Open Heart (Nov 2023)
Ancestral diversity in lipoprotein(a) studies helps address evidence gaps
- Adolfo Correa,
- Annie Green Howard,
- Kari E North,
- Jerome I Rotter,
- Stephen S Rich,
- Ulrike Peters,
- Zhe Wang,
- Michael Y Tsai,
- Penny Gordon-Larsen,
- Christie Ballantyne,
- Shia T Kent,
- Ruth J F Loos,
- Christy L Avery,
- Xiuqing Guo,
- Jie Yao,
- Yao Hu,
- Mariaelisa Graff,
- Paul S de Vries,
- Keri L Monda,
- Moa P Lee,
- Sofia F Dimos,
- Laura M Raffield,
- Anna F Ballou,
- Carolina G Downie,
- Christopher H Arehart,
- Zhaohui Du,
- Christopher R Gignoux,
- Jeffrey Haessler,
- Helina Kassahun,
- J Antonio G Lopez,
- Michael H Preuss,
- Shannon L Rhodes,
- Rina Yarosh,
- Charles L Kooperberg
Affiliations
- Adolfo Correa
- Department of Population Health Science, The University of Mississippi Medical Center, Jackson, Mississippi, USA
- Annie Green Howard
- Department of Biostatistics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Kari E North
- Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Jerome I Rotter
- Department of Pediatrics, UCLA Medical Center, Los Angeles, California, USA
- Stephen S Rich
- University of Virginia School of Medicine, Charlottesville, Virginia, USA
- Ulrike Peters
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Zhe Wang
- Department of Joint Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Michael Y Tsai
- Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, Minnesota, USA
- Penny Gordon-Larsen
- Department of Nutrition, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Christie Ballantyne
- Department of Medicine, Section of Cardiology, Baylor College of Medicine, Houston, Texas, USA
- Shia T Kent
- Center for Observational Research, Amgen Inc, Thousand Oaks, California, USA
- Ruth J F Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Christy L Avery
- Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Xiuqing Guo
- Department of Pediatrics, UCLA Medical Center, Los Angeles, California, USA
- Jie Yao
- Department of Pediatrics, UCLA Medical Center, Los Angeles, California, USA
- Yao Hu
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Mariaelisa Graff
- Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Paul S de Vries
- Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, USA
- Keri L Monda
- Center for Observational Research, Amgen Inc, Thousand Oaks, California, USA
- Moa P Lee
- Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Sofia F Dimos
- Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Laura M Raffield
- Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Anna F Ballou
- Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Carolina G Downie
- Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Christopher H Arehart
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Zhaohui Du
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Christopher R Gignoux
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Jeffrey Haessler
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Helina Kassahun
- Global Development, Amgen Inc, Thousand Oaks, California, USA
- J Antonio G Lopez
- Global Development, Amgen Inc, Thousand Oaks, California, USA
- Michael H Preuss
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Shannon L Rhodes
- Center for Observational Research, Amgen Inc, Thousand Oaks, California, USA
- Rina Yarosh
- Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Charles L Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- DOI
- https://doi.org/10.1136/openhrt-2023-002382
- Journal volume & issue
-
Vol. 10,
no. 2
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 (R2=15% in East Asians) to high (R2=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.
