Ancestral diversity in lipoprotein(a) studies helps address evidence gaps. Lee, M. P, Dimos, S. F, Raffield, L. M, Wang, Z., Ballou, A. F, Downie, C. G, Arehart, C. H, Correa, A., de Vries, P. S, Du, Z., Gignoux, C. R, Gordon-Larsen, P., Guo, X., Haessler, J., Howard, A. G., Hu, Y., Kassahun, H., Kent, S. T, Lopez, J A. G, Monda, K. L, North, K. E, Peters, U., Preuss, M. H, Rich, S. S, Rhodes, S. L, Yao, J., Yarosh, R., Tsai, M. Y, Rotter, J. I, Kooperberg, C. L, Loos, R. J F, Ballantyne, C., Avery, C. L, & Graff, M. Open Heart, August, 2023.
Ancestral diversity in lipoprotein(a) studies helps address evidence gaps [link]Paper  abstract   bibtex   5 downloads  
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.
@ARTICLE{Lee2023-cf,
  title    = "Ancestral diversity in lipoprotein(a) studies helps address
              evidence gaps",
  author   = "Lee, Moa P and Dimos, Sofia F and Raffield, Laura M and Wang, Zhe
              and Ballou, Anna F and Downie, Carolina G and Arehart,
              Christopher H and Correa, Adolfo and de Vries, Paul S and Du,
              Zhaohui and Gignoux, Christopher R and Gordon-Larsen, Penny and
              Guo, Xiuqing and Haessler, Jeffrey and Howard, Annie Green and
              Hu, Yao and Kassahun, Helina and Kent, Shia T and Lopez, J
              Antonio G and Monda, Keri L and North, Kari E and Peters, Ulrike
              and Preuss, Michael H and Rich, Stephen S and Rhodes, Shannon L
              and Yao, Jie and Yarosh, Rina and Tsai, Michael Y and Rotter,
              Jerome I and Kooperberg, Charles L and Loos, Ruth J F and
              Ballantyne, Christie and Avery, Christy L and Graff, Mariaelisa",
  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$\times$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.",
  journal  = "Open Heart",
  volume   =  10,
  number   =  2,
  month    =  aug,
  year     =  2023,
  keywords = "biomarkers; epidemiology; genetic association studies;
              genome-wide association study",
  language = "en",
  pmid = {37648373},
	url = {https://pubmed.ncbi.nlm.nih.gov/37648373/},
  bdsk-url-1 = {https://doi.org/10.1136/openhrt-2023-002382}
}

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