The genetic basis of lipoprotein(a) variation in the Māori and Pacific populations

21 Nov 2012

Lipoprotein(a) [Lp(a)] is a plasma lipoprotein, characterised by an apo(a) molecule bound via a disulphide bond to apoB of a low density lipoprotein- (LDL-) like particle. Elevated Lp(a) levels are a well established risk factor for development of atherosclerosis. Intriguingly, there is enormous inter-individual variation in plasma Lp(a) concentration, with up to 69% of this variation due to different sized isoforms. Lp(a) size is determined by the number of kringle four type 2 (KIV2) repeats within the LPA gene encoding the apo(a) moiety of Lp(a); and is inversely correlated with Lp(a) levels. Furthermore, other genetic variants play a smaller role in influencing levels.Despite genetic variation being well characterised in most populations, very little has been done in Māori and Pacific populations. Contradictory to the higher rates of cardiovascular disease (CVD) in these two ethnicities, their median Lp(a) levels (12.5 & 12.1 nmol/L, respectively) were significantly lower than in Caucasians (18.9 nmol/L; p<0.03).Analysis of the KIV2 repeats in Māori and Pacific concluded shift towards larger numbers of KIV2 repeats are the largest influence towards the lower median Lp(a) levels observed in these two ethnicities. 1000 Genomes was used to identify genetic variation at the LPA locus, and from this rs783149, located 1.5kb upstream of LPA, and rs3124784, located in the protease-like domain, were chosen to be genotyped in the sample populations. The SNP rs783149 was present at a higher frequency in Māori and Pacific compared to Caucasians (p<0.0001). Interestingly, in the Pacific sample set, there was a significant decrease in Lp(a) levels between rs783149 major homozygotes and minor homozygotes, as well as between heterozygotes and minor homozygotes (p<0.45) The second SNP, rs3124784, was present at a lower frequency in Māori and Pacific compared to Caucasian (p<0.0001), and associated with higher Lp(a) levels in the Caucasian and Māori people. Hence a lower frequency of the Lp(a) increasing SNP rs3124784 in Māori could be influencing the lower levels either itself, or be in linkage disequilibrium with a genetic variant that directly affects Lp(a) levels.We conclude that the genetic make up of the LPA gene in Māori and Pacific is significantly different to Caucasians, influencing the lower median Lp(a) levels seen in these two ethnicities.

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