ABCMdb

PMID: 19929409

Koblos G, Andrikovics H, Prohaszka Z, Tordai A, Varadi A, Aranyi T
The R1141X loss-of-function mutation of the ABCC6 gene is a strong genetic risk factor for coronary artery disease.
Genet Test Mol Biomarkers. 2010 Feb;14(1):75-8., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC6 p.Arg1141* The R1141X Loss-of-Function Mutation of the ABCC6 Gene Is a Strong Genetic Risk Factor for Coronary Artery Disease Gabriella Ko¨blo¨s,1 Hajnalka Andrikovics,2 Zolta´n Proha´szka,3 Attila Tordai,2 Andra´s Va´radi,1 and Tama´s Ara´nyi1 Loss-of-function mutations of ABCC6 cause pseudoxanthoma elasticum (PXE). Login to comment 13 ABCC6 p.Arg1141* The most frequent mutation, accounting for 20-30% of all mutations, is the c.3421C>T nucleotide change leading to the R1141X nonsense mutation (Pfendner et al., 2008). Login to comment 32 ABCC6 p.Arg1141* Indeed, a strong correlation between a rare sequence variant of the ABCC6 gene (c.3421C>T leading to the R1141X nonsense mutation) and CAD has been demonstrated in a Dutch cohort (Trip et al., 2002). Login to comment 37 ABCC6 p.Arg1141* We analyzed the allele frequency (AF) of the c.3421C > T (R1141X) mutation in healthy blood donors, patients with CAD, and patients suffering from ischemic stroke. Login to comment 61 ABCC6 p.Arg1141* ABCC6 p.Arg1141* The following equation was used to calculate the prevalence of PXE (P) in the control population: P ¼ 1=(AF · 4 · 0:01)2 (1) The maximal and minimal prevalence (Pm) were calculated by taking into account the 95% CI of AF determined in the various studies: Pm ¼ 1=[(AF Æ 95% CI · 0:01) · 4]2 (2) Results and Discussion Determination of the frequency of R1141X in the control population Before investigating the eventual association of the R1141X loss-of-function mutation of ABCC6 with CAD or stroke, we determined the frequency of this allele in our control population consisting of 749 healthy blood donors. Login to comment 62 ABCC6 p.Arg1141* This seemed to be important, since the two existing studies on the AF of the R1141X mutation in healthy Caucasians reported significantly different results ( p ¼ 0.028; Table 1) (Trip et al., 2002; Gotting et al., 2004). Login to comment 65 ABCC6 p.Arg1141* The corresponding frequency of the R1141X allele is almost identical to the German cohort (Gotting et al., 2004) ( p ¼ 0.495). Login to comment 68 ABCC6 p.Arg1141* Determination of the frequency of R1141X in patients with ischemic stroke Various anecdotal reports exist about a higher incidence of stroke in PXE patients than in unaffected individuals. Login to comment 73 ABCC6 p.Arg1141* This frequency of heterozygotes among stroke patients is not significantly different from controls ( p ¼ 0.44); thus, the carrier status of R1141X mutation of the ABCC6 gene is not a risk factor for stroke. Login to comment 77 ABCC6 p.Arg1141* ABCC6 p.Arg1141* Determination of the frequency of R1141X in patients with CAD Trip et al. found that the carrier status for the R1141X mutation of the ABCC6 gene is a risk factor for the development of CAD. Login to comment 79 ABCC6 p.Arg1141* We determined the number of heterozygotes among the CAD patients and found five individuals carrying the R1141X mutation (Table 2). Login to comment 88 ABCC6 p.Arg1141* Accordingly, Trip et al. found a significantly higher R1141X AF in the CAD group than we did. Login to comment 90 ABCC6 p.Arg1141* Nevertheless, both this and the previous study demonstrated a very strong correlation between CAD and the haploinsufficiency of ABCC6 due to the R1141X mutation. Login to comment 95 ABCC6 p.Arg1141* Based on the frequency of ABCC6 R1141X allele, approximately 0.5% of the control Caucasian population is a carrier of a loss-of-function mutation concerning several hundred thousands of individuals. Login to comment 97 ABCC6 p.Arg1141* Frequency of R1141X Heterozygotes in the Control Groups of the Three Different Studies Population Dutch German Hungarian n 1057 910 749 Carriers 8 1 1 AF 95% CI 0.38 Æ 0.27% 0.06 Æ 0.11% 0.07 Æ 0.13% n, cohort size; AF, allele frequency; CI, confidence interval. Login to comment 99 ABCC6 p.Arg1141* Frequency of R1141X Heterozygotes in the Stroke, Control, and Coronary Artery Disease Groups Cohort Stroke Blood donors Coronary artery disease n 363 749 361 Carriers 1 1 5 AF 95% CI 0.14 Æ 0.28% 0.07 Æ 0.13% 0.69 Æ 0.62% ABCC6 AND CORONARY ARTERY DISEASE screening would not be appropriate, but as most of them are relatives of PXE patients they can easily be identified. Login to comment