Causal Relevance of Lp(a) for Coronary Heart Disease and Stroke Types in East Asian and European Ancestry Populations: A Mendelian Randomization Study

Abstract

Background: Elevated plasma levels of Lp(a) [lipoprotein(a)] are a causal risk factor for coronary heart disease and stroke in European individuals, but the causal relevance of Lp(a) for different stroke types and in East Asian individuals with different Lp(a) genetic architecture is uncertain.

Methods: We measured plasma levels of Lp(a) in a nested case-control study of 18 174 adults (mean [SD] age, 57 [10] years; 49% female) in the China Kadoorie Biobank (CKB) and performed a genome-wide association analysis to identify genetic variants affecting Lp(a) levels, with replication in ancestry-specific subsets in UK Biobank. We further performed 2-sample Mendelian randomization analyses, associating ancestry-specific Lp(a)-associated instrumental variants derived from CKB or from published data in European individuals with risk of myocardial infarction (n=17 091), ischemic stroke (IS [n=29 233]) and its subtypes, or intracerebral hemorrhage (n=5845) in East Asian and European individuals using available data from CKB and genome-wide association analysis consortia.

Results: In CKB observational analyses, plasma levels of Lp(a) were log-linearly and positively associated with higher risks of myocardial infarction and IS, but not with intracerebral hemorrhage. In genome-wide association analysis, we identified 29 single nucleotide polymorphisms independently associated with Lp(a) that together explained 33% of variance in Lp(a) in Chinese individuals. In UK Biobank, the lead Chinese variants identified in CKB were replicated in 1260 Chinese individuals, but explained only 10% of variance in Lp(a) in European individuals. In Mendelian randomization analyses, however, there were highly concordant effects of Lp(a) across both ancestries for all cardiovascular disease outcomes examined. In combined analyses of both ancestries, the proportional reductions in risk per 100 nmol/L lower genetically predicted Lp(a) levels for myocardial infarction were 3-fold greater than for total IS (rate ratio, 0.78 [95% CI, 0.76-0.81] versus 0.94 [0.92-0.96]), but were similar to those for large-artery IS (0.80 [0.73-0.87]; n=8134). There were weaker associations with cardioembolic IS (0.92 [95% CI, 0.86-0.98]; n=11 730), and no association with small-vessel IS (0.99 [0.91-1.07]; n=12 343) or with intracerebral hemorrhage (1.08 [0.96-1.21]; n=5845).

Conclusions: The effects of Lp(a) on risk of myocardial infarction and large-artery IS were comparable in East Asian and European individuals, suggesting that people with either ancestry could expect comparable proportional benefits for equivalent reductions in Lp(a), but there was little effect on other stroke types.

Keywords: East Asian people; European people; coronary disease; heart diseases; lipoprotein(a); stroke.

Figure 1.

Study design and number of participants in the genome-wide association study of Lp(a) and in Mendelian randomization studies of Lp(a) and myocardial infarction, ischemic stroke, ischemic stroke subtypes, and intracerebral hemorrhage in East Asian and European individuals. A, East Asian individuals. B, European individuals. BBJ indicates Biobank Japan; CKB, China Kadoorie Biobank; CVD, cardiovascular disease; GW, genome-wide genotyping; GWAS, genome-wide association study; ICH, intracerebral hemorrhage; IS, ischemic stroke; Lp(a), lipoprotein(a); MI, myocardial infarction; MR, Mendelian randomization; SNP, single nucleotide polymorphism; and UKB, UK Biobank.

Figure 2.

Distribution of Lp(a) and apo(a) isoforms and associations of Lp(a) levels with apolipoprotein(a) isoforms in China Kadoorie Biobank. A, The distribution of Lp(a) [lipoprotein(a)] in 6339 control participants. B, apo(a) [apolipoprotein(a)] isoforms (kringle IV type 2 repeats) in 2016 participants. C, Associations of Lp(a) levels with apo(a) isoforms in 1324 control participants with isoform data.

Figure 3.

Observational associations of plasma levels of Lp(a) with risk of myocardial infarction, ischemic stroke, and intracerebral hemorrhage in China Kadoorie Biobank. The values shown are odds ratios (ORs) and 95% CIs for myocardial infarction (left), ischemic stroke (center), and intracerebral hemorrhage (right) for fifths of Lp(a) [lipoprotein(a)] relative to the bottom fifth (reference group). Values in the top fifth were subdivided into 2 tenths. Analyses used 6339 control participants plus incident cases (numbers in subtitles). P values for tests of nonlinearity among the 6 groups for all disease outcomes were nonsignificant.

Figure 4.

Associations of LPA genetic variants with plasma levels of Lp(a) and apo(a) isoform size in Chinese adults in China Kadoorie Biobank. The values shown are regression coefficients (95% CI) for effects of individual SNPs on Lp(a) [lipoprotein(a)] estimated in 4482 control participants with genetic data (excluding related participants and immigrants; left) and median (interquartile range [IQR]) kringle IV repeats in 2016 participants with isoform data (right). Rows were ordered by decreasing percentage of variance in Lp(a) levels explained by different the variants. Median kringle IV repeats refer to the predominant apo(a) [apolipoprotein(a)] isoforms. EA indicates effect allele; EAF, effect allele frequency; and OA, other allele.

Figure 5.

Comparison of 100 nmol/L lower genetically predicted Lp(a) levels on risk of myocardial infarction, ischemic stroke, and intracerebral hemorrhage in East Asian and European populations. The values shown are rate ratios (RRs) with 95% CIs for 100 nmol/L lower Lp(a) [lipoprotein(a)] on myocardial infarction, ischemic stroke, ischemic stroke subtypes, and intracerebral hemorrhage in East Asian and European individuals and all participants. Additional details of the studies and numbers of cases and controls for each outcome are provided in Table S4.