Ancestral diversity in lipoprotein(a) studies helps address evidence gaps

Moa P. Lee, Sofia F. Dimos, Laura M. Raffield, Zhe Wang, Anna F. Ballou, Carolina G. Downie, Christopher H. Arehart, Adolfo Correa, Paul S. De Vries, Zhaohui Du, Christopher R. Gignoux, Penny Gordon-Larsen, Xiuqing Guo, Jeffrey Haessler, Annie Green Howard, Yao Hu, Helina Kassahun, Shia T. Kent, J. Antonio G. Lopez, Keri L. MondaKari E. North, Ulrike Peters, Michael H. Preuss, Stephen S. Rich, Shannon L. Rhodes, Jie Yao, Rina Yarosh, Michael Y. Tsai, Jerome I. Rotter, Charles L. Kooperberg, Ruth J.F. Loos, Christie Ballantyne, Christy L. Avery, Mariaelisa Graff

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Introduction The independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in >1.5 billion individuals worldwide, but studies have prioritised European populations. Methods Here, we examined how ancestrally diverse studies could clarify Lp(a)'s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations. Results Fourteen genome-wide significant loci with numerous population specific signals of large effect were identified that enabled construction of Lp(a) PRS of moderate (R 2 =15% in East Asians) to high (R 2 =50% in Europeans) accuracy. For all populations, PRS showed promise as a 'rule out' for elevated Lp(a) because certainty of assignment to the low-risk threshold was high (88.0%-99.9%) across PRS thresholds (80th-99th percentile). Causal effects of increased Lp(a) with increased glycated haemoglobin were estimated for Europeans (p value =1.4×10 -6), although inverse effects in Africans and East Asians suggested the potential for heterogeneous causal effects. Finally, Hispanic/Latinos were the only population in which known associations with coronary atherosclerosis and ischaemic heart disease were identified in external testing of Lp(a) PRS phenotypic effects. Conclusions Our results emphasise the merits of prioritising ancestral diversity when addressing Lp(a) evidence gaps.

    Original languageEnglish
    Article numbere002382
    JournalOpen Heart
    Volume10
    Issue number2
    DOIs
    StatePublished - 30 Aug 2023

    Keywords

    • biomarkers
    • epidemiology
    • genetic association studies
    • genome-wide association study

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