ABCMdb

PMID: 18984885

Brunham LR, Kastelein JJ, Hayden MR
ABCA1 gene mutations, HDL cholesterol levels, and risk of ischemic heart disease.
JAMA. 2008 Nov 5;300(17):1997-8; author reply 1998., [PubMed]

Sentences

No. Mutations Sentence Comment

24 ABCA1 p.Asn1800His The N1800H mutation, although known to impair ABCA1-mediated cholesterol efflux,1,2 was associated with only a 28% reduction in HDL levels in this cohort.1 Complete loss-of-function mutations in ABCA1 tend to be associated with a 50% reduction in HDL levels, corresponding to a complete loss of function of one ABCA1 allele.3 The mild nature of these variants is again indicated by the modest impairment in efflux, especially for the rare variants, reported as 74% to 79% of normal.1 Such a small reduction in function is of questionable significance given the relatively large variability of this assay. Login to comment 25 ABCA1 p.Lys776Asn In contrast, many of the pathogenic ABCA1 mutations that have been extensively characterized have less than 20% to 30% of normal efflux activity.2 These findings are also in contrast to reports from the same group on the same cohort that showed that genetic variation in ABCA1 influences IHD in the general population and, in the case of the variants K776N (in men)4 and R1587K,5 is associated with low HDL cholesterol levels. Login to comment 27 ABCA1 p.Asn1800His The N1800H mutation, although known to impair ABCA1-mediated cholesterol efflux,1,2 was associated with only a 28% reduction in HDL levels in this cohort.1 Complete loss-of-function mutations in ABCA1 tend to be associated with a 50% reduction in HDL levels, corresponding to a complete loss of function of one ABCA1 allele.3 The mild nature of these variants is again indicated by the modest impairment in efflux, especially for the rare variants, reported as 74% to 79% of normal.1 Such a small reduction in function is of questionable significance given the relatively large variability of this assay. Login to comment 28 ABCA1 p.Lys776Asn In contrast, many of the pathogenic ABCA1 mutations that have been extensively characterized have less than 20% to 30% of normal efflux activity.2 These findings are also in contrast to reports from the same group on the same cohort that showed that genetic variation in ABCA1 influences IHD in the general population and, in the case of the variants K776N (in men)4 and R1587K,5 is associated with low HDL cholesterol levels. Login to comment 54 ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser Third, our findings are consistent with our previous reports on the same cohort showing that polymorphisms and mutations in ABCA1 may or may not affect HDL levels, but that risk of IHD is independent of these HDL effects.2-4 Fourth, it is not correct that to state that heterozygosity for the 3 rare mutations in the CCHS (P1065S, G1216V, or R2144X; n=6) was associated with a 25% reduction in LDL cholesterol levels compared with noncarriers because this was not statistically significant. Login to comment 61 ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser Third, our findings are consistent with our previous reports on the same cohort showing that polymorphisms and mutations in ABCA1 may or may not affect HDL levels, but that risk of IHD is independent of these HDL effects.2-4 Fourth, it is not correct that to state that heterozygosity for the 3 rare mutations in the CCHS (P1065S, G1216V, or R2144X; n=6) was associated with a 25% reduction in LDL cholesterol levels compared with noncarriers because this was not statistically significant. Login to comment