.Arg230Cys In conclusion, our data suggest that the R230C ABCA1 gene variant plays an important role in HDL-C level regulation and HDL subclass distribution in healthy Mexican school-aged children. Login to comment