ABCMdb

PMID: 20418488

Acuna-Alonzo V, Flores-Dorantes T, Kruit JK, Villarreal-Molina T, Arellano-Campos O, Hunemeier T, Moreno-Estrada A, Ortiz-Lopez MG, Villamil-Ramirez H, Leon-Mimila P, Villalobos-Comparan M, Jacobo-Albavera L, Ramirez-Jimenez S, Sikora M, Zhang LH, Pape TD, Granados-Silvestre Mde A, Montufar-Robles I, Tito-Alvarez AM, Zurita-Salinas C, Bustos-Arriaga J, Cedillo-Barron L, Gomez-Trejo C, Barquera-Lozano R, Vieira-Filho JP, Granados J, Romero-Hidalgo S, Huertas-Vazquez A, Gonzalez-Martin A, Gorostiza A, Bonatto
A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.
Hum Mol Genet. 2010 Jul 15;19(14):2877-85. Epub 2010 Apr 23., [PubMed]

Sentences

No. Mutations Sentence Comment

6 ABCA1 p.Arg230Cys A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. Login to comment 9 ABCA1 p.Arg230Cys A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. Login to comment 15 ABCA1 p.Arg230Cys We recently found a frequent non-synonymous variant (R230C, rs9282541) within the ATP-binding cassette transporter A1 gene (ABCA1) associated with low high-density lipoprotein cholesterol (HDL-C) levels (the most common dyslipidemia in populations with Native American ancestry), obesity and T2D in Mexican Mestizos (4,5). Login to comment 17 ABCA1 p.Arg230Cys The R230C variant was initially described in the Oji-Cree population (8). Login to comment 18 ABCA1 p.Arg230Cys We recently found a frequent non-synonymous variant (R230C, rs9282541) within the ATP-binding cassette transporter A1 gene (ABCA1) associated with low high-density lipoprotein cholesterol (HDL-C) levels (the most common dyslipidemia in populations with Native American ancestry), obesity and T2D in Mexican Mestizos (4,5). Login to comment 20 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys Because it was previously suggested that R230C may have conferred selective advantage as a thrifty gene and/or resistance against certain infectious diseases (4), we performed a more thorough analysis seeking evidence of positive selection. Login to comment 23 ABCA1 p.Arg230Cys Because it was previously suggested that R230C may have conferred selective advantage as a thrifty gene and/or resistance against certain infectious diseases (4), we performed a more thorough analysis seeking evidence of positive selection. Login to comment 28 ABCA1 p.Arg219Lys The phylogenetic reconstruction uncovered two major lineages (haplogroups A and B) defined by the non-synonymous polymorphism R219K within the ABCA1 gene. Login to comment 31 ABCA1 p.Arg219Lys The phylogenetic reconstruction uncovered two major lineages (haplogroups A and B) defined by the nonsynonymous polymorphism R219K within the ABCA1 gene. Login to comment 34 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys Furthermore, in Native Americans from the Human Genome Diversity Panel (HGDP) (R230C genotypes not available), the ABCA1 5' region ( 75 kb upstream R230C) was clearly enriched for outliers of the integrated haplotype score (iHS) statistic genome-wide distribution (iHS . Login to comment 37 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys Association of R230C with HDL-C levels and other metabolic traits Overall, the prevalence of hypoalphalipoproteinemia (HA) was the most common dyslipidemia (65% in Mexican and South American natives; Supplementary Material, Table S4). Login to comment 38 ABCA1 p.Arg230Cys Table 1 shows the effect of R230C on HDL-C and total cholesterol levels and body mass index (BMI). Login to comment 39 ABCA1 p.Arg230Cys The R230C/C230C genotypes were significantly associated with low HDL-C levels in Pimas (P ¼ 6.4 × 1025 ) and in the combined analysis of eight Mexican native groups (P ¼ 5.3 × 1028 ). Login to comment 40 ABCA1 p.Arg230Cys Association of R230C with HDL-C levels and other metabolic traits Overall, the prevalence of hypoalphalipoproteinemia (HA) was the most common dyslipidemia (65% in Mexican and South American natives; Supplementary Material, Table S4). Login to comment 41 ABCA1 p.Arg230Cys Table 1 shows the effect of R230C on HDL-C and total cholesterol levels and body mass index (BMI). Login to comment 42 ABCA1 p.Arg230Cys The R230C/C230C genotypes were significantly associated with low HDL-C levels in Pimas (P &#bc; 6.4 &#d7; 1025 ) and in the combined analysis of eight Mexican native groups (P &#bc; 5.3 &#d7; 1028 ). Login to comment 49 ABCA1 p.Arg219Lys The phylogenetic reconstruction uncovered two major lineages (haplogroups A and B) defined by the non-synonymous polymorphism R219K. Login to comment 50 ABCA1 p.Arg230Cys The R230C variant occurred on haplogroup B characterized by the ancestral R219 allele, which is frequent in Europe, Asia and America but infrequent in African populations. Login to comment 52 ABCA1 p.Arg219Lys The phylogenetic reconstruction uncovered two major lineages (haplogroups A and B) defined by the non-synonymous polymorphism R219K. Login to comment 53 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys EHH and REHH of ABCA1/R230C and 23 additional SNPs × physical distance in Native American individuals. Login to comment 56 ABCA1 p.Arg230Cys EHH and REHH of ABCA1/R230C and 23 additional SNPs &#d7; physical distance in Native American individuals. Login to comment 58 ABCA1 p.Arg230Cys Interestingly, differences in the effect of R230C on lipid profiles were observed in some Native American populations. Login to comment 59 ABCA1 p.Arg230Cys R230C was strongly associated with low total cholesterol and triglyceride levels in Pimas (P ¼ 1.8 × 1027 and P ¼ 7.0 × 1024 , respectively) and Mayans (P ¼ 0.004 and 0.010, respectively). Login to comment 61 ABCA1 p.Arg230Cys Interestingly, differences in the effect of R230C on lipid profiles were observed in some Native American populations. Login to comment 62 ABCA1 p.Arg230Cys R230C was strongly associated with low total cholesterol and triglyceride levels in Pimas (P &#bc; 1.8 &#d7; 1027 and P &#bc; 7.0 &#d7; 1024 , respectively) and Mayans (P &#bc; 0.004 and 0.010, respectively). Login to comment 65 ABCA1 p.Arg230Cys Association of R230C with lipid levels and BMI in Native American populations Native American population (n) HDL-C levels Total cholesterol BMI Effect (SE) P-value Effect (SE) P-value Effect (SE) P-value North America USA Pima (2563)a 20.075 (0.019) 6.4 × 1025 20.071 (0.014) 1.8 × 1027 0.008 (0.015) 0.586 Mexico Yaquis (45) - - - - 0.044 (0.018) 0.012 Teenek (67) 20.051 (0.026) 0.057 20.010 (0.024) 0.671 0.001 (0.016) 0.978 Coras (123) 20.033 (0.014) 0.021 20.006 (0.013) 0.681 0.032 (0.011) 0.006 Purepechas (15) 20.040 (0.074) 0.603 20.048 (0.046) 0.333 0.034 (0.019) 0.097 Mazahuas (83) 20.039 (0.036) 0.281 20.031 (0.041) 0.444 0.006 (0.019) 0.758 Nahuas (267) 20.040 (0.014) 0.014 20.014 (0.020) 0.470 20.004 (0.008) 0.617 Totonacas (113) 20.028 (0.021) 0.180 20.031 (0.015) 0.042 0.022 (0.013) 0.085 Zapotecs (106) 20.047 (0.022) 0.038 0.007 (0.019) 0.723 0.007 (0.013) 0.605 Mayans (110) 20.040 (0.017) 0.023 20.043 (0.015) 0.004 20.007 (0.013) 0.554 Mexican natives combined 20.038 (0.007) 5.3 × 1028 20.019 (0.007) 0.027 0.010 (0.004) 0.012 South America Kichwas (79) 20.043 (0.030) 0.153 20.005 (0.020) 0.791 0.024 (0.012) 0.050 Parkateje´ (78) 20.029 (0.026) 0.270 20.002 (0.030) 0.945 0.046 (0.012) 0.0003 All Native Americans combined 20.042 (0.006) 1.77 × 10211 20.021 (0.006) 7.15 × 1025 0.011 (0.003) 0.0001 Effect values are presented as effect size per C230 allele copy, standard error (SE). Login to comment 68 ABCA1 p.Arg230Cys Association of R230C with lipid levels and BMI in Native American populations Native American population (n) HDL-C levels Total cholesterol BMI Effect (SE) P-value Effect (SE) P-value Effect (SE) P-value North America USA Pima (2563)a 20.075 (0.019) 6.4 &#d7; 1025 20.071 (0.014) 1.8 &#d7; 1027 0.008 (0.015) 0.586 Mexico Yaquis (45) - - - - 0.044 (0.018) 0.012 Teenek (67) 20.051 (0.026) 0.057 20.010 (0.024) 0.671 0.001 (0.016) 0.978 Coras (123) 20.033 (0.014) 0.021 20.006 (0.013) 0.681 0.032 (0.011) 0.006 Purepechas (15) 20.040 (0.074) 0.603 20.048 (0.046) 0.333 0.034 (0.019) 0.097 Mazahuas (83) 20.039 (0.036) 0.281 20.031 (0.041) 0.444 0.006 (0.019) 0.758 Nahuas (267) 20.040 (0.014) 0.014 20.014 (0.020) 0.470 20.004 (0.008) 0.617 Totonacas (113) 20.028 (0.021) 0.180 20.031 (0.015) 0.042 0.022 (0.013) 0.085 Zapotecs (106) 20.047 (0.022) 0.038 0.007 (0.019) 0.723 0.007 (0.013) 0.605 Mayans (110) 20.040 (0.017) 0.023 20.043 (0.015) 0.004 20.007 (0.013) 0.554 Mexican natives combined 20.038 (0.007) 5.3 &#d7; 1028 20.019 (0.007) 0.027 0.010 (0.004) 0.012 South America Kichwas (79) 20.043 (0.030) 0.153 20.005 (0.020) 0.791 0.024 (0.012) 0.050 Parkateje &#b4; (78) 20.029 (0.026) 0.270 20.002 (0.030) 0.945 0.046 (0.012) 0.0003 All Native Americans combined 20.042 (0.006) 1.77 &#d7; 10211 20.021 (0.006) 7.15 &#d7; 1025 0.011 (0.003) 0.0001 Effect values are presented as effect size per C230 allele copy, standard error (SE). Login to comment 71 ABCA1 p.Arg230Cys Sequencing and in vitro functional analysis To rule out the presence of another possible causal variant in LD with C230, all 50 exons and the promoter region of ABCA1 were sequenced in a limited number of individuals (2 of each genotype); however, no promoter or coding variant in LD with R230C was found. Login to comment 73 ABCA1 p.Arg230Cys Sequencing and in vitro functional analysis To rule out the presence of another possible causal variant in LD with C230, all 50 exons and the promoter region of ABCA1 were sequenced in a limited number of individuals (2 of each genotype); however, no promoter or coding variant in LD with R230C was found. Login to comment 75 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys DISCUSSION R230C, a private allele to the Americas The R230C allele first identified in Oji-Crees and Mexican Mestizos was found in most Amerindian groups throughout the Americas, but not in any ethnic group from other continents (4,8). Login to comment 77 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys DISCUSSION R230C, a private allele to the Americas The R230C allele first identified in Oji-Crees and Mexican Mestizos was found in most Amerindian groups throughout the Americas, but not in any ethnic group from other continents (4,8). Login to comment 81 ABCA1 p.Arg230Cys It is noteworthy that D9S1120 and R230C (ABCA1) are both located on chromosome 9q, although separated by a 19 Mb distance. Login to comment 83 ABCA1 p.Arg230Cys It is noteworthy that D9S1120 and R230C (ABCA1) are both located on chromosome 9q, although separated by a 19 Mb distance. Login to comment 87 ABCA1 p.Arg230Cys Evidence suggesting R230C underwent positive selection Understanding the impact of natural selection acting on particular genes in human populations can provide insights into the genetic etiology of human disease. Login to comment 89 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys The results of the REHH and iHS analyses for the ABCA1 gene region in Native Americans are not compatible with a simple neutral evolutionary model, but are consistent with the hypothesis that the R230C variant resides on a haplotype which is the target of an ongoing directional selective sweep. Login to comment 90 ABCA1 p.Arg230Cys It must be acknowledged, however, that with the currently available genotyping data, it is not possible to define whether the R230C haplotype is also responsible for the signal resulting from the iHS test. Login to comment 91 ABCA1 p.Arg230Cys The results of the REHH and iHS analyses for the ABCA1 gene region in Native Americans are not compatible with a simple neutral evolutionary model, but are consistent with the hypothesis that the R230C variant resides on a haplotype which is the target of an ongoing directional selective sweep. Login to comment 92 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys In the context of Neel`s hypothesis (24), R230C carriers could have had a selective advantage. Login to comment 94 ABCA1 p.Arg230Cys In the context of Neel`s hypothesis (24), R230C carriers could have had a selective advantage. Login to comment 95 ABCA1 p.Arg230Cys However, under current westernized lifestyle changes, this allele may have become a major susceptibility allele for low HDL-C levels and other metabolic traits, which is consistent with the association of the R230C variant with higher BMI in Native American populations, and with obesity, T2D and metabolic syndrome in Mexican Mestizos (4,5). Login to comment 97 ABCA1 p.Arg230Cys However, under current westernized lifestyle changes, this allele may have become a major susceptibility allele for low HDL-C levels and other metabolic traits, which is consistent with the association of the R230C variant with higher BMI in Native American populations, and with obesity, T2D and metabolic syndrome in Mexican Mestizos (4,5). Login to comment 98 ABCA1 p.Arg230Cys Functional characterization of the ABCA1/R230C variant by lipid efflux assay. Login to comment 99 ABCA1 p.Met1091Thr ABCA1 p.Arg230Cys (A) Polyclonal stable cell lines expressing the ABCA1 wild-type (WT), variant R230C and mutant M1091T (known defective in lipid efflux) were generated, and efflux activity for cholesterol was performed as described in Materials and Methods. Login to comment 100 ABCA1 p.Arg230Cys Functional characterization of the ABCA1/R230C variant by lipid efflux assay. Login to comment 101 ABCA1 p.Met1091Thr ABCA1 p.Arg230Cys (A) Polyclonal stable cell lines expressing the ABCA1 wild-type (WT), variant R230C and mutant M1091T (known defective in lipid efflux) were generated, and efflux activity for cholesterol was performed as described in Materials and Methods. Login to comment 103 ABCA1 p.Met1091Thr ABCA1 p.Arg230Cys (B) The expression of WT, variant R230C and mutant M1091T ABCA1 protein in Flp-In cells was assessed by western immunoblotting. Login to comment 105 ABCA1 p.Met1091Thr ABCA1 p.Arg230Cys (B) The expression of WT, variant R230C and mutant M1091T ABCA1 protein in Flp-In cells was assessed by western immunoblotting. Login to comment 108 ABCA1 p.Arg230Cys Association of R230C with HDL-C levels and other metabolic traits Overall, the prevalence of low HDL-C levels was not only higher in Native Americans than in European, Asian and African individuals (3), but also the most common dyslipidemia (65% in Mexican and South American natives). Login to comment 110 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys R230C/C230C genotypes were strongly associated with low HDL-C levels in Native American rural populations, Pimas and urban Mexican Mestizos (4,9). Login to comment 112 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys This is consistent with both in silico (PANTHER subPSEC score 24.27) and in vitro evidence confirming that the R230C variant is functional (27% decrease in cholesterol efflux) (22). Login to comment 114 ABCA1 p.Arg230Cys This is consistent with both in silico (PANTHER subPSEC score 24.27) and in vitro evidence confirming that the R230C variant is functional (27% decrease in cholesterol efflux) (22). Login to comment 117 ABCA1 p.Arg230Cys Moreover, a gender effect was observed, as the association of R230C with higher BMI was more significant in males. Login to comment 119 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys Further studies are required to confirm the role of R230C in these metabolic and other fat storage-related traits such as non-alcoholic fatty liver disease, which is highly prevalent in Hispanic populations (34,35). Login to comment 121 ABCA1 p.Arg230Cys Further studies are required to confirm the role of R230C in these metabolic and other fat storage-related traits such as non-alcoholic fatty liver disease, which is highly prevalent in Hispanic populations (34,35). Login to comment 122 ABCA1 p.Arg230Cys Interestingly, the R230C was only marginally associated with T2D in Pimas (P ¼ 0.06) despite the large sample size and the previous finding that HDL-C concentrations in non-diabetic Pima Indian women were negatively associated with the development of T2D (36). Login to comment 124 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys The highly significant association of R230C with reduced total cholesterol and triglyceride serum levels observed in Pimas may be one of the factors explaining this marginal association. Login to comment 125 ABCA1 p.Arg230Cys The role of R230C as a risk allele for T2D in Mexican native groups and its interaction with environmental factors requires further analysis. Login to comment 126 ABCA1 p.Arg230Cys The highly significant association of R230C with reduced total cholesterol and triglyceride serum levels observed in Pimas may be one of the factors explaining this marginal association. Login to comment 127 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys We present several lines of evidence in favor of positive selection for the R230C allele possibly contributing to the adaptive evolution of Native American populations and providing insight into the genetic etiology of currently prevalent metabolic disease. Login to comment 129 ABCA1 p.Arg230Cys We present several lines of evidence in favor of positive selection for the R230C allele possibly contributing to the adaptive evolution of Native American populations and providing insight into the genetic etiology of currently prevalent metabolic disease. Login to comment 140 ABCA1 p.Arg230Cys The 50 exons and proximal promoter region of the 2882 ABCA1 gene were amplified in samples from six individuals (two R230R, two R230C and two C230C) as described previously (8). Login to comment 142 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys SNP genotyping The R230C variant and 23 SNPs spanning an 800 kb region were genotyped using TaqMan assays (ABI Prism 7900HT Sequence Detection System; Applied Biosystems). Login to comment 144 ABCA1 p.Arg230Cys SNP genotyping The R230C variant and 23 SNPs spanning an 800 kb region were genotyped using TaqMan assays (ABI Prism 7900HT Sequence Detection System; Applied Biosystems). Login to comment 147 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys Generation of R230C variant constructs and cell lines Polyclonal stable cell lines expressing the ABCA1 R230C variant were generated using the Flp-In system (Invitrogen, Carlsbad, CA, USA) as described previously (42). Login to comment 149 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys Briefly, the R230C variant was generated by PCR-based site-directed mutagenesis using the primers 230F,5' -GAGCGAGTACTT TGTTCCAACATG and 230R,5' -CATGTTGGAACAAAGT ACTCGCTC and cloned into pcDNA5/FRT (Invitrogen). Login to comment 151 ABCA1 p.Met1091Thr ABCA1 p.Arg230Cys The M1091T ABCA1 mutation previously identified in Tangier patients was used as control (32). Login to comment 153 ABCA1 p.Met1091Thr The M1091T ABCA1 mutation previously identified in Tangier patients was used as control (32). Login to comment 169 ABCA1 p.Arg230Cys The LRH test was applied to examine the decay of LD (Sweep software) (48) within an 800 kb region flanking R230C using data obtained from the 20 Native American trios described earlier. Login to comment 171 ABCA1 p.Arg230Cys The LRH test was applied to examine the decay of LD (Sweep software) (48) within an 800 kb region flanking R230C using data obtained from the 20 Native American trios described earlier. Login to comment 177 ABCA1 p.Arg230Cys Associations of R230C genotypes with HDL-C and other metabolic traits were tested using linear regression models (assuming an additive model) adjusting for covariates including age, sex and BMI (SPSS, version 15.0, statistical package; Chicago, IL, USA). Login to comment 179 ABCA1 p.Arg230Cys Associations of R230C genotypes with HDL-C and other metabolic traits were tested using linear regression models (assuming an additive model) adjusting for covariates including age, sex and BMI (SPSS, version 15.0, statistical package; Chicago, IL, USA). Login to comment