title: Genetics of Plasminogen Activator Inhibitor-1 (PAI-1) in a Ghanaian Population.
abstract: Plasminogen activator inhibitor 1 (PAI-1), a major modulator of the fibrinolytic system, is an important factor in cardiovascular disease (CVD) susceptibility and severity. PAI-1 is highly heritable, but the few genes associated with it explain only a small portion of its variation. Studies of PAI-1 typically employ linear regression to estimate the effects of genetic variants on PAI-1 levels, but PAI-1 is not normally distributed, even after transformation. Therefore, alternative statistical methods may provide greater power to identify important genetic variants. Additionally, most genetic studies of PAI-1 have been performed on populations of European descent, limiting the generalizability of their results. We analyzed >30,000 variants for association with PAI-1 in a Ghanaian population, using median regression, a non-parametric alternative to linear regression. Three variants associated with median PAI-1, the most significant of which was in the gene arylsulfatase B (ARSB) (p = 1.09 x 10(-7)). We also analyzed the upper quartile of PAI-1, the most clinically relevant part of the distribution, and found 19 SNPs significantly associated in this quartile. Of note an association was found in period circadian clock 3 (PER3). Our results reveal novel associations with median and elevated PAI-1 in an understudied population. The lack of overlap between the two analyses indicates that the genetic effects on PAI-1 are not uniform across its distribution. They also provide evidence of the generalizability of the circadian pathway's effect on PAI-1, as a recent meta-analysis performed in Caucasian populations identified another circadian clock gene (ARNTL).
authors: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Genetics and Institute of Quantitative Biomedical Sciences, Dartmouth College, Hanover, New Hampshire, United States of America.
authors: Marquitta J
authors: MJ
authors: White
authors: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Genetics and Institute of Quantitative Biomedical Sciences, Dartmouth College, Hanover, New Hampshire, United States of America.
authors: Nuri M
authors: NM
authors: Kodaman
authors: Department of Genetics and Institute of Quantitative Biomedical Sciences, Dartmouth College, Hanover, New Hampshire, United States of America.
authors: Reed H
authors: RH
authors: Harder
authors: Department Heart & Lungs, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, the Netherlands; Institute of Cardiovascular Science, University College London, 222 Euston Road, London, United Kingdom; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
authors: Folkert W
authors: FW
authors: Asselbergs
authors: Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors: Douglas E
authors: DE
authors: Vaughan
authors: Department of Medicine Vanderbilt University, Nashville, Tennessee, United States of America.
authors: Nancy J
authors: NJ
authors: Brown
authors: Department of Genetics and Institute of Quantitative Biomedical Sciences, Dartmouth College, Hanover, New Hampshire, United States of America.
authors: Jason H
authors: JH
authors: Moore
authors: Department of Genetics and Institute of Quantitative Biomedical Sciences, Dartmouth College, Hanover, New Hampshire, United States of America.
authors: Scott M
authors: SM
authors: Williams
mesh_terms: D000328:Adult; D002318:Cardiovascular Diseases / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics; D005260:Female; D005869:Ghana; D006801:Humans; D008297:Male; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000235:genetics; D056950:Period Circadian Proteins / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: C512644:PER3 protein, human; D056950:Period Circadian Proteins; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D020051:N-Acetylgalactosamine-4-Sulfatase; C581941:ARSB protein, human