<i>LPA</i> and <i>PLG</i> Sequence Variation and Kringle IV-2 Copy Number in Two Populations

Abstract

Background/Aims: Lp(a) levels have long been recognized as a potential risk factor for coronary heart disease that is almost completely under genetic control. Much of the genetics impacting Lp(a) levels has been attributed to the highly polymorphic LPA kringle IV-2 copy number variant, and most of the variance in Lp(a) levels in populations of European-descent is inversely correlated with kringle IV copy number. However, less of the variance is explained in African-descent populations for the same structural variation. African-descent populations have, on average, higher levels of Lp(a), suggesting other genetic factors contribute to Lp(a) level variability across populations. Methods: To identify potential cis-acting factors, we re-sequenced the gene LPA for single nucleotide polymorphism (SNP) discovery in 23 European-Americans and 24 African-Americans. We also re- sequenced the neighboring gene plasminogen (PLG) and genotyped the kringle IV copy number variant in the same reference samples. Results: These data are the most comprehensive description of sequence variation in LPA and its relationship with the kringle IV copy number variant. With these data, we demonstrate that only a fraction of LPA sequence diversity has been previously documented. Also, we identify several high frequency SNPs present in the African-American sample but absent in the European-American sample. Finally, we show that SNPs within PLG are not in linkage disequilibrium with SNPs in LPA, and we show that kringle IV copy number variation is not in linkage disequilibrium with either LPA or PLG SNPs. Conclusions: Together, these data suggest that LPA SNPs could independently contribute to Lp(a) levels in the general population.

Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q

“…Studies of kringle IV copy number in the Hutterites and the CLEAR cohort indicate that there is little LD between kringle IV size and SNPs in genes on chromosome 6q, including SNPs in the LPA gene itself. Consistent with our observation, a recent resequencing study of the LPA and PLG genes in 23 European Americans and 24 African Americans showed that kringle IV copy number was not in LD with any biallelic markers in LPA or PLG (39). Moreover, while small kringle IV number was associated with high plasma Lp(a) levels in both the Hutterites (Fig.…”

“…We identified a novel SNP in the LPA gene that is associated with high Lp(a) protein levels in the Hutterites and in the CLEAR cohort, and with carotid artery disease in the latter patient population, both independent of the kringle IV number and variation in known transcriptional enhancer elements of LPA. The mechanism through which this intronic SNP acts is unknown, but the fact that it is not in LD with any other SNPs in the LPA gene (39) and that it resides within a CREB site suggest that rs6919346 could influence gene expression.…”

Lipoprotein (a) and Cardiovascular Risk

“…Variations in nucleotide polymorphisms in LPA may be an important contributor to the observed Lp(a) between-population variance and increase Lp(a) level in some populations (45)(46)(47). Once again, ethnical differences have been reported in people of European continental ancestry where apo(a) isoform polymorphism contributes between 40% and 70% of the variation of Lp(a) concentration showing fewer number of KIV 2 repeats (41,46), (Table 1).…”

“…Apo(a) gen (6q2.6-q2.7) (39,40) have different kringle domains that show a high degree of homology to the kringle domains IV and V of plasminogen (41).…”

“…Apo(a) gen polymorphisoms as well certain gene cluster associated to LPA have been shown to modulate Lp(a) concentrations leading to an increase in the risk for coronary artery disease (44). The genetic basis for apo(a) isoform variation is a segment existing in multiple repeats (KIV 2 polymorphism) located in the LPA gene (41). Variations in nucleotide polymorphisms in LPA may be an important contributor to the observed Lp(a) between-population variance and increase Lp(a) level in some populations (45)(46)(47).…”