Ancestral Diversity in Lipoprotein(a) Studies Helps Address Evidence Gaps

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Citation

Lee, Moa P.; Dimos, Sofia F.; Raffield, Laura M.; Wang, Zhe; Ballou, Anna F.; Downie, Carolina G.; Arehart, Christopher H.; Correa, Adolfo; de Vries, Paul S.; & Du, Zhaohui, et al. (2023). Ancestral Diversity in Lipoprotein(a) Studies Helps Address Evidence Gaps. Open Heart, 10(2), e002382. PMCID: PMC10471864

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.

URL

http://dx.doi.org/10.1136/openhrt-2023-002382

Reference Type

Journal Article

Year Published

2023

Journal Title

Open Heart

Author(s)

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

Article Type

Regular

PMCID

PMC10471864

Data Set/Study

Population Architecture using Genomics and Epidemiology (PAGE) Study
UK Biobank Study

Continent/Country

United States
United Kingdom

State

Nonspecific

Race/Ethnicity

European Ancestry
African Ancestry
East Asian Ancestry
South Asian Ancestry

ORCiD

Avery - 0000-0002-1044-8162
Graff - 0000-0001-6380-1735
Howard, AG - 0000-0003-0837-8166