ABCMdb

PMID: 16507104

Pandit B, Ahn GS, Hazard SE, Gordon D, Patel SB
A detailed Hapmap of the Sitosterolemia locus spanning 69 kb; differences between Caucasians and African-Americans.
BMC Med Genet. 2006 Feb 28;7:13., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCG8 p.Glu238Leu ABCG8 p.Ala259Val ABCG8 p.Gly575Arg Three polymorphisms in ABCG8 were unique to the Caucasian population (E238L, INT10-50 and G575R), whereas one variant (A259V) was unique to the African-American population. Login to comment 27 ABCG5 p.Cys600Tyr ABCG8 p.Met429Val In this paper, we report the detailed characterization of the SNPs present at the STSL in Caucasians drawn from Table 1: Polymorphisms reported at the STSL locus Name Position in the gene Polymorphism dbSNP cluster ID Restriction enzyme site altered Nucleotide Position ABCG5 P9P Exon 1 C/T rs49854016 BstN 1 22881725 R50C* Exon 2 C/T rs6756629 - 22881023 V523I Exon 11 G/A ss49854017 - 22863069 C600Y Exon 13 G/A ss49854018 - 22856345 Q604E* Exon 13 G/C rs6720173 Sml I 22856334 V622M Exon 13 G/A ss49854019 - 22856280 ABCG8 5' UTR-41 5' UTR C/T ss49854020 BstE II 22882085 5' UTR-19* 5' UTR T/G rs3806471 Tsp45 I 22882107 P17P Exon 1 G/C ss49854021 - 22882176 D19H* Exon 1 G/C rs11887534 - 22882180 INT1-21* Intron 1 C/A ss4148209 Mnl I 22887558 INT1-7* Intron 1 C/T ss4148210 BsmA 1 22887572 C54Y* Exon 2 G/A ss4148211 SexA I 22887676 E238L* Exon 6 G/A ss49854010 - 22895692 A259V* Exon 6 C/T ss49854012 Hae III 22895756 Q340E Exon 7 C/G ss49854024 - 22915101 T400K* Exon 8 C/A ss4148217 Mse I 22915366 M429V Exon 9 G/A - 22916932 INT9-19 Intron 9 C/T ss49854025 - 22917460 INT10-50* Intron 10 C/T ss4148220 - 22918168 A565A* Exon 11 C/T ss4148221 - 22918424 G575R* Exon 11 G/C rs49584011 Hha I 22918452 A632V* Exon 13 C/T rs6544718 Sty I 22920858 *Only these SNPs were found to be variant in the present study and the haplotypes (See Table 2 and 3) are ordered with these reported in sequence. Login to comment 49 ABCG8 p.Trp361* We selected 12 parents (24 chromosomes) carrying the commonest mutation, W361X, and where complete genotype information was available to compute recombination frequencies. Login to comment 64 ABCG5 p.Gln604Glu ABCG5 p.Arg50Cys Only two loci in ABCG5, R50C and Q604E showed variations in our study population, the remaining 4 SNPs were invariant in all subjects and are not depicted in the haplotype analyses. Login to comment 66 ABCG8 p.Met429Val All of the SNPs shown in Table 1 except M429V in ABCG8 were analyzed. Login to comment 67 ABCG8 p.Met429Val M429V was reported only recently in a Japanese cohort [29], and was not included for analyses in this study. Login to comment 70 ABCG8 p.Ala259Val The A259V polymorphism was present only in African-Americans. Login to comment 71 ABCG8 p.Glu238Leu ABCG8 p.Gly575Arg The C/T polymorphism at INT10-50 position, E238L and G575R in ABCG8 were variable only in the Caucasians. Login to comment 73 ABCG8 p.Arg50Cys Among the unrelated parents (Caucasians) all the SNPs, except R50C were in Hardy-Weinberg Equilibrium (p > 0.005, χ Square test). Login to comment 85 ABCG8 p.Asp19His ABCG8 p.Ala259Val Weinberg equilibrium (5' UTR-19, D19H, A259V, A565A) all of which are located in ABCG8. Login to comment 88 ABCG8 p.Glu238Leu ABCG8 p.Ala259Val Additionally, a SNP that results in A259V in ABCG8 was detected in this cohort, but was absent in Caucasians, and a SNP that was variant in Caucasian (E238L in ABCG8) but was non-variant in African-Americans. Login to comment 100 ABCG8 p.Asp19His ABCG8 p.Arg50Cys Of note, for the non-synonymous SNPs, R50C and D19H showed some LD in both populations, though the Ch-square statistic was only moderate (Table 4). Login to comment 106 ABCG5 p.Gln604Glu and INT1-7, and to a lesser extent between INT1-7 and both 5'UTR-19 and Q604E (Table 4). Login to comment 114 ABCG8 p.Met429Val Of the remaining 9 SNPs we genotyped and found no variants (Table 1), with the exception of M429V, which we did not genotype, the HapMap Consortium also do not report any genotyping data. Login to comment 122 ABCG8 p.Trp361* Age of mutation was calculated considering W361X as the most common disease causing mutation. Login to comment 124 ABCG8 p.Thr400Lys Of the non-synonymous cSNPs, T400K of ABCG8 was found to be oldest polymorphism that arose GOLD plot of pair-wise ∆2 values for SNPs in CEPH and Yoruba Africans genotyped by the HapMap ConsortiumFigure 3 GOLD plot of pair-wise ∆2 values for SNPs in CEPH and Yoruba Africans genotyped by the HapMap Consortium. Login to comment 130 ABCG8 p.Trp361* This SNP was also closely spaced to W361X mutation. Login to comment 132 ABCG5 p.Gln604Glu The only cSNP we could estimate by this methodology in ABCG5 was Q604E (~4,000 y old). Login to comment 144 ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Arg50Cys ABCG8 p.Arg50Cys ABCG8 p.Arg50Cys ABCG8 p.Arg50Cys ABCG8 p.Arg50Cys ABCG8 p.Arg50Cys ABCG8 p.Glu238Leu ABCG8 p.Glu238Leu A number of studies have been implicated this locus in disease (or physiologi- Table 4: Results of pair-wise LD analyses Population M1 M2 ChiSq Pval ∆2 D' Caucasian INT1-21 INT1-7 20.01 1E-05 0.545 0.866 5'UTR-19 INT1-7 9.61 0.002 0.256 0.594 Q604E INT1-7 7.14 0.008 0.239 0.489 T400K A632V 6.13 0.013 0.125 1.000 5'UTR-19 T400K 5.84 0.016 0.153 1.000 Q604E D19H 5.02 0.025 0.174 1.000 INT1-7 T400K 4.94 0.026 0.111 1.000 R50C D19H 4.79 0.029 0.234 0.484 INT1-21 T400K 4.45 0.035 0.153 1.000 E238L INT10-50 4.42 0.036 0.238 1.000 INT1-7 C54Y 4.41 0.036 0.138 0.739 5'UTR-19 C54Y 4.24 0.040 0.134 0.619 T400K INT10-50 3.92 0.048 0.040 1.000 5'UTR-19 A565A 3.86 0.049 0.127 1.000 Q604E INT1-21 3.66 0.056 0.128 0.420 INT10-50 A632V 3.29 0.070 0.132 0.641 5'UTR-19 INT1-21 2.86 0.091 0.071 0.267 C54Y T400K 2.74 0.098 0.082 0.433 African-American 5'UTR-19 T400K 11.01 9E-04 0.080 1.000 INT1-7 A565A 8.09 0.004 0.085 0.587 R50C D19H 6.96 0.008 0.205 1.000 T400K A565A 6.56 0.010 0.088 0.557 Q604E INT1-21 5.82 0.016 0.119 0.505 5'UTR-19 A565A 5.10 0.024 0.059 0.460 C54Y A565A 3.93 0.047 0.053 0.270 5'UTR-19 C54Y 3.49 0.062 0.047 0.481 R50C INT1-7 3.05 0.081 0.044 1.000 INT1-7 A632V 3.05 0.081 0.044 1.000 Q604E D19H 3.01 0.083 0.038 1.000 M1 = 1st marker in pair of SNPs, M2 = 2nd marker in pair of SNPs, ChiSq = Value of chi-square test of association, Pval = Two-sided P-value corresponding to chi-square value in ChiSq column assuming 1 degree of freedom. Login to comment 158 ABCG8 p.Met429Val Additionally, one cSNP, M429V, which was reported to be relatively more frequent in the Japanese population [29], was also absent from the HapMap dataset analyzing the Chinese Han and the Tokyo Japanese DNA samples. Login to comment 166 ABCG5 p.Gln604Glu SNPs in intron 1 of ABCG8 show some linkage to a common non-synonymous SNP, Q604E, in ABCG5, but present in exon 13 (almost 20 kb apart). Login to comment 169 ABCG8 p.Asp19His ABCG8 p.Ala259Val Four SNPs, 5' UTR-19, D19H, A259V, and A565A, in ABCG8 were not in Hardy-Weinberg equilibrium for the African-Americans. Login to comment 177 ABCG5 p.Gln604Glu ABCG5 p.Arg50Cys ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Glu238Leu ABCG8 p.Gly575Arg SNP Allele Number of Disease Chromosomes* Number of Healthy Chromosomes* Frequency (disease chromosome) Frequency (healthy chromosome) Recombination Fraction Age Estimate (generations) R50C C 12 12 1 1 NA Q604E G 2 1 0.167 0.083 0.058833 17.7 5'UTR-19 T 11 10 0.917 0.833 0.033059 9.1 D19H G 12 12 1 1 NA NA INT1-21 C 12 7 1 0.583 0.005 0 INT1-7 C 11 11 0.917 0.917 NA C54Y A 9 5 0.75 0.417 0.02749 8.8 E238L G 12 12 1 1 NA T400K A 10 3 0.833 0.25 0.0002 2387 INT10-50 T 12 12 1 1 NA A565A C 12 12 1 1 NA G575R G 12 12 1 1 NA A632V C 11 10 0.917 0.833 0.005692 52.9 *Out of a total of 12 disease and 12 normal chromosomes, see Methods and ABCG8 are proposed to function as obligate heterodimers [54], and complete mutations in either gene seems to result in an identical phenotype [8], these genetic findings posit an enigma. Login to comment 197 ABCG8 p.Met429Val For example, the M429V SNP was reported in the Japanese samples and seems to play a role in cholesterol absorption [29]. Login to comment