TABLE 1

COL18A1 variants associated with serum endostatin (ES) levels, gene expression and clinical measures

QTL dataES β#ES p-valueeQTL βeQTL p-valueFDR
EA subjects
 Omni5 array
  rs9976834−35100.0001983−0.662.22×10−197<1.34×10−5
  rs9976784−32050.0003702−0.6662.27×10−200<1.34×10−5
  rs2838932−31370.0004473−0.6361.17×10−184<1.34×10−5
  rs2236461−30890.0004758−0.6434.78×10−191<1.34×10−5
  rs9977482−29030.0006399−0.7059.81×10−254<1.34×10−5
  rs2236470−28640.0007104−0.7072.57×10−255<1.34×10−5
  rs8133622−29880.0007197−0.6321.27×10−182<1.34×10−5
  rs9980531−29470.0008603−0.6255.94×10−177<1.34×10−5
  rs11702782−31390.001041−0.5846.75×10−37<1.34×10−5
  rs12482088+−27580.001153−0.6951.02×10−248<1.34×10−5
  rs201577993−25520.001393NANANA
  rs2330180−28980.001514−0.6325.80×10−180<1.34×10−5
  rs2236459−24750.001694−0.5131.35×10−143<1.34×10−5
  rs2236464−26770.002145−0.6541.06×10−196<1.34×10−5
  rs11702494−25670.00237−0.6741.76×10−231<1.34×10−5
  rs2236451+−22890.00332−0.551.20×10−176<1.34×10−5
  rs55684533−24790.004203NANANA
  rs10854470−19150.01018−0.4451.32×10−122<1.34×10−5
  rs2236454−19020.01065−0.4659.84×10−134<1.34×10−5
  rs4819124−18020.01436−0.3671.74×10−86<1.34×10−5
  rs61633029−18640.02498−0.4731.06×10−115<1.34×10−5
  rs17338076−24090.02935−0.6741.38×10−34<1.34×10−5
  rs2236479−16410.03106−0.4555.77×10−127<1.34×10−5
  rs2150443−15440.03625−0.3672.40×10−86<1.34×10−5
  rs7409857−15310.03885−0.326.64×10−65<1.34×10−5
  rs728113817520.04298NANANA
 WES
  rs9979845−26750.0013−0.7059.81×10−254<1.34×10−5
  rs11702425−21070.0058−0.5324.67×10−157<1.34×10−5
  rs749627−16820.022−0.3046.79×10−58<1.34×10−5
AA subjects
 Omni5 array
  rs4819124−55980.01829−0.3671.74×10−86<1.34×10−5
  rs2150443−54150.0219−0.3672.40×10−86<1.34×10−5
  rs7337084068990.025080.311.30×10−23<1.34×10−5
  rs2838917−49310.028280.1537.35×10−13<1.34×10−5
  rs11425571610 2600.0306NANANA
  rs7862010610 8100.0308NANANA
  rs6163302955480.03098−0.4731.06×10−115<1.34×10−5
  rs56327327−43980.04565NANANA
 WES
  rs74962751720.025−0.3046.79×10−58<1.34×10−5
Phenotypic data§Clinical measureEffect estimateƒp-value
EA subjects
 rs7499Survival0.77 (0.62–0.96)¶¶0.018
 rs1050351Survival0.76 (0.61–0.95)¶¶0.015
 rs11311006MWD (m)30.61 (2.09–59.13)++0.035
 rs11311016MWD (m)30.61 (2.09–59.13)++0.035
 rs22364676MWD (m)30.16 (1.80–58.53)++0.037
 rs11311026MWD (m)30.11 (1.72–58.49)++0.038
 rs22364666MWD (m)28.49 (−0.02–57.01)++0.050
 rs7281138##Cardiac index (L·min−1·m−2)−0.11 (−0.23– −0.004)§§0.043
 rs2838917##Cardiac index (L·min−1·m−2)−0.12 (−0.23– −0.01)§§0.028
 rs2230688Cardiac index (L·min−1·m−2)0.19 (0.04–0.33)§§0.010
 rs2230687Cardiac index (L·min−1·m−2)0.19 (0.05–0.33)§§0.009
 rs2236456Cardiac index (L·min−1·m−2)0.14 (0.002–0.28)§§0.047

QTL: quantitative trait locus; eQTL: expression QTL; FDR: false discovery rate; EA: European ancestry; WES: whole exome sequencing; AA: African ancestry; 6MWD: 6-min walk distance; NA: no association between variant and gene expression. #: ES β-coefficients (protein QTL analysis) reflect differences in ES in pg·mL−1 for each copy of the minor allele; linear regressions on ES levels are adjusted for age and sex. : eQTL β-coefficients reflect differences in robust multi-array analysis, a measure of intensity derived from Affymetrix gene expression data; methods for eQTL models have been previously published [11]. +: single nucleotide polymorphism (SNP) that appears on both Omni5 and WES arrays. §: phenotypic data are reported for EA only. ƒ: effect estimates are hazard ratios for associations with survival and β-coefficients for associations with all other clinical measures; coefficients reflect differences in clinical measures for subjects with the presence versus the absence of the minor allele. ##: SNP from Omni5 array; all others in the phenotypic data section are WES SNPs. ¶¶: associations with survival are adjusted for age at enrolment, sex, pulmonary arterial hypertension (PAH) subtype and PAH therapies, and additionally for difference in time from PAH diagnosis to cohort enrolment. ++: associations with 6MWD are adjusted for body mass index and the following comorbid conditions: hypertension, diabetes, obstructive lung disease, cardiomyopathy and chronic kidney disease. §§: associations with cardiac index are adjusted for age at enrolment, sex, PAH subtype and PAH therapies.