Objective
The purpose of this study was to determine whether maternal/fetal single nucleotide polymorphisms (SNPs) in candidate genes are associated with spontaneous preterm labor/delivery.
Study Design
A genetic association study was conducted in 223 mothers and 179 fetuses (preterm labor with intact membranes who delivered <37 weeks of gestation [preterm birth (PTB)]), and 599 mothers and 628 fetuses (normal pregnancy); 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; the false discovery rate was used to correct for multiple testing.
Results
The strongest single locus associations with PTB were interleukin-6 receptor 1 (fetus; P = .000148) and tissue inhibitor of metalloproteinase 2 (mother; P = .000197), which remained significant after correction for multiple comparisons. Global haplotype analysis indicated an association between a fetal DNA variant in insulin-like growth factor F2 and maternal alpha 3 type IV collagen isoform 1 (global, P = .004 and .007, respectively).
Conclusion
An SNP involved in controlling fetal inflammation (interleukin-6 receptor 1) and DNA variants in maternal genes encoding for proteins involved in extracellular matrix metabolism approximately doubled the risk of PTB.
Preterm birth (PTB) is the leading cause of perinatal morbidity and death worldwide. The frequency of PTB varies from 5-12%, depending on geographic region. PTB may be the result of spontaneous preterm labor, with intact or ruptured membranes, or indicated PTB (for fetal or maternal indications).
For Editors’ Commentary, see Table of Contents
See related editorial, page 407
Genetic predisposition for PTB has been hypothesized based on (1) demonstration of familial aggregation, (2) measures of heritability, (3) identification of disease-susceptibility genes, and (4) racial disparity in PTB rate that may be related to frequency differences in risk-predisposing alleles. Familial aggregation , which is defined as the cooccurrence of a trait in members of a family that cannot readily be accounted for by chance, has been demonstrated for PTB. Studies in twins have demonstrated a heritability range from 17-40%. Polymorphisms in several genes have been studied, and many have identified DNA variants that are associated with spontaneous preterm labor with and without intact membranes and with PTB.
The purpose of this genetic association study was to identify DNA variants in the maternal and fetal genomes that can alter the risk for spontaneous preterm labor and delivery. Seven hundred seventy-five single nucleotide polymorphisms (SNPs) from 190 candidate genes that have been implicated in the mechanisms of disease that are responsible for spontaneous preterm labor, preterm prelabor rupture of membranes (pPROM), small-for-gestational age (SGA), and preeclampsia were analyzed. The study was conducted in a Hispanic population at a single site from Chile that has an estimated PTB rate of 6% and with extreme care to phenotypic characterization.
Materials and Methods
Study design
This was a case-control study that included patients with spontaneous preterm labor and intact membranes who delivered a preterm neonate (mothers, 223; fetuses, 179) and control subjects (mothers, 599; fetuses, 628). Spontaneous preterm labor and delivery was defined by the presence of regular uterine contractions that occurred at a frequency of at least 2 every 10 minutes that resulted in a preterm delivery (<37 weeks of gestation). The control group included women who delivered at term (37-42 weeks of gestation) without complications of pregnancy, which included preterm labor with term delivery, preeclampsia, eclampsia, HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome, pPROM, SGA, large-for-gestational age neonates, fetal death, placental abruption, placenta previa, or chorioamnionitis.
Patients of Hispanic origin were recruited at the Sotero del Rio Hospital, in Puente Alto, Chile. All eligible mothers were enrolled in a research protocol that requested permission to collect DNA from the mother and her neonate for research purposes. The exclusion criteria, beside those explained earlier for control subjects, included (1) known major fetal chromosomal and/or structural anomalies, (2) multiple pregnancy, (3) serious medical illness (eg, chronic renal failure, congestive heart failure, connective tissue disorders), (4) refusal to provide written informed consent, and (5) a clinical emergency that prevented counseling of the patient about participation in the study, such as fetal distress or maternal hemorrhage. A blood sample was obtained from the mother at the time of enrollment in the protocol and from the umbilical cord (blood of fetal origin) after delivery. Demographic and clinical characteristics of the mothers were obtained from a data collection form that was administered by trained medical and paramedical personnel. The collection of samples and their use for research purposes was approved by the Institutional Review Boards of the Sotero del Rio Hospital, Santiago, Chile (an affiliate of the Pontificia Catholic University of Santiago, Chile), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services.
Genotyping
Candidate genes were selected for analysis on the basis of biologic plausibility for a role in preterm labor and other pregnancy complications that included SGA, pPROM, and preeclampsia. Genes that are involved in processes such as the control of the immune response (pattern recognition receptors, cytokines, chemokines, and their respective receptors), uteroplacental ischemia, and angiogenesis were considered appropriate candidates for this study. A complete list of the 190 genes and all SNPs that were genotyped are included in the supplemental materials ( Supplemental Table 1 ).
| Gene code | Single nucleotide polymorphisms rs no. |
|---|---|
| ACE | rs4298 |
| ACE | rs4309 |
| ACE | rs4311 |
| ACE | rs4331 |
| ACE | rs4354 |
| ADRB2 | rs2053044 |
| ADRB2 | rs1800888 |
| AGT | rs4762 |
| AGT | rs2478522 |
| AGTR1 | rs275652 |
| AGTR1 | rs5182 |
| AGTR1 | rs5183 |
| ANG | rs11701 |
| ANGPT2 | rs2515507 |
| ANGPT2 | rs3739391 |
| ANGPT2 | rs3020221 |
| ANGPT2 | rs963496 |
| ANGPT2 | rs1961222 |
| ANGPT2 | rs2442622 |
| ANGPT2 | rs2979671 |
| APOA1 | rs12718466 |
| APOB | rs1367117 |
| APOB | rs570877 |
| APOB | rs1801700 |
| APOB | rs12720828 |
| APOB | rs2854725 |
| APOB | rs533617 |
| APOB | rs693 |
| APOB | rs1801701 |
| APOC3 | rs35536400 |
| APOC3 | GNSC_633938806 |
| APOC3 | GNSC_633938845 |
| APOC3 | rs4520 |
| APOC3 | rs2070666 |
| APOC3 | rs34635405 |
| APOE | rs769446 |
| APOE | rs405509 |
| APOE | rs440446 |
| APOE | rs769449 |
| AQP2 | rs3759126 |
| AQP2 | GNSC_629722626 |
| AQP2 | rs3741559 |
| AQP2 | rs426496 |
| AQP2 | GNSC_629722653 |
| CARD15 | rs2066850 |
| CARD15 | rs2067085 |
| CARD15 | rs1861759 |
| CARD15 | rs5743291 |
| CCL2 | rs2857657 |
| CCL2 | rs4586 |
| CCR2 | rs3749461 |
| CCR2 | rs61751656 |
| CD14 | GNSC_13154561 |
| CD14 | GNSC_13154559 |
| CETP | rs17245715 |
| CETP | rs4783962 |
| CETP | rs17231534 |
| CETP | rs289714 |
| CETP | rs891144 |
| CETP | rs5880 |
| CETP | rs1800774 |
| CETP | rs5882 |
| CETP | rs289741 |
| COL1A1 | rs11079898 |
| COL1A1 | rs17639446 |
| COL1A1 | rs2141279 |
| COL1A1 | rs1007086 |
| COL1A1 | rs2586490 |
| COL1A1 | rs2586488 |
| COL1A1 | rs2277632 |
| COL1A1 | rs2249492 |
| COL1A2 | GNSC_28207362 |
| COL1A2 | rs4729131 |
| COL1A2 | rs42518 |
| COL1A2 | rs28754326 |
| COL1A2 | rs2521206 |
| COL1A2 | rs2621208 |
| COL1A2 | rs2301643 |
| COL1A2 | rs13240759 |
| COL1A2 | rs13240759 |
| COL1A2 | rs1800248 |
| COL1A2 | rs10046552 |
| COL1A2 | rs11764718 |
| COL3A1 | rs7579903 |
| COL3A1 | rs13306272 |
| COL3A1 | rs13306257 |
| COL3A1 | rs3765161 |
| COL3A1 | rs28763878 |
| COL4A1 | GNSC_633869360 |
| COL4A1 | rs41275106 |
| COL4A1 | rs626444 |
| COL4A1 | rs645114 |
| COL4A1 | rs598893 |
| COL4A1 | rs12867220 |
| COL4A1 | rs685884 |
| COL4A1 | rs17591246 |
| COL4A1 | GNSC_633878169 |
| COL4A1 | rs16975492 |
| COL4A1 | rs16975491 |
| COL4A1 | rs503053 |
| COL4A1 | GNSC_633856439 |
| COL4A1 | rs1778817 |
| COL4A1 | rs1816884 |
| COL4A1 | rs16975424 |
| COL4A2 | rs3803229 |
| COL4A2 | rs3803228 |
| COL4A2 | rs2296852 |
| COL4A2 | rs41315048 |
| COL4A2 | rs2296849 |
| COL4A2 | rs421177 |
| COL4A2 | rs12873113 |
| COL4A2 | rs7338575 |
| COL4A2 | rs391859 |
| COL4A2 | rs2479426 |
| COL4A3 | rs13424243 |
| COL4A3 | rs1882435 |
| COL4A3 | rs10178458 |
| COL4A3 | rs55997063 |
| COL4A3 | rs12621551 |
| COL4A3 | rs13386404 |
| COL4A3 | rs7559693 |
| COL4A3 | rs35467545 |
| COL4A3 | GNSC_634673660 |
| COL4A3 | rs10933172 |
| COL4A3 | rs56326869 |
| COL4A4 | rs12465531 |
| COL4A4 | rs12475686 |
| COL4A4 | rs1800516 |
| COL4A4 | rs13027659 |
| COL4A4 | rs3752896 |
| COL4A4 | rs3752895 |
| COL4A5 | rs55941015 |
| COL4A5 | rs2273051 |
| COL4A5 | rs28465565 |
| COL4A6 | rs1266731 |
| COL4A6 | GNSC_634841755 |
| COL4A6 | GNSC_634410330 |
| COL5A1 | rs3811149 |
| COL5A1 | rs7036997 |
| COL5A1 | GNSC_634237373 |
| COL5A1 | rs7868111 |
| COL5A1 | rs13946 |
| COL5A2 | rs4128539 |
| COL5A2 | GNSC_635138172 |
| COL5A2 | GNSC_635136454 |
| COL5A2 | GNSC_635148121 |
| COL5A2 | GNSC_635148713 |
| COL5A2 | rs6750027 |
| COL5A2 | rs6434312 |
| COL5A2 | GNSC_635134938 |
| COL5A2 | rs10208525 |
| COL5A2 | rs7420715 |
| CRHR1 | rs12936511 |
| CRHR1 | rs17762882 |
| CRHR1 | rs17425752 |
| CRHR1 | rs16940668 |
| CRHR1 | rs17689966 |
| CRHR1 | rs28364026 |
| CRHR2 | rs41417745 |
| CRHR2 | rs8192496 |
| CRHR2 | rs4723000 |
| CRHR2 | rs8192498 |
| CRHR2 | rs7812133 |
| CSF1 | rs2297706 |
| CSF1 | rs2275123 |
| CSF1 | rs333970 |
| CSF1 | rs1058885 |
| CSF1 | rs2229165 |
| CSF2 | rs1469149 |
| CSF3 | rs25645 |
| CSPG2 | rs11742293 |
| CSPG2 | rs12332199 |
| CSPG2 | rs4470745 |
| CSPG2 | rs2287926 |
| CSPG2 | rs2548541 |
| CSPG2 | rs309559 |
| CSPG2 | rs188703 |
| CSPG2 | rs160279 |
| CSPG2 | rs160277 |
| DAF | rs28371583 |
| DAF | rs10746462 |
| DEFA5 | rs4610776 |
| DEFA5 | rs2272719 |
| DEFB1 | rs5743418 |
| DEFB1 | rs5743420 |
| DLAT | GNSC_659891580 |
| EDN1 | rs2070699 |
| EDN1 | rs1800543 |
| EDN1 | rs5369 |
| ELN | rs2301995 |
| ELN | rs28763981 |
| ELN | rs2528796 |
| ELN | rs2071307 |
| ELN | rs2856728 |
| ELN | rs28763986 |
| ELN | rs17855988 |
| ESR1 | rs867239 |
| ESR1 | rs746432 |
| ESR2 | rs3829768 |
| ESR2 | rs944050 |
| ESR2 | rs4986938 |
| F12 | rs1801020 |
| F12 | rs17876029 |
| F12 | rs17876047 |
| F13A1 | rs5981 |
| F13A1 | rs2274393 |
| F13A1 | rs3024444 |
| F13A1 | rs5982 |
| F13A1 | rs3024458 |
| F13B | rs1412632 |
| F13B | rs5996 |
| F13B | rs1759009 |
| F13B | rs5990 |
| F2 | rs2070850 |
| F2 | rs3136434 |
| F2 | rs3136435 |
| F2 | rs2070852 |
| F2 | rs5896 |
| F2 | rs5900 |
| F2 | rs3136516 |
| F3 | rs13306321 |
| F3 | rs610277 |
| F5 | rs6019 |
| F5 | rs6012 |
| F5 | rs2239854 |
| F5 | rs6015 |
| F5 | rs6020 |
| F5 | rs9332607 |
| F5 | rs9332608 |
| F5 | rs9332620 |
| F5 | rs6030 |
| F5 | rs2301517 |
| F7 | rs2774030 |
| F7 | rs6046 |
| FABP2 | rs13306357 |
| FABP2 | rs1397614 |
| FGB | GNSC_12297445 |
| FGF1 | rs9324894 |
| FGF1 | rs17217240 |
| FGF1 | rs34003 |
| FGF2 | rs41456044 |
| FGF2 | rs4554090 |
| FGF2 | rs45627736 |
| FGF4 | rs2073464 |
| FGF4 | GNSC_634043245 |
| FGF4 | rs3740640 |
| FIGF | GNSC_634828146 |
| FLT1 | GNSC_634778804 |
| FLT1 | rs17086747 |
| FLT1 | rs17086681 |
| FLT1 | GNSC_634071775 |
| FLT1 | rs2296190 |
| FLT1 | rs2296189 |
| FLT1 | rs2296188 |
| FLT1 | rs9579177 |
| FLT4 | rs3736061 |
| FLT4 | GNSC_22175089 |
| FLT4 | rs728986 |
| FLT4 | rs307826 |
| FLT4 | rs2242213 |
| FLT4 | rs2242215 |
| FN1 | rs2289202 |
| FN1 | rs3796123 |
| FN1 | rs7570208 |
| FN1 | rs1053238 |
| FN1 | rs1250215 |
| FN1 | GNSC_633954160 |
| FN1 | rs1250204 |
| FN1 | rs2304573 |
| FN1 | rs7568287 |
| FN1 | rs10498037 |
| FN1 | rs11651 |
| GJA4 | rs56078817 |
| GJA4 | rs1764389 |
| GJA4 | rs41266431 |
| GJA4 | GNSC_10346829 |
| GJB2 | GNSC_20116657 |
| GJB2 | rs2274084 |
| GNB3 | rs5440 |
| GNB3 | GNSC_43188143 |
| GNB3 | rs28395781 |
| GNB3 | rs2301339 |
| GNB3 | rs5445 |
| GP1BA | rs6066 |
| HLA-E | GNSC_632164643 |
| HLA-E | rs1059510 |
| HLA-E | rs1264457 |
| HLA-G | rs1233334 |
| HLA-G | rs1630185 |
| HLA-G | rs12722477 |
| HLA-G | rs1049033 |
| HPGD | rs17524423 |
| HPGD | rs17524423 |
| HSPG2 | rs28546127 |
| HSPG2 | rs2290498 |
| HSPG2 | GNSC_634045807 |
| HSPG2 | rs6658388 |
| HSPG2 | rs2290501 |
| HSPG2 | GNSC_634098268 |
| HSPG2 | rs2229489 |
| HSPG2 | rs2229491 |
| HSPG2 | rs35570238 |
| HSPG2 | rs17459097 |
| HSPG2 | rs2229487 |
| HSPG2 | rs4654771 |
| HSPG2 | rs2229488 |
| HTR2A | rs6314 |
| IFNGR1 | rs1327474 |
| IFNGR1 | rs1887415 |
| IFNGR2 | rs9808753 |
| IFNGR2 | rs11910627 |
| IFNGR2 | rs1532 |
| IGF1 | rs5742612 |
| IGF1 | rs5742620 |
| IGF1R | rs7174918 |
| IGF1R | rs2272037 |
| IGF1R | rs951715 |
| IGF1R | rs34816681 |
| IGF1R | rs2684806 |
| IGF1R | rs3743262 |
| IGF1R | rs28401726 |
| IGF1R | rs2293117 |
| IGF2 | rs3213223 |
| IGF2 | rs3213225 |
| IGF2 | rs2230949 |
| IGF2R | rs2277070 |
| IGF2R | rs8191754 |
| IGF2R | rs894817 |
| IGF2R | rs998074 |
| IGF2R | rs2282139 |
| IGF2R | rs6909681 |
| IGF2R | rs8191819 |
| IGF2R | rs2274849 |
| IGF2R | rs8191888 |
| IGF2R | rs629849 |
| IGF2R | rs8191890 |
| IGF2R | rs1805075 |
| IGF2R | rs2297367 |
| IL10 | rs1800895 |
| IL10 | rs1800872 |
| IL10 | rs3024509 |
| IL10 | rs5743627 |
| IL10RA | rs4252303 |
| IL10RA | rs17121493 |
| IL10RA | rs4252274 |
| IL10RA | rs2229115 |
| IL10RA | rs2229114 |
| IL12A | rs2243115 |
| IL12B | GNSC_632292870 |
| IL12B | rs11574790 |
| IL12B | rs3213119 |
| IL12RB1 | rs436857 |
| IL12RB1 | rs2305743 |
| IL12RB1 | rs11086087 |
| IL12RB1 | rs11673460 |
| IL12RB1 | rs383483 |
| IL12RB1 | rs3746190 |
| IL12RB2 | rs1495963 |
| IL12RB2 | rs4297265 |
| IL12RB2 | rs2229546 |
| IL13RA2 | rs5988195 |
| IL18 | rs1946519 |
| IL18 | rs549908 |
| IL18BP | rs5743658 |
| IL18BP | rs5743661 |
| IL18BP | rs1892919 |
| IL1A | rs2071374 |
| IL1A | rs17561 |
| IL1A | rs3783550 |
| IL1B | rs3136558 |
| IL1B | rs1143634 |
| IL1B | rs1143643 |
| IL1R1 | rs997049 |
| IL1R1 | rs3917318 |
| IL1R2 | rs3218852 |
| IL1R2 | rs2230400 |
| IL1R2 | rs2282747 |
| IL1R2 | rs2072479 |
| IL1R2 | rs3218974 |
| IL1R2 | rs3218977 |
| IL1RAPL1 | GNSC_634739537 |
| IL1RN | rs439154 |
| IL1RN | rs451578 |
| IL1RN | rs454078 |
| IL2 | rs2069762 |
| IL2 | rs2069771 |
| IL2 | rs2069772 |
| IL2RA | rs4986791 |
| IL2RA | rs12358961 |
| IL2RA | rs11256360 |
| IL2RA | rs10752175 |
| IL2RA | rs28360490 |
| IL2RA | rs7899538 |
| IL2RA | rs7076103 |
| IL3 | rs31480 |
| IL3 | rs40401 |
| IL3 | rs2069790 |
| IL3RA | GNSC_649033887 |
| IL4 | rs2243247 |
| IL4 | rs2243290 |
| IL4R | rs3024544 |
| IL4R | rs2234895 |
| IL4R | rs2301807 |
| IL4R | rs4787423 |
| IL4R | rs3024668 |
| IL4R | rs2234897 |
| IL4R | rs1805015 |
| IL4R | rs3024678 |
| IL4R | rs1805016 |
| IL4R | rs8674 |
| IL4R | rs1029489 |
| IL5 | rs2069812 |
| IL5RA | rs13090169 |
| IL5RA | rs2290608 |
| IL5RA | rs13097407 |
| IL5RA | rs17878995 |
| IL6 | GNSC_30713312 |
| IL6 | GNSC_632284204 |
| IL6 | rs2066992 |
| IL6 | rs2069840 |
| IL6 | rs2069849 |
| IL6R | GNSC_24750639 |
| IL6R | rs8192282 |
| IL6R | rs2229237 |
| IL6R | rs7521458 |
| IL8 | rs4073 |
| IL8RA | rs16858811 |
| IL8RB | rs4674259 |
| IL9 | rs1799962 |
| IL9 | rs2069882 |
| IL9 | rs2069885 |
| IL9R | GNSC_14430798 |
| IL9R | GNSC_14433537 |
| IRS1 | GNSC_632344426 |
| IRS1 | rs3731597 |
| IRS1 | rs1801278 |
| ITGB3 | rs3809862 |
| ITGB3 | rs5918 |
| ITGB3 | rs13306478 |
| ITGB3 | rs2292864 |
| ITGB3 | rs41315064 |
| ITGB3 | rs15908 |
| ITGB3 | rs11870252 |
| ITGB3 | rs3760372 |
| ITGB3 | rs3809863 |
| LEP | rs6976701 |
| LEP | rs28954080 |
| LIPC | rs1077835 |
| LIPC | GNSC_16324977 |
| LIPC | GNSC_11247957 |
| LIPC | rs6078 |
| LIPC | rs2414592 |
| LIPC | rs6080 |
| LIPC | rs6083 |
| LIPC | rs6074 |
| LPA | rs41269142 |
| LPA | rs9365178 |
| LPA | rs41272110 |
| LPA | rs41272112 |
| LPA | rs41272114 |
| LPA | rs4708871 |
| LPA | rs3798220 |
| LPA | rs3127596 |
| LPL | GNSC_12584682 |
| LPL | rs1801177 |
| LPL | rs1121923 |
| LPL | rs254 |
| LPL | rs270 |
| LPL | rs327 |
| LPL | rs11570891 |
| LPL | rs4922115 |
| LTA | rs2229094 |
| LTA | rs3093542 |
| LTA | rs1041981 |
| LTF | rs4683227 |
| LTF | GNSC_633839426 |
| LTF | rs17141147 |
| LTF | rs1475967 |
| LTF | rs2239692 |
| LTF | rs2269435 |
| LTF | GNSC_633838636 |
| LTF | GNSC_633838704 |
| LTF | rs2073493 |
| LTF | GNSC_617330042 |
| LYZ | rs511589 |
| LYZ | rs513342 |
| LYZ | rs1800973 |
| LYZ | rs686407 |
| MBL2 | GNSC_633877244 |
| MBL2 | rs5030737 |
| MBL2 | rs35805975 |
| MGP | rs1800801 |
| MIF | GNSC_641918458 |
| MMP1 | rs514921 |
| MMP1 | rs470132 |
| MMP1 | rs470558 |
| MMP1 | rs5031036 |
| MMP1 | rs1051121 |
| MMP1 | rs488178 |
| MMP1 | rs1938901 |
| MMP1 | rs470747 |
| MMP1 | rs2071230 |
| MMP10 | rs17435959 |
| MMP10 | rs486055 |
| MMP10 | rs17293607 |
| MMP10 | rs17860949 |
| MMP10 | rs17860950 |
| MMP10 | rs470277 |
| MMP10 | rs17860995 |
| MMP10 | rs470168 |
| MMP11 | rs28363645 |
| MMP11 | rs738792 |
| MMP11 | rs28363648 |
| MMP11 | rs9612427 |
| MMP11 | rs28363665 |
| MMP11 | rs2877173 |
| MMP12 | rs2276109 |
| MMP12 | rs632009 |
| MMP13 | rs2252070 |
| MMP14 | rs2236302 |
| MMP14 | rs2236303 |
| MMP14 | rs2236304 |
| MMP14 | rs2236307 |
| MMP14 | rs743257 |
| MMP15 | rs28733439 |
| MMP15 | rs2241774 |
| MMP16 | rs28907871 |
| MMP16 | rs16892543 |
| MMP16 | rs28907593 |
| MMP16 | rs3739381 |
| MMP16 | rs3739382 |
| MMP17 | rs12322870 |
| MMP17 | rs11835665 |
| MMP19 | rs2291267 |
| MMP19 | rs1056784 |
| MMP19 | GNSC_20236865 |
| MMP2 | rs243864 |
| MMP2 | rs2285053 |
| MMP2 | rs1132896 |
| MMP2 | rs243849 |
| MMP2 | rs243843 |
| MMP2 | rs11541998 |
| MMP2 | rs243832 |
| MMP3 | GNSC_962641 |
| MMP3 | rs646910 |
| MMP7 | GNSC_9685579 |
| MMP7 | rs14983 |
| MMP8 | rs1320632 |
| MMP8 | rs17099443 |
| MMP8 | rs3740938 |
| MMP8 | rs35866072 |
| MMP9 | rs3918253 |
| MMP9 | rs2274755 |
| MMP9 | rs2250889 |
| MTHFR | rs2066470 |
| MTHFR | rs1994798 |
| NFKB1 | rs1609993 |
| NFKB1 | rs4648110 |
| NFKB1 | rs3817685 |
| NFKB1 | rs1609798 |
| NOS2A | rs2779248 |
| NOS2A | rs10459953 |
| NOS2A | rs3730013 |
| NOS2A | rs3730017 |
| NOS2A | rs3729508 |
| NOS2A | rs1137933 |
| NOS2A | rs28999412 |
| NOS2A | rs3729727 |
| NOS2A | rs41337547 |
| NOS3 | rs1549758 |
| NOS3 | rs1800782 |
| NOS3 | rs2853796 |
| NOS3 | rs3730305 |
| NOS3 | rs3730006 |
| NOS3 | rs743507 |
| NOS3 | rs891512 |
| NPPA | rs17376426 |
| NPPA | rs5063 |
| NPPA | rs5064 |
| NPPA | rs5065 |
| NPPA | rs5068 |
| NPR1 | rs3891075 |
| NPY | rs16147 |
| NPY | rs16145 |
| NPY | rs16143 |
| NPY | rs16478 |
| NPY | GNSC_3047601 |
| OXTR | GNSC_631469588 |
| OXTR | GNSC_631469608 |
| OXTR | rs237911 |
| PAFAH1B1 | GNSC_451949 |
| PDGFB | rs9622979 |
| PDGFB | GNSC_635156599 |
| PDGFC | GNSC_634820282 |
| PDGFC | rs3815861 |
| PECAM1 | GNSC_632346114 |
| PECAM1 | rs668 |
| PGF | rs2159907 |
| PGF | GNSC_632345684 |
| PIGF | GNSC_15616680 |
| PIGF | rs2242033 |
| PLAT | rs8178674 |
| PLAT | rs2020919 |
| PLAT | rs2020920 |
| PLAT | rs8178750 |
| PLAT | rs2020922 |
| PLAT | rs1136159 |
| PLAU | rs2227562 |
| PLAU | rs2227564 |
| PLAU | rs2227571 |
| PLAUR | GNSC_7898646 |
| PLAUR | rs4251831 |
| PLAUR | rs4251877 |
| PLAUR | rs4251883 |
| PLAUR | rs3786953 |
| PLAUR | rs2302525 |
| PLAUR | rs2302524 |
| PLAUR | rs4251923 |
| PON1 | rs705381 |
| PON1 | rs2074351 |
| PON1 | rs854560 |
| PON1 | rs3917541 |
| PPARA | rs1800246 |
| PPARA | rs1800234 |
| PPARA | rs4253772 |
| PPARG | rs1801282 |
| PPARG | rs3856806 |
| PROC | rs5937 |
| PROS1 | rs8178610 |
| PTGER1 | rs3810254 |
| PTGER1 | rs28364035 |
| PTGER1 | rs28364039 |
| PTGER1 | rs3745459 |
| PTGER1 | rs10421765 |
| PTGER1 | rs10419296 |
| PTGER2 | rs1254600 |
| PTGER2 | rs2229187 |
| PTGER3 | rs5673 |
| PTGER4 | rs2228058 |
| PTGER4 | GNSC_626750174 |
| PTGS1 | rs1236913 |
| PTGS1 | rs3842787 |
| PTGS1 | rs3842788 |
| PTGS1 | rs2282169 |
| PTGS1 | rs5788 |
| PTGS1 | rs5789 |
| PTGS1 | rs3842798 |
| PTGS1 | rs10306183 |
| PTGS2 | rs20424 |
| PTGS2 | rs2066826 |
| PTGS2 | rs4648276 |
| REN | rs1464816 |
| REN | rs3730102 |
| REN | rs3730103 |
| REN | rs2368564 |
| SELE | rs5361 |
| SELE | rs2076059 |
| SELE | rs1534904 |
| SELE | rs5363 |
| SELE | rs1076637 |
| SELE | rs5356 |
| SELP | rs3917727 |
| SELP | rs6136 |
| SELP | rs6128 |
| SERPINC1 | rs5878 |
| SERPINC1 | rs2759328 |
| SERPINC1 | rs677 |
| SERPINE1 | rs6092 |
| SERPINE1 | rs6090 |
| SERPINE1 | rs2227684 |
| SERPINE1 | rs2227692 |
| SERPINE1 | GNSC_629203538 |
| SOD3 | rs8192288 |
| SOD3 | rs8192290 |
| SPARC | rs4958281 |
| SPARC | rs2304052 |
| SPARC | rs2116780 |
| SPARC | rs7719521 |
| SPARC | rs1060151 |
| TAP1 | rs1351382 |
| TAP1 | rs4148878 |
| TAP1 | rs2071538 |
| TAP1 | rs2071482 |
| TAP1 | rs16871027 |
| TAP1 | rs1135216 |
| TAP1 | rs1057149 |
| TBXAS1 | rs10256282 |
| TBXAS1 | GNSC_53711588 |
| TBXAS1 | rs3735355 |
| TBXAS1 | rs2072179 |
| TBXAS1 | rs5763 |
| TGFB1 | rs1800468 |
| TGFB1 | rs1800469 |
| TGFB1 | rs1800471 |
| TGFB1 | rs2241716 |
| TGFB1 | rs1800472 |
| THBD | rs1042579 |
| THBD | rs1962 |
| THBS1 | rs2292305 |
| THBS1 | rs2228263 |
| THBS1 | rs17632916 |
| THBS4 | rs2241826 |
| THBS4 | rs1866389 |
| THBS4 | rs256439 |
| THBS4 | rs16877469 |
| THBS4 | rs17885983 |
| THBS4 | rs2288395 |
| THPO | rs956732 |
| THPO | rs2280740 |
| THPO | rs6142 |
| TIMP1 | rs11551797 |
| TIMP2 | rs8080623 |
| TIMP2 | rs55743137 |
| TIMP2 | rs2277698 |
| TLR1 | rs5743553 |
| TLR1 | rs5743557 |
| TLR1 | rs5743611 |
| TLR1 | rs3923647 |
| TLR2 | rs3804100 |
| TLR2 | rs5743700 |
| TLR3 | rs5743309 |
| TLR3 | rs5743312 |
| TLR3 | rs3775290 |
| TLR4 | rs4986790 |
| TLR4 | rs4986791 |
| TLR5 | rs1773766 |
| TLR5 | rs5744168 |
| TLR5 | rs2072493 |
| TLR6 | rs5743818 |
| TLR9 | rs352140 |
| TNF | rs361525 |
| TNF | rs1800610 |
| TNF | rs3093664 |
| TNF | rs3093665 |
| TNFRSF1A | rs4149570 |
| TNFRSF1A | rs4149621 |
| TNFRSF1A | rs1800692 |
| TNFRSF1A | rs12426675 |
| TNFRSF1B | rs5746016 |
| TNFRSF1B | rs472093 |
| TNFRSF1B | rs1061622 |
| TNFRSF1B | rs5746026 |
| TNFRSF1B | rs2275416 |
| TNFRSF1B | rs5746051 |
| TNR | GNSC_633863341 |
| TNR | rs859398 |
| TNR | rs2239818 |
| TNR | rs2239819 |
| TNR | rs859400 |
| TNR | rs859427 |
| TNR | rs1385540 |
| TNR | rs2228359 |
| TNR | rs2301432 |
| TNR | rs2213635 |
| TNR | rs34842046 |
| VEGF | rs2146323 |
| VEGF | rs3024997 |
| VEGF | rs3025000 |
| VEGF | rs3025039 |
| VEGFB | rs11603042 |
| VEGFC | GNSC_636236098 |
| VEGFC | rs4604006 |
| VEGFC | rs7664413 |
| VWF | GNSC_635156524 |
| VWF | rs1800377 |
| VWF | GNSC_635285421 |
| VWF | rs216325 |
| VWF | rs216321 |
| VWF | GNSC_634065200 |
| VWF | rs1800380 |
| VWF | rs17491334 |
| VWF | rs216900 |
| VWF | rs2270151 |
| VWF | rs2362483 |
| VWF | rs7976955 |
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