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Genetic variants in ADAMTS13 as well as smoking are major determinants of plasma ADAMTS13 levels

Qianyi Ma, Paula M. Jacobi, Brian T. Emmer, Colin A. Kretz, Ayse Bilge Ozel, Beth McGee, Chava Kimchi-Sarfaty, David Ginsburg, Jun Z. Li and Karl C. Desch

Data supplements

Article Figures & Data

Figures

  • Figure 1.

    Meta-analysis of ADAMTS13 levels in GABC and TSS. (A) Genome-wide plot of –log10(P) for ∼5.82 million SNPs. The red line marks the 5.0E-8 threshold of genome-wide significance. (B) Quantile-quantile plot of observed vs expected –log10(P) for ADAMTS13 meta-analysis. The observed P < 5.0E-8 are shown in red. (C) Regional plot for the associated region near ADAMTS13 on Chr9. (D) Regional plot for ADAMTS13 and STKLD1 (C9orf96) genes on chromosome 9 (chr9) conditioned by the top SNP rs28673647 from meta-analysis. (E) Regional plot for ADAMTS13 conditioned by the top 2 independent SNPs, rs28673647 and rs3739893. (F) Regional plot for PRDM15 on chr21 when using the top 2 independent SNPs, rs28673647 and rs3739893, as covariates.

  • Figure 2.

    Functional tests of ADAMTS13 variant expression secretion and activity. (A) Cell lines expressing wild-type, Q448E, and A732V ADAMTS13 were generated by using an FLP-recombinase system in 293 cells. Q448E is rs2301612 and A732V is rs41314453. (B-C) Concentrations of ADAMTS13 in (B) conditioned media and (C) cell lysate were measured by using AlphaLISA and adjusted by cell lysate glyceraldehyde-3-phosphate dehydrogenase levels to account for variations in cell number. Mean and standard deviations are plotted as well as individual values. (D) Recombinant enzyme-specific activity was measured with FRETS-VWF73 substrate. Differences in group levels were determined by the Mann Whitney U test. 1-8, thrombospondin type 1 repeats; CUB, C1r-C1s urinary epidermal growth factor bone morphogenetic protein domains; Cys-rich, cysteine-rich domain; P, propeptide; S, signal peptide.

Tables

  • Table 1.

    Characteristics of study cohorts

    CohortGABCTSS
    Sibship size (no. of sibships)n/N%Q1Q3Sibship size (no. of sibships)n/N%Q1Q3
    No. of participants11522304
    Age, y211923222124
    Females72162.6135358.7
    Weight, lbs (kg)145 (65.8)125 (56.7)165 (74.8)148 (67.1)133 (60.3)167 (75.7)
    Height, inches (cm)67 (170)64 (163)70 (178)68 (173)65 (165)71 (180)
    BMI, kg/m222.520.725.022.621.024.5
    Current smoker53/1151*4.6723/229931.4
    Sibships2 (366)
    3 (94)
    4 (22)
    5 (5)
    6 (2)
    2 (66)
    3 (2)
    ADAMTS13, IU/dL115.4*101.8131.676.3*68.085.2
    • Values are medians for age, height, weight, body mass index (BMI), and raw ADAMTS13 levels.

    • N or n, number of individuals in the indicated study cohort(s); Q1, first quartile; Q3, third quartile.

    • * Previously unreported data. All other tabulated data are adapted from Ma et al.14

  • Table 2.

    Significant SNPs in conditional meta-analysis in individual cohorts

    CHRGABC + TSS (N = 3238)GABC (n = 934)TSS (n = 2304)
    SNPMAFβJ (%)SE (%)PJMAFβ (%)SE (%)PMAFβ (%)SE (%)P
    9q34.2rs286736470.387.10.51.2E-570.366.91.08.1E-130.396.60.59.3E-42
    rs37398930.02−22.31.81.2E-300.01−15.64.71.7E-30.02−23.31.92.0E-28
    21q22.3rs40759700.452.40.46.8E-90.485.01.01.4E-70.441.40.54.6E-03
    9q34.2rs31247620.163.50.68.9E-90.15−1.21.4.380.170.90.7.18
    • β, percentage change per allele; CHR, chromosome; J, joint effects of independently associated SNPs; N or n, number of individuals in the indicated study cohort(s); SE, standard error.