Evidence for several independent genetic variants affecting lipoprotein (a) XXXX levels.

@entity15783 @entity71404 @entity4991 @entity67470 @entity3452 @entity50402 @entity1675 @entity12436 @entity731 @entity23353 @entity165
Lipoprotein (a) [ @entity3452 ] is an independent risk factor for @entity731 -related events that is under strong genetic control (heritability = 0.68-0.98). However, causal mutations and functional validation of biological pathways modulating @entity3452 metabolism are lacking. We performed a genome-wide association scan to identify genetic variants associated with @entity3452 - @entity165 levels in the Old Order Amish. We confirmed a previously known locus on chromosome 6q25-26 and found @entity3452 levels also to be significantly associated with a SNP near the @entity23353 - @entity15783 - @entity12436 - @entity1675 gene cluster on chromosome 11q23 linked in the Amish to the @entity12436 @entity71404 null mutation. On 6q locus, we detected associations of @entity3452 - @entity165 with 118 common variants (P = 5 * 10(-8) to 3.91 * 10(-19)) spanning a    5.3 Mb region that included the @entity4991 gene. To further elucidate variation within @entity4991 , we sequenced @entity4991 and identified two variants most strongly associated with @entity3452 - @entity165 , @entity67470 (P = 1.07 * 10(-14)) and @entity50402 (P = 1.85 * 10(-12)). We also measured copy numbers of kringle IV-2 (KIV-2) in @entity4991 using qPCR. KIV-2 numbers were significantly associated with @entity3452 - @entity165 (P = 2.28 * 10(-9)). Conditional analyses revealed that @entity67470 and @entity50402 were associated with @entity3452 - @entity165 levels independent of each other and KIV-2 copy number. Furthermore, we determined for the first time that levels of @entity4991 mRNA were higher in the carriers than non-carriers of @entity50402 (P = 0.0001) and were not different between carriers and non-carriers of @entity67470 . Protein levels of apo(a) were higher in the carriers than non-carriers of both @entity50402 and @entity67470 . In summary, we identified multiple independent genetic determinants for @entity3452 - @entity165 . These findings provide new insights into @entity3452 regulation.
