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

Qibin Qi, Tsegaselassie Workalemahu, Cuilin Zhang, Frank B. Hu, Lu Qi

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


AimsTo 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 resultsIn 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): 0.951.15], 1.05 (0.961.15), 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).ConclusionOur 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.

Original languageEnglish (US)
Pages (from-to)325-334
Number of pages10
JournalEuropean heart journal
Issue number3
StatePublished - Feb 2012
Externally publishedYes


  • Cardiovascular disease
  • Genome-wide association
  • Lipoprotein(a)
  • Type 2 diabetes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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