Abstract 3940: Identification of Novel Genetic Variants within the LPA Gene that are Associated with Serum Lp(a) Levels and Myocardial Infarction
Background: Serum Lp(a) levels of the atherogenic Lipoprotein (a) [Lp(a)] are under the genetic control of the Apo(a) locus. In Caucasians several polymorphisms of the LPA gene have been shown to influence the size and amount of apo (a): 50 % of the Lp(a) level are determined by the number of kringle IV type 2 repeats (KIV-2), with a low number of repeats causing higher levels. Another 45% of the genetic variation of Lp(a) levels can be explained with polymorphisms in the promoter region (i.e. the pentanucleotidrepeat (PNR) polymorphism) of the gene and other, yet unidentified variations in the LPA gene. Thus, we associated additional polymorphisms within the LPA gene with Lp(a) levels and MI.
Methods: Four SNPs within the LPA gene were explored in addition to the formerly investigated KIV and PNR polymorphisms. The TaqMan technology was used for genotyping of subjects in whom Lp(a) levels were available: 975 individuals of the general population (echocardiographic substudy of the third MONICA survey Augsburg), as well as 595 MI patients and 586 sibs affected from CAD from the Regensburg MI sib-pair registry. Moreover, n=450 samples from the KORA MI registry were used to verify the results.
Results: Three of the four SNPs were in linkage disequilibrium with each other but not with the KIV-2 and PNR polymorphisms. Particularly one SNP (Intron 34) was strongly associated with Lp(a) levels across all populations, in both men and women (MONICA: CC genotype: 50±11, CT: 30±2, TT: 21±1 mg/dl (±SEM), p=0,0019; MI patients: CC: 66±16, CT: 51±3, TT: 32±2 mg/dl, p<0,0001; MI sibs: CC: 77±13, CT: 45±4, TT: 31±2 mg/dl, p=0,0004; KORA: CC: 72±13, CT: 57±5, TT: 31±2 mg/dl, p<0,0001) with higher levels in MI patients than in the general population. This could even be observed in individuals with a low (≤ 21) number of KIV-2 repeats. Moreover, this SNP was significantly associated with risk of MI (i.e. C allele SNP Intron 34: OR 1,4 [1,2–1,7], p=0,0008).
Conclusion: We identified novel genetic variants within the LPA gene, that are associated with Lp(a) serum levels and a higher risk of MI in independent populations. These effects seem to be somewhat independent from the size of apo(a) isoforms, and may thus contribute significantly to the variability of Lp(a) levels and its risk of coronary syndrome.