Causal relevance of Lp(a) for coronary heart disease and stroke types in East Asian and European ancestry populations: a Mendelian randomization study
Clarke R., Wright N., Lin K., Yu C., Walters RG., Lv J., Hill M., Kartsonaki C., Millwood IY., Bennett DA., Avery D., Yang L., Chen Y-P., Du H., Sherliker P., Yang X., Sun D., Li L., Qu C., Marcovina S., Collins R., Chen Z., Parish S.
Background Elevated plasma levels of lipoprotein (a) [Lp(a)] are a causal risk factor for coronary heart disease (CHD) and stroke in Europeans, but the causal relevance of Lp(a) for different stroke types and in East Asians 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 undertook a genome-wide association analysis (GWAS) to identify genetic variants affecting Lp(a) levels, with replication in ancestry-specific subsets in UK Biobank (UKB). We further undertook two-sample Mendelian randomization (MR) analyses, associating ancestry-specific Lp(a)-associated instrumental variants derived from CKB or from published data in Europeans with risk of myocardial infarction (MI, n=17,091), ischemic stroke (IS, n=29,233) and its subtypes, and with intracerebral hemorrhage (ICH, n=5845) in East Asians and in Europeans using available data from CKB and genome-wide (GWAS) consortia. Results In CKB observational analyses, plasma levels of Lp(a) were log-linearly and positively associated with higher risks of MI and IS, but not with ICH. In GWAS, we identified 29 SNPs independently associated with Lp(a) that together explained 33% of variance in Lp(a) in Chinese. In UKB, the lead Chinese variants identified in CKB were replicated in 1260 Chinese, but explained only 10% of variance in Lp(a) in Europeans. In MR analyses, however, there were highly concordant effects of Lp(a) across both ancestries for all CVD outcomes examined. In combined analyses of both ancestries, the proportional reductions in risk per 100 nmol/L lower genetically-predicted Lp(a) levels for MI were 3-fold greater than for total IS (rate ratio, 0.78 [95%CI, 0.76-0.81] vs 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 cardio-embolic 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 ICH (1.08 [0.96-1.21]; n=5845). Conclusions The effects of Lp(a) on risk of MI and large artery IS were comparable in East Asians and Europeans suggesting that both ancestries could expect comparable proportional benefits for equivalent reductions in Lp(a), but there was little effect on other stroke types.