A study identifies two genetic variants in the LPA gene associated with elevated levels of Lp(a) lipoprotein and increased risk of coronary disease. The variants, rs10455872 and rs3798220, were strongly linked to higher Lp(a) levels and a greater risk of coronary disease. These variants also correlated with reduced copy numbers of LPA, which affects the size of the apolipoprotein(a) isoform. The study, involving over 8000 case subjects with coronary disease and 4846 additional case subjects, confirmed the association of these variants with both Lp(a) levels and coronary disease risk. A meta-analysis showed that individuals with two or more variant alleles had a significantly higher risk of coronary disease. However, after adjusting for Lp(a) levels, the association between the LPA genotype score and coronary disease risk was no longer significant, suggesting that Lp(a) levels are a key mediator. The study highlights the role of Lp(a) lipoprotein in coronary disease and provides evidence for its causal involvement. The findings support the use of LPA variants as biomarkers for coronary disease risk. The study was conducted by the PROCARDIS Consortium and funded by various organizations including the British Heart Foundation and AstraZeneca. The results have implications for understanding the genetic basis of coronary disease and may lead to new therapeutic strategies targeting Lp(a) levels.A study identifies two genetic variants in the LPA gene associated with elevated levels of Lp(a) lipoprotein and increased risk of coronary disease. The variants, rs10455872 and rs3798220, were strongly linked to higher Lp(a) levels and a greater risk of coronary disease. These variants also correlated with reduced copy numbers of LPA, which affects the size of the apolipoprotein(a) isoform. The study, involving over 8000 case subjects with coronary disease and 4846 additional case subjects, confirmed the association of these variants with both Lp(a) levels and coronary disease risk. A meta-analysis showed that individuals with two or more variant alleles had a significantly higher risk of coronary disease. However, after adjusting for Lp(a) levels, the association between the LPA genotype score and coronary disease risk was no longer significant, suggesting that Lp(a) levels are a key mediator. The study highlights the role of Lp(a) lipoprotein in coronary disease and provides evidence for its causal involvement. The findings support the use of LPA variants as biomarkers for coronary disease risk. The study was conducted by the PROCARDIS Consortium and funded by various organizations including the British Heart Foundation and AstraZeneca. The results have implications for understanding the genetic basis of coronary disease and may lead to new therapeutic strategies targeting Lp(a) levels.