Comprehensive Analysis of Genomic Variation in the LPA Locus and Its Relationship to Plasma Lipoprotein(a) in South Asians, Chinese, and European Caucasians

Abstract

Background— Functional copy number variation in the apolipoprotein(a) gene ( LPA ) underlies a variable number of protein kringle domains repeated in tandem in the lipoprotein(a) [Lp(a)] particle. Genomic analysis of LPA , including both single-nucleotide polymorphisms (SNPs) and kringle IV type 2 (KIV-2) copy number, has yet to be performed. Methods and Results— First, we genotyped 49 SNPs within 100 kb of LPA in a multiethnic sample comprising South Asians (n=330), Chinese (n=304), and European Caucasians (n=272). Second, using quantitative polymerase chain reaction, we estimated the KIV-2 copy number in each sample. European Caucasians had the lowest KIV-2 copy number but displayed the strongest correlation between KIV-2 copy number and plasma Lp(a) concentration ( r s =−0.31, P =4.2�10 −7 ). SNP rs10455872, only prevalent in European Caucasians, was strongly associated with both plasma Lp(a) concentration ( P =4.2�10 −29 ) and KIV-2 copy number ( P =7.2�10 −5 ). LPA SNP rs6415084, within the same haplotype block as the KIV-2 variation, was significantly associated with both Lp(a) concentration and KIV-2 copy number in the same direction in all 3 ethnicities [Lp(a), P =5.3�10 −7 ; KIV-2, P =2.6�10 −4 ]. SNPs and KIV-2 copy number together explain a larger proportion of variation in plasma Lp(a) concentrations in European Caucasians (36%) than in Chinese (27%) or South Asians (21%). Conclusions— LPA SNPs are in linkage disequilibrium with KIV-2 copy number, but KIV-2 copy number explains an increment in plasma Lp(a) variation over SNPs alone. Thus, both SNPs and KIV-2 copy number should be included in future genetic epidemiology studies of Lp(a).

Serum lipoprotein (a) concentrations are inversely associated with T2D, prediabetes, and insulin resistance in a middle-aged and elderly Chinese population

“…Serum Lp(a) concentrations are reported to be genetically determined ( 2 ) and different in various races ( 33 ). Although related large population studies have been performed in individuals of European or American origin, it is worth exploring this subject in Asians.…”

Lipoprotein (a): impact by ethnicity and environmental and medical conditions

“…The question arises, to what extent does this pattern vary across ethnicity? Studies in South Asians, Chinese, and Caucasians revealed that SNP rs10455872 was prevalent only in the latter (29). In addition, SNP rs6415084 within the same haplotype block as the KIV repeat polymorphism was associated with both Lp(a) concentrations and the size polymorphism in all three ethnic groups.…”

“…Ronald et al (32) identified a set of nine SNPs accounting for 30% of the variation in Lp(a) con centration, five of which overlapped with a set of seven SNPs identified by others (31). Six of these nine SNPs, of which four had previously been reported (29,30), pre dicted Lp(a) concentrations conditional on the number of KIV repeats. Accounting for apo(a) size, SNPs rs3798220 and rs10455872 were associated with Lp(a) concentra tions, and together explained 22% of Lp(a) variance.…”

“…A substantial heterogeneity in estimating the propor tion of Lp(a) variance explained by SNPs alone or in con junction with the size polymorphism has been observed (29,31,32). Ronald et al (32) identified a set of nine SNPs accounting for 30% of the variation in Lp(a) con centration, five of which overlapped with a set of seven SNPs identified by others (31).…”

“…A report from the Jackson Heart Study identified multiple common SNPs as sociated with Lp(a), accounting for up to 7% of Lp(a) level variation, as well as >70% of the AfricanAmerican/ Caucasian interethnic difference (40). In contrast to Cau casians, no single common SNP has been found to explain a large portion of variation in Lp(a) concentrations in AfricanAmericans (29,31). A limited LD between the apo(a) size polymorphism and common SNPs on the Afri can ancestral background could account for this contrast ing result (29).…”