A common LPA null allele carried by 3% of people lowers Lp(a) and cuts coronary disease risk, the PROCARDIS study of 4073 CAD cases and 4225 controls (Arterioscler Thromb Vasc Biol 2014)

Original title: A common LPA null allele associates with lower lipoprotein(a) levels and coronary artery disease risk

Arterioscler Thromb Vasc Biol · 12 June 2014 · 8

Kyriakou T, Seedorf U, Goel A, Hopewell JC, Clarke R, Watkins H, Farrall M, PROCARDIS Consortium

This study tested whether a common null allele of the LPA gene (rs41272114) affects Lp(a) levels and coronary artery disease (CAD) risk in the PROCARDIS case-control cohort (4073 CAD cases, 4225 controls), with Lp(a) measured in 909 cases and 922 controls and apolipoprotein(a) isoform size estimated by gel electrophoresis and quantitative PCR. Null allele carriers, at a frequency of 3%, had significantly lower Lp(a) (P=2.1x10-10) and reduced CAD risk (odds ratio 0.79, 0.66-0.97, P=0.023) compared with non-carriers. Combining null allele genotype with apolipoprotein(a) isoform size revealed a sigmoid relationship with Lp(a) levels, with progressively higher Lp(a) for shorter isoform alleles. The findings show the LPA null allele independently lowers Lp(a) and CAD risk, and refines the relationship between apolipoprotein(a) isoform size and circulating Lp(a) consistent with a threshold effect on lipoprotein secretion.

Original abstract

Objective: Increased levels of lipoprotein(a) are a highly heritable risk factor for coronary artery disease (CAD). The genetic determinants of lipoprotein(a) levels are mainly because of genetic variation in the apolipoprotein(a) gene (LPA). We have tested the association of a relatively common null allele of LPA with lipoprotein(a) levels and CAD risk in a large case-control cohort. We have also examined how null allele genotyping complements apolipoprotein(a) isoform typing to refine the relationship between LPA isoform size and circulating lipoprotein(a) levels.

Approach And Results: The LPA null allele (rs41272114) was genotyped in the PROCARDIS (Precocious Coronary Artery Disease) case-control cohort (4073 CAD cases and 4225 controls). Lipoprotein(a) levels were measured in 909 CAD cases and 922 controls; apolipoprotein(a) isoform size was estimated using sodium dodecyl sulfate-agarose gel electrophoresis and a high-throughput quantitative polymerase chain reaction-based method. Null carriers are common (null allele frequency, 3%) and have significantly lower circulating lipoprotein(a) levels (P=2.1×10(-10)) and reduced CAD risk (odds ratio, 0.79 [0.66-0.97]; P=0.023) compared with noncarriers. An additive allelic model of apolipoprotein(a) isoform size, refined by null allele genotype and quantitative polymerase chain reaction values, showed a sigmoid relationship with lipoprotein(a) levels, with baseline levels for longer isoform alleles and progressively higher levels of lipoprotein(a) for shorter isoform alleles.

Conclusions: The LPA null allele (rs41272114) is associated with decreased circulating lipoprotein(a) levels and decreased CAD risk. Incorporating rs41272114 refined apolipoprotein(a) isoform size typing obtained by immunoblotting and quantitative polymerase chain reaction. A joint genomic and isoform analysis revealed details of the relationship between apolipoprotein(a) isoform size and circulating lipoprotein(a) level consistent with a threshold effect on lipoprotein secretion.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.