In people with type 2 diabetes, genetically high Lp(a) does not raise cardiovascular risk, unlike in the general population, a GWAS of 2308 diabetic patients (Eur Heart J 2012)

Original title: Genetic variants, plasma lipoprotein(a) levels, and risk of cardiovascular morbidity and mortality among two prospective cohorts of type 2 diabetes

Eur Heart J · 6 September 2011 · 7

Qi Q, Workalemahu T, Zhang C, Hu FB, Qi L

This study performed genome-wide association scans for Lp(a) and tested its relationship with cardiovascular disease (CVD) risk in 2,308 patients with type 2 diabetes from the Nurses Health Study and Health Professionals Follow-Up Study. Meta-analysis of two GWA scans identified 71 SNPs on chromosome 6q associated with Lp(a) at genome-wide significance, with rs10455872 in LPA most strongly associated (P=4.60x10-39); six independent SNPs across the LPA, PLG, SLC22A3 and LPAL2 region jointly explained about 20% of Lp(a) variation in diabetic patients. In prospective analysis, plasma Lp(a) was not significantly associated with coronary heart disease, CVD, or CVD death (relative risks 1.05, 1.05, and 1.21 per 1-SD higher log Lp(a)), and none of the Lp(a) SNPs, including rs10455872, were associated with CVD risk or mortality (all P>0.09), with significant heterogeneity in genetic effect on coronary heart disease risk between diabetic and general populations (P=0.006). The findings suggest diabetes status may attenuate the relationship between Lp(a) and cardiovascular risk seen in the general population.

Original abstract

Aims: To examine the relations between genetic loci, plasma lipoprotein(a) [Lp(a)] levels, and cardiovascular disease (CVD) risk among diabetic patients and compare with the observations in the general population.

Methods And Results: In two prospective cohorts of patients with type 2 diabetes (n= 2308) from the Nurses' Health Study and the Health Professional Follow-Up Study, we performed (i) genome-wide association (GWA) scans for plasma Lp(a); (ii) prospective analysis of plasma Lp(a) for CVD risk and mortality; and (iii) genetic association analysis for CVD risk and mortality. Meta-analysis of the two GWA scans yielded 71 single-nucleotide polymorphisms (SNPs) on chromosome 6q associated with plasma Lp(a) levels at a genome-wide significance level (P< 5 × 10(-8)). The SNP rs10455872 in LPA was most strongly associated with Lp(a) (P= 4.60 × 10(-39)). Forward-selection analysis indicated that rs10455872 and other five SNPs in a region encompassing LPA, PLG, SLC22A3, and LPAL2 genes were independently associated with Lp(a) levels and jointly explained ∼20% of variation in diabetic patients. In prospective analysis, we did not find any significant association between plasma levels and CVD incidence; the relative risk for coronary heart disease (CHD), CVD, and CVD death was 1.05 [95% confidence interval (CI): 0.95-1.15], 1.05 (0.96-1.15), and 1.21 (0.99-1.47) per 1-SD higher log-transformed Lp(a) levels, respectively. Consistently, none of the Lp(a) SNPs were associated with CVD risk or mortality (all P> 0.09). For the best SNP rs10455872 for plasma Lp(a) levels, the OR for CHD, CVD, and CVD death was 0.94 (95% CI: 0.69-1.28), 0.97 (0.72-1.29), and 1.23 (0.79-1.92), respectively. The genetic effect on CHD risk showed a significant heterogeneity between the diabetic and the general populations (P= 0.006).

Conclusion: Our data indicate that the effect of Lp(a) on CVD risk among diabetic patients might be different from that in the general population. Diabetes status may attenuate the relation between Lp(a) and cardiovascular risk.

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