Dataset Information

Differential effects of PCSK9 loss of function variants on serum lipid and PCSK9 levels in Caucasian and African Canadian populations.

ABSTRACT:

Objectives

Variants of the secreted glycoprotein, proprotein convertase subtilisin/kexin 9 (PCSK9), associate with both hypo- and hyper-cholesterolemic phenotypes. Herein, we carried out full exonic sequencing of PCSK9 documenting the frequency of single and multiple PCSK9 variations and their effects on serum lipoprotein and PCSK9 levels in Caucasian Canadians.

Methods

The 12 exons of PCSK9 were sequenced in 207 unrelated Caucasian Canadians. Minor allele frequencies of PCSK9 variants were compared amongst LDL cholesterol (LDLC) quintiles. Serum PCSK9 levels were measured by ELISA and lipoproteins by enzymatic methods. Comparisons were made with a Caucasian family cohort (n=51) and first generation African Canadians (n=31).

Results

In Caucasians, but not African Canadians, the c.61_63insCTG (denoted L10Ins) and A53V PCSK9 variations were linked and their frequency was significantly higher among Caucasian Canadians with LDLC levels in the <25th percentile. In both the unrelated and family Caucasian cohorts those carrying the L10A53V PCSK9 variant had significantly lower LDLC without reduction in plasma PCSK9. The I474V PCSK9 variant associated with significantly lower serum PCSK9 and LDLC. A novel PCSK9 variant was identified; E206K. We found that the frequency of multiple PCSK9 variations was higher in first generation African Canadians.

Conclusions

We showed that the L10A53V and I474V PCSK9 variants were significantly associated with lower LDLC levels in Caucasian Canadians but differed in their effect on serum PCSK9 concentrations, illuminating differences in their mechanism of inaction and indicating that that PCSK9 measurement alone may not always be a good indicator of PCSK9 function.Full exonic sequencing of PCSK9 pointed to factors that may contribute to L10Ins PCSK9 variant loss of function in Canadians of Caucasian but not those of African descent. These included; (1) its tight linkage with the A53V variant in Caucasians and/or (2) for both the L10 and I474V, the combined (and negating) effect of multiple, differing phenotypic PCSK9 variants within individuals of African ancestry for which combinations of PCSK9 variations and their overall frequency was higher. No population studies, to our knowledge, have addressed or accessed the effect of multiple PCSK9 variants on cholesterol profiles. Our results indicate that this should be considered.

SUBMITTER: Mayne J

PROVIDER: S-EPMC3661383 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Publications

Differential effects of PCSK9 loss of function variants on serum lipid and PCSK9 levels in Caucasian and African Canadian populations.

Mayne Janice J Ooi Teik Chye TC Raymond Angela A Cousins Marion M Bernier Lise L Dewpura Thilina T Sirois Francine F Mbikay Majambu M Davignon Jean J Chrétien Michel M

Lipids in health and disease 20130510

<h4>Objectives</h4>Variants of the secreted glycoprotein, proprotein convertase subtilisin/kexin 9 (PCSK9), associate with both hypo- and hyper-cholesterolemic phenotypes. Herein, we carried out full exonic sequencing of PCSK9 documenting the frequency of single and multiple PCSK9 variations and their effects on serum lipoprotein and PCSK9 levels in Caucasian Canadians.<h4>Methods</h4>The 12 exons of PCSK9 were sequenced in 207 unrelated Caucasian Canadians. Minor allele frequencies of PCSK9 var ...[more]

PMID: 23663650

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Project description:Non-communicable diseases, including cardiovascular diseases (CVDs), are increasing in African populations. High serum low density lipoprotein cholesterol (LDL-cholesterol) levels are a known risk factor for CVDs in European populations, but the link remains poorly understood among Africans. This study investigated the associations between serum LDL-cholesterol levels and selected variants in the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9) and low density lipoprotein receptor adaptor protein 1 (LDLRAP1) genes in some selected African populations. Nineteen SNPs were selected from publicly available African whole genome sequence data based on functional prediction and allele frequency. SNPs were genotyped in 1000 participants from the AWI-Gen, study selected from the extremes of LDL-cholesterol level distribution (500 with LDL-cholesterol>3.5 mmol/L and 500 with LDL-cholesterol<1.1 mmol/L). The minor alleles at five of the six associated SNPs were significantly associated (P<0.05) with lower LDL-cholesterol levels: LDLRAP1 rs12071264 (OR 0.56, 95% CI: 0.39-0.75, P = 2.73x10-4) and rs35910270 (OR 0.78, 95% CI: 0.64-0.94, P = 0.008); APOB rs6752026 (OR 0. 55, 95% CI: 0.41-0.72, P = 2.82x10-5); LDLR: rs72568855 (OR 0.47, 95% CI: 0.27-0.82, P = 0.008); and PCSK9 rs45613943 (OR = 0.72, 95% CI: 0.58-0.88, P = 0.001). The minor allele of the sixth variant was associated with higher LDL-cholesterol levels: APOB rs679899 (OR 1.41, 95% CI: 1.06-1.86, P = 0.016). A replication analysis in the Africa America Diabetes Mellitus (AADM) study found the PCSK9 variant to be significantly associated with low LDL-cholesterol levels (Beta = -0.10). Since Africans generally have lower LDL-cholesterol levels, these LDL-cholesterol associated variants may be involved in adaptation due to unique gene-environment interactions. In conclusion, using a limited number of potentially functional variants in four genes, we identified significant associations with lower LDL-cholesterol levels in sub-Saharan Africans.

Project description:BACKGROUND:Genetic and environment factors affect the occurrence and development of coronary artery disease (CAD). Proprotein convertase subtilisin/kexin type 9 (PCSK9), has been investigated extensively in the field of lipid metabolism and CAD. We performed this case-control study to investigate the relationship between serum PCSK9 levels and PCSK9 polymorphisms and lipid levels and CAD risk in a southern Chinese population. METHODS:A hospital-based case-control study with 1, 096 subjects, including 626 CAD patients and 470 controls, were conducted. Genotyping of PCSK9 polymorphisms was performed using polymerase chain reaction-ligase detection reaction (PCR-LDR) method. RESULTS:The frequencies of the AA, AG and GG genotypes of PCSK9 E670G polymorphism were 90.58, 9.27, and 0.16% in the CAD patients, compared with 88.72, 10.85 and 0.43% in the controls, respectively. No R46L variant was detected in this population. There were no significant differences in genotype and allele frequencies of PCSK9E670G polymorphism between the CAD group and the controls. Serum lipid levels were not significantly different in carriers with the G allele and those with the AA genotype. The median (QR) of PCSK9 concentration was 1205.00 ng/l (577.28-1694.13 ng/l) in cases and 565.87 ng/l (357.17-967.50 ng/l) in controls, respectively. Compared with controls, CAD patients had significantly higher PCSK9 levels (z?=?4.559, P?<?0.001). After adjusting for age, gender, essential hypertension, diabetic mellitus, smoking and lipid profiles, PCSK9 levels remain significantly associated with increased CAD susceptibility (OR?=?1.002, 95% CI?=?1.001-1.002, P?<?0.001). The correlation analyses showed that serum PCSK9 levels were positively associated with triglyceride (TG), Apo B and atherogenic index of plasma (AIP) levels in controls. No significant association between the PCSK9 E670G polymorphism and serum PCSK9 levels was observed in the CAD group and the controls. CONCLUSIONS:The present study shows that serum PCSK9 levels, but not PCSK9 polymorphisms, are associated with CAD risk in Southern Chinese Han population, and that serum PCSK9 levels are positively associated with AIP.

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Dataset Information

Differential effects of PCSK9 loss of function variants on serum lipid and PCSK9 levels in Caucasian and African Canadian populations.

Objectives

Methods

Results

Conclusions

Publications

Differential effects of PCSK9 loss of function variants on serum lipid and PCSK9 levels in Caucasian and African Canadian populations.

Similar Datasets

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