ABCMdb

PMID: 26243156

Fawzy MS, Alhadramy O, Hussein MH, Ismail HM, Ismail NM, Biomy NM, Toraih EA
Functional and Structural Impact of ATP-Binding Cassette Transporter A1 R219K and I883M Gene Polymorphisms in Obese Children and Adolescents.
Mol Diagn Ther. 2015 Aug;19(4):221-34. doi: 10.1007/s40291-015-0150-7., [PubMed]

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No. Mutations Sentence Comment

4 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Two genetic variants in ABCA1 gene-R219K (rs2230806; G/A) and I883M (rs2066714; A/G)-were genotyped in 128 normal weight and 128 overweight/obese subjects using polymerase chain reaction-restriction fragment length polymorphism technology. Login to comment 6 ABCA1 p.Arg219Lys Results Our findings suggest that the heterozygote GA genotype of R219K polymorphism increased susceptibility to obesity under the heterozygous model (odds ratio 2.75, 95 % CI 1.01-6.12; p = 0.014) compared with the control group. Login to comment 9 ABCA1 p.Ile883Met On the other hand, individuals with the G variant of I883M polymorphism showed lower susceptibility to obesity under all genetic models (allelic, homozygote, heterozygote, dominant, and recessive models; p \ 0.05), with no observed association with body mass index or degree of obesity. Login to comment 11 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Conclusions The study results suggest that R219K and I883M SNPs of the ABCA1 gene may play a role in susceptibility to obesity in our Egyptian population; the former increases susceptibility and phenotype severity, and the latter is protective. Login to comment 14 ABCA1 p.Arg219Lys & Manal S. Fawzy manal2_khashana@ymail.com & Eman A. Toraih emantoraih@gmail.com 1 Department of Medical Biochemistry, Faculty of Medicine, Suez Canal University, Ismailia, Egypt 2 Department of Medicine, Faculty of Medicine, Taibah University, Almadinah Almunawwarah, Kingdom of Saudi Arabia 3 Department of Chest Diseases, Faculty of Medicine, Cairo University, Giza, Egypt 4 Department of Cardiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt 5 Department of Rheumatology and Rehabilitation, Faculty of Medicine, Suez Canal University, Ismailia, Egypt 6 Department of Pediatrics, Faculty of Medicine, Suez Canal University, Ismailia, Egypt 7 Department of Histology and Cell Biology (Genetics Unit), Faculty of Medicine, Suez Canal University, Ismailia, Egypt Mol Diagn Ther (2015) 19:221-234 DOI 10.1007/s40291-015-0150-7 Key Points ABCA1 R219K and M883I polymorphisms may play a role in susceptibility to obesity in the Egyptian population. Login to comment 15 ABCA1 p.Arg219Lys ABCA1 R219K and M883I polymorphisms showed significant association with lipid levels among different genotype carriers. Login to comment 16 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys The GA genotype of R219K polymorphism increased susceptibility to obesity under the heterozygous model, the A variant was associated with a higher degree of obesity, the G variant of I883M polymorphism significantly decreased the risk of obesity under all genetic models. Login to comment 37 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys One of the most common single nucleotide polymorphisms (SNPs) affecting the amino acid sequence is the R219K (rs2230806) that results from nucleotide change G[A in exon 7 at position 1060, causing substitution of lysine for arginine at amino acid 219 (electronic supplementary Table S1). Login to comment 39 ABCA1 p.Arg219Lys Despite the high number of case-control studies conducted to investigate the functionality of R219K variant, the results have been inconclusive [10, 20-22]. Login to comment 40 ABCA1 p.Ile883Met Another missense polymorphism, I883M with nucleotide change A[G in exon 18 at position 3044 (rs4149313, replaced by rs2066714), has been reported as a milder phenotype with a significant reduction of HDL-cholesterol (HDL-c) and cholesterol efflux (approximately 70 % of wild-type) [23-25]. Login to comment 43 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys In this study, we investigated the prevalence of these frequently occurring variants of the ABCA1 gene, R219K and I883M polymorphisms, in association with anthropometric parameters and lipid profile in Egyptian overweight/obese children and adolescents. Login to comment 60 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys The most frequent endocrine diseases causing obesity (such as Cushing syndrome, hypothyroidism, and pseudohypoparathyroidism), or genetic syndromes associated with obesity (such as Prader- Fig. 3 Workflow for PCR genotyping of R219K and I883M polymorphisms in the study population. Login to comment 80 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Genotyping of ABCA1 R219K and I883M variations were conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Login to comment 102 ABCA1 p.Arg219Lys In R219K rs2230806, 174 bp- amplified fragment includes the genetic variant (AGG/AAG) existing in exon 7 (coordinates: 104,858,698-104,858,522) of two protein-coding transcripts (ABCA1-001 and ABCA1-002). Login to comment 105 ABCA1 p.Ile883Met In I883M rs2066714, 129-bp amplified fragment containing the genetic variant (ATA/ATG) in exon 18 (coordinates: 104,824,578- 104,824,465) and part of intron 18 (coordinates: 104,824,464- 104,822,668) existed in ABCA1-002 transcript only. Login to comment 111 ABCA1 p.Arg219Lys R219K (rs2230806): M, DNA marker 50 bp each; Lanes 1, 6 AA genotype with two bands at 109 and 65 bp; Lanes 2, 5,7,9 GG genotype with only one band at 174 bp; Lanes 3, 4, 8 GA genotype with three bands at 174, 109, and 65 bp. Login to comment 112 ABCA1 p.Ile883Met I883M (rs2066714): M, DNA marker 50 bp each. Login to comment 124 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Experimentally-genotyped polymorphisms (R219K and I883M) in the study population are shown in electronic supplementary Fig. 5. Login to comment 127 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys However, R219K (rs2230806) and I883M (rs2066714) are in linkage disequilibrium with other nearby intronic SNPs which might have deleterious effects on the protein function. Login to comment 129 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Both ABCA1 R219K (g.1060G[A) and I883M (g.3044A[G) genotypes were in agreement with those expected by the HWE (p [ 0.05). Login to comment 130 ABCA1 p.Arg219Lys In R219K polymorphism, there was a significant difference in genotype frequencies between overweight/obese and control groups (p = 0.042). Login to comment 133 ABCA1 p.Ile883Met Regarding I883M polymorphism, significantly decreased susceptibility of obesity was observed among G carriers (M allele) in the overall and stratified analysis, with OR showing protective effects in all genetic models. Login to comment 135 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys R219K and I883M polymorphisms are far apart, existing in different haplotype blocks in the ABCA1 gene. Login to comment 138 ABCA1 p.Arg219Lys 3.3 ABCA1 Gene Polymorphisms in Relation to Clinical Characteristics AA-R219K genotype was associated with more BMI (p = 0.03) and showed a higher degree of obesity (p \ 0.001) (Table 3 and Fig. 6). Login to comment 140 ABCA1 p.Ile883Met In contrast, no observed association was determined between I883M polymorphism and any of the clinical characteristics, even under all genetic models. Login to comment 142 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys However, overweight/obese subjects with AA-R219K had significantly higher levels of TC, LDL-c, and TC/HDL-c ratio, and lower HDL-c compared with non-carriers, while GG-I883M carriers had decreased levels of TC, HDL-c and LDL-c levels compared with those with other genotypes (p \ 0.05) (Table 3 and electronic supplementary Fig. 7). Login to comment 148 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys To the best of our knowledge, there are no published data on the screening of the ABCA1 R219K and I883M polymorphisms in association with obesity and lipid profile among the Egyptian population. Login to comment 153 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys In silico data analysis predicted our cSNPs (R219K and I883M) to be functionally neutral using the PolyPhen and MutPred web-based programs. Login to comment 155 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys In our study population, the R219K variant showed increased risk of developing obesity among GA heterozygote carriers, especially in children and females, whereas in I883M SNP analysis, carriers of the M allele (GA and GG genotypes) displayed reduced susceptibility to obesity in children and adolescents and in both genders compared with those with the AA genotype (I allele). Login to comment 156 ABCA1 p.Arg219Lys This was consistent with others who reported that the presence of ABCA1 polymorphisms could be a risk Table 2 Genotype and allele frequencies of ABCA1 gene polymorphisms in the study groups Polymorphism Controls (n = 128) OW/OB (n = 128) Chi-square p value Crude OR (95 % CI) Adjusted OR (95 % CI) R219K (G/A) Genotypes GG 21 (16.4) 10 (7.8) 6.306 0.042 Reference Reference GA 51 (39.8) 67 (52.4) 2.75 (1.19-6.36) 2.75 (1.01-6.12) AA 56 (43.8) 51 (39.8) 1.91 (0.82-44.0) 1.04 (0.76-42.5) GA ? Login to comment 157 ABCA1 p.Ile883Met AA 107 (83.6) 118 (92.2) 2.31 (1.04-5.13) 2.10 (0.85-5.07) HWE-P 0.116 0.059 Alleles G 93 (36.3) 87 (34) 0.308 0.578 Reference Reference A 163 (63.7) 169 (66) 1.10 (0.77-1.59) 0.85 (0.52-1.38) I883M (A/G) Genotypes AA 37 (28.9) 66 (51.6) 14.72 <0.001 Reference Reference AG 70 (54.7) 52 (40.6) 0.41 (0.24-0.71) 0.38 (0.21-0.64) GG 21 (16.4) 10 (7.8) 0.26 (0.11-0.62) 0.24 (0.09-0.54) AG ? Login to comment 158 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys GG 91 (71.1) 62 (48.4) 0.38 (0.22-0.63) 0.37 (0.20-0.58) HWE-P 0.208 0.956 Alleles A 144 (56.2) 184 (71.9) 13.57 <0.001 Reference Reference G 112 (43.8) 72 (28.1) 0.50 (0.34-0.72) 0.49 (0.31-0.77) Data are expressed as n (%) Bold values indicate statistically significant at p \ 0.05 ABCA1 ATP-binding cassette transporter A1, OW/OB overweight/obese group, R219K c.656G[A, I883M c.2649A[G, adjusted OR (95 % CI) odds ratio for confidence interval adjusted for confounding variables (age, gender, degree of obesity, and dyslipidemia) Fig. 5 Linkage disequilibrium between R219K and I883M. Login to comment 159 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Experimentally-tested SNPs in ABCA1 gene: I883M (rs2066714) and R219K (rs2230806) are noted. Login to comment 168 ABCA1 p.Ile883Met Brunham et al. found I883M to cause modest reduction of cholesterol efflux and significant suppression of ABCA1 protein expression by 70 % in the wild-type allele [52]. Login to comment 169 ABCA1 p.Arg219Lys Consistent with our results, Villard et al. reported R219K SNP to be associated with a significant modification of cholesterol efflux capacity in a sex-dependent manner [53]. Login to comment 175 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Intracellular ABCA1 domains could interact and hydrolyze ATP, generating energy for Table 3 Anthropometric measurements and lipid profile in overweight/obese subjects according to R219K and I883M genotypesa R219K (G/A) genotypes p value I883M (A/G) genotypes p value GG (n = 10) GA (n = 67) AA (n = 51) AA (n = 66) AG (n = 52) GG (n = 10) Age, years 11.3 &#b1; 3.1 12.5 &#b1; 3.8 12.5 &#b1; 3.5 0.61 12.9 &#b1; 3.3 12.1 &#b1; 3.6 14.8 &#b1; 2.5 0.05 Anthropometric data BMI, kg/m2 29.8 &#b1; 2.7 33.6 &#b1; 6.7 35.6 &#b1; 7.0b 0.03b 34.7 &#b1; 6.3 33.7 &#b1; 6.4 33.7 &#b1; 5.4 0.67 WHR 0.84 &#b1; 0.1 0.86 &#b1; 0.1 0.89 &#b1; 0.1 0.17 0.88 &#b1; 0.1 0.87 &#b1; 0.1 0.89 &#b1; 0.1 0.84 WHtR 0.63 &#b1; 0.1 0.64 &#b1; 0.1 0.68 &#b1; 0.2 0.30 0.70 &#b1; 0.2 0.66 &#b1; 0.1 0.68 &#b1; 0.2 0.43 Lipid profile TC, mg/dl 196.0 &#b1; 70.4 221.0 &#b1; 38.0 235.9 &#b1; 38.6b 0.02b 209.4 &#b1; 44.7 232.9 &#b1; 35.5b 166.0 &#b1; 38.4c <0.001b TG, mg/dl 74.7 &#b1; 18.2 92.9 &#b1; 30.4 99.8 &#b1; 34.4 0.07 94.1 &#b1; 35.6 96.6 &#b1; 30.2 100.0 &#b1; 33.0 0.84 HDL-c, mg/dl 67.0 &#b1;26.9 67.9 &#b1; 20.5 57.5 &#b1; 19.9c 0.03b 56.5 &#b1;18.0 69.4 &#b1; 19.6b 39.7 &#b1; 9.6b,c <0.001b LDL-c, mg/dl 114.0 &#b1; 43.0 132.2 &#b1; 30.6 158.0 &#b1; 37.2b,c <0.001b 134.2 &#b1; 39.8 140.9 &#b1; 31.6 106.7 &#b1; 25.6b,c 0.02b Values are expressed as mean &#b1; SD or n (%) Comparisons between genotypes of each polymorphism were performed by one-way ANOVA followed by Newman-Keuls multiple comparisons test Bold values indicate statistically significant at p \ 0.05 BMI body mass index, WHR waist/hip ratio, WHtR waist/height ratio, TC total cholesterol, TG triglycerides, HDL-c high-density lipoprotein cholesterol, LDL-c low-density lipoprotein cholesterol, ANOVA analysis of variance a Age and sex were used as covariates in the analysis to adjust for the genotyping effect. Login to comment 176 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Degree of obesity was classified according to the BMI z score b Indicates significant difference from homozygous carriers of the wild allele in the same group at p \ 0.05 c Indicates significant difference from heterozygous carriers in the same group at p \ 0.05 0% 20% 40% 60% 80% 100% OW OB1 OB2 Degree of obesity R219K genotype GG (n=10) GA (n=67) AA (n=51) p<0.001* 0% 20% 40% 60% 80% 100% OW OB1 OB2 Degree of obesity I883M genotype AA (n=66) AG (n=52) GG (n=10) p=0.098 (b) (a) Fig. 6 Genotype frequencies according to the degree of obesity. Login to comment 181 ABCA1 p.Arg219Lys Thus, we could propose the hypothesis that homo- or heterodimerization could have differential effects on the function of the protein, and this could provide a possible explanation for the increased obesity risk in our study among GA heterozygotes of R219K polymorphism compared with homozygotes. Login to comment 189 ABCA1 p.Arg219Lys However, patients with GA and AA genotypes of R219K SNP exhibited higher frequency of severe obesity and more BMI levels compared with other genotypes. Login to comment 190 ABCA1 p.Ile883Met On the other hand, no association of I883M SNP was observed with the degree or distribution of obesity, independent of age, gender, and pubertal status. Login to comment 192 ABCA1 p.Arg219Lys R219K polymorphism is located at the binding site of the lipid acceptor ApoA-1, and thus is strongly associated with protein activity and stabilization against ABCA1 degradation [6]. Login to comment 198 ABCA1 p.Arg219Lys In the current study, overweight/obese subjects with the AA-R219K genotype had an unfavorable lipid profile; mainly higher levels of TC, LDL-c, TG/HDL-c ratio, and TC/HDL-c ratio, and lower HDL-c compared with other genotypes. Login to comment 199 ABCA1 p.Ile883Met However, GG-I883M carriers had significantly lower levels of TC, HDL-c, and LDL-c when compared with other corresponding carriers of similar age and sex. Login to comment 200 ABCA1 p.Ile883Met There was no association between I883M genotypes and the ratio of lipid parameters associated with cardiometabolic burden. Login to comment 206 ABCA1 p.Arg219Lys In healthy-weight subjects, R219K SNP was shown to be associated with altered HDL-c phenotype [65, 66]. Login to comment 207 ABCA1 p.Arg219Lys Homozygotes of the A allele of R219K were associated with increased LDL-C and TC and decreased HDL-c concentrations in Turkish population [54]. Login to comment 209 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys In obesity, the K allele of the R219K polymorphism was also associated with lower HDL-c levels than controls among overweight/ obese Thai males, with no difference in HDL-c concentrations among genotypes of I883M polymorphism [10]. Login to comment 212 ABCA1 p.Arg219Lys The AA genotype of the R219K polymorphism was significantly associated with increased concentrations of HDL-C in the Tunisian population [47], and the GG genotype had lower HDL-c levels than those with the AA genotype in the Chinese population [69]. Login to comment 220 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met Moreover, in the ABCA1 gene, a strong linkage disequilibrium exists between R219K/V771M and M825I/I883M (D0 [ 0.9) [21]. Login to comment 221 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met The two SNPs (V771M and M825I) were previously found to be associated with increased plasma HDL-c and cholesterol concentration, respectively, thus speculating the probability that R219K and I883M may not be the true associated variants, but could instead reflect the functional impact of other nearby linked gene polymorphisms. Login to comment 228 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys 5 Conclusions The present study suggested that the R219K (rs2230806) polymorphism of the ABCA1 gene is associated with higher susceptibility to obesity and unfavorable outcome in the Egyptian population, while I883M (rs2066714) polymorphism is associated with a reduced risk of obesity in childhood and adolescence. Login to comment