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

Abstract

ObjectivesVariants 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.MethodsThe 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).ResultsIn 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.ConclusionsWe 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.

Combined PCSK9 and APOE Polymorphisms are Genetic Risk Factors Associated with Elevated Plasma Lipid Levels in a Thai Population

“…This finding in urban subjects was similar to that of a Japanese population (2.48 %) [24]. However, the higher frequency of the V allele of I474V has been observed in many populations: Brazilian subjects (17.59 %) [26], Caucasian Canadian (12.60 %) [23], African Canadians (19.40 %) [23], African Americans (22 %) [23], and healthy UK men (17.68 %) [15], as well as in the Dallas heart study (DHS) (18 % in whites, 9.7 % in Hispanics, and 22 % in blacks) [22] and the PLIC study (17.59 %) [25]. The frequency of the G allele of PCSK9 E670G polymorphism was 1.95 and 1.06 %, in urban and rural subjects, respectively.…”

“…This allele frequency in urban subjects was similar to the Caucasian individuals (2.40 %) [23], whereas lower frequency of the L allele of R46L was observed in an Italian (1.04 %) population [18], in the CARDIA study (1.64 % in whites) [16], in the Dallas Heart Study (DHS) (1.6 % in whites, 0.75 % in Hispanics, and 0.28 % in black) [22], in the Copenhagen City Heart Study (1.22 %) [19], Copenhagen General Population Study (1.41 %) [19], and Copenhagen Ischemic Heart Disease Study (1.18 %) [19]. In addition, a higher frequency of L allele of R46L was observed in the French Canadian population (4.80 %) [23].…”

“…It has been shown that 474V carriers are associated with lower LDL-C and PCSK9 levels in Caucasian, African Canadian [23], and Japanese [24] populations, but the association of 474V carriers with lipid levels was not observed in healthy UK men [15], Brazilian subjects [26], or in the PLIC study [25]. This suggests that differences in study population characteristics, study design, and the frequency of the 474V allele may explain the inconsistent results.…”

“…Several studies in European, African American, and white populations, hypobetalipoproteinemia subjects, as well as in the Dallas Heart Study (DHS) and the PROSPER study group have shown that PCSK9 46L carriers had decreased LDL-C levels [14][15][16][17][18][19][20][21][22]. Additionally, Caucasian, African Canadian [23], and Japanese [24] individuals carrying the V allele of PCSK9 I474V had lower total cholesterol (TC) and/or LDL-C levels than non-carriers. However, PCSK9 I474V was not associated with lipid levels in healthy UK men [15], Brazilian subjects [26], and the PLIC study [25].…”

The Central Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Septic Pathogen Lipid Transport and Clearance

“…Plasma PCSK9 levels are also altered according to which gain-of-function PCSK9 genetic variants (106) or loss-of-function genetic variants of PCSK9 one has (96).…”