Genetic contributions to preterm birth: Implications from epidemiological and genetic association studies

Figures & data

Figure 1 Illustration of population stratification in case‐control studies. Case and control groups come from two subpopulations, A and B, which differ in allele frequency for the polymorphism tested, 50% versus 90% for allele 1. If the case and control groups differ in the number of individuals coming from subpopulation A (40% versus 60%), this will create a difference in observed allele 1 frequencies between the groups (74% versus 66%) simply due to population substructure, rather than any relationship between allele 1 and disease status.

Table

Summary of case/control studies
Gene name	Ref	Population	n	Preterm definition	Exclusion criteria	PPROM included?	Proband	Polymorphism(s) tested	Association?
Infection/inflammation pathway
TNF	32	Pennsylvania, white and black	125 cases, 250 controls	<37 wks	induced labor	yes	mother	‘−308’	Y
TNF	42	UK, mixed (white, black, other)	48 cases, 82 controls	<37 wks	multiple gestation, medical complications, induction of labor, hypertension, or diabetes while pregnant	yes	mother	‘−308’	Y
TNF	43	Seattle, mixed	50 cases, 68 controls	⩽32 wks	cervical dilation, ruptured membranes, amniotic fluid infection	no	both	‘−308, −863’	Y
TNF	48	Kenya, African	1048 total	<37 wks	multiple gestation, no siblings	unknown	child	‘−308’	Y
TNF	49	Chinese	54 case trios, 79 control trios	<37 wks?	unknown	unknown	child	‘−308’	Y
TNF	50	Australian, white	202 cases, 185 controls	<35 wks	autoimmune disease, preeclampsia, in vitro fertilization, uterine malformation, placental abruption, nonspontaneous labor, ultrasound‐confirmed fetal abnormality, insulin‐dependent diabetes mellitus, multiple pregnancy	yes	mother	‘+488, −238, −308’	Y
TNF	47	Pennsylvania, black	55 cases, 110 controls	<37 wks	unknown	yes, analyzed separately	mother	‘−308’	PPROM only
TNF	30	Nashville, white and black	black: 50 cases, 223 controls; white: 77 cases, 184 controls	<36 wks	mixed race, excluded term births treated for preterm labor or intraamniotic infection from controls, excluded cases with PPROM, multiple gestations, preeclampsia, fetal abnormalities, medical complications such as gestational diabetes, surgeries during pregnancies	no	mother	LD SNPs	G×G
TNF	31	North Carolina, white and black	black: 67 cases, 238 controls; white: 69 cases, 336 controls	<37 wks	medically indicated, induction	yes	mother	‘−488’ i.e. ‘−308’	N
TNF	44	Utah, white?	203 cases mothers+ 44 infants, 41 control women	<37 wks	induced labor	yes	mother	‘−308’	N
TNF	45	Nashville, white and black	black: mothers 49 cases, 225 controls, infants 46 cases, 224 controls; white: mothers 77 cases, 184 controls, infants 86 cases, 191 controls	<36 wks	mixed race, excluded term births treated for preterm labor or intraamniotic infection from controls, excluded cases with PPROM, multiple gestations, preeclampsia, fetal abnormalities, medical complications such as gestational diabetes, surgeries during pregnancies	no	both	5 LD SNPs+ ‘−308’	N
TNF	46	Nashville, white and black	black: 50 cases, 223 controls; white: 77 cases, 184 controls	<36 wks	mixed race, excluded term births treated for preterm labor or intraamniotic infection from controls, excluded cases with PPROM, multiple gestations, preeclampsia, fetal abnormalities, medical complications such as gestational diabetes, surgeries during pregnancies	no	mother	‘−308’	N
TNF	46	meta‐analysis of 7 studies, black, white, Hispanic	643 cases, 1208 controls	<37 wks (mixed definitions among studies)	multiple studies	yes	mother	‘−308’	N
TNFR1	30	Nashville, white and black	black: 50 cases, 223 controls, white: 77 cases, 184 controls	<36 wks	mixed race, excluded term births treated for preterm labor or intraamniotic infection from controls, excluded cases with PPROM, multiple gestations, preeclampsia, fetal abnormalities, medical complications such as gestational diabetes, surgeries during pregnancies	no	mother	LD SNPs	Y
TNFR1	45	Nashville, white and black	black: mothers 49 cases, 225 controls, infants 46 cases, 224 controls; white: mothers 77 cases, 184 controls, infants 86 cases, 191 controls	<36 wks	mixed race, excluded term births treated for preterm labor or intraamniotic infection from controls, excluded cases with PPROM, multiple gestations, preeclampsia, fetal abnormalities, medical complications such as gestational diabetes, surgeries during pregnancies	no	both	6 LD SNPs	Y
TNFR2	30	Nashville, white and black	black: 50 cases, 223 controls, white: 77 cases, 184 controls	<36 wks	mixed race, excluded term births treated for preterm labor or intraamniotic infection from controls, excluded cases with PPROM, multiple gestations, preeclampsia, fetal abnormalities, medical complications such as gestational diabetes, surgeries during pregnancies	no	mother	LD SNPs	Y
TNFR2	45	Nashville, white and black	black: mothers 49 cases, 225 controls, infants 46 cases, 224 controls; white: mothers 77 cases, 184 controls, infants 86 cases, 191 controls	<36 wks	mixed race, excluded term births treated for preterm labor or intraamniotic infection from controls, excluded cases with PPROM, multiple gestations, preeclampsia, fetal abnormalities, medical complications such as gestational diabetes, surgeries during pregnancies	no	both	7 LD SNPs	Y
IL1A	31	North Carolina, white and black	black: 67 cases, 238 controls; white: 69 cases, 336 controls	<37 wks	medically indicated, induction	yes	mother	‘+4845’, ‘IVS‐109’	N
IL1A	50	Australian, white	202 cases, 185 controls	<35 wks	autoimmune disease, preeclampsia, in vitro fertilization, uterine malformation, placental abruption, nonspontaneous labor, ultrasound‐confirmed fetal abnormality, insulin‐dependent diabetes mellitus, multiple pregnancy	yes	mother	‘−889’	N
IL1A	51	Boston, white, black, Hispanic	304 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
IL1B	31	North Carolina, white and black	black: 67 cases, 238 controls; white: 69 cases, 336 controls	<37 wks	medically indicated, induction	yes	mother	‘+3954’, ‘−581’, ‘−1061’	N
IL1B	42	UK, mixed: white, black, ‘other’	48 cases, 82 controls	<37 wks	multiple gestation, medical complications, induction of labor, hypertension or diabetes while pregnant	yes	mother	3953	N
IL1B	50	Australian, white	202 cases, 185 controls	<35 wks	autoimmune disease, preeclampsia, in vitro fertilization, uterine malformation, placental abruption, nonspontaneous labor, ultrasound‐confirmed fetal abnormality, insulin‐dependent diabetes mellitus, multiple pregnancy	yes	mother	‘3962, −511’	N
IL1R1	50	Australian, white	202 cases, 185 controls	<35 wks	autoimmune disease, preeclampsia, in vitro fertilization, uterine malformation, placental abruption, nonspontaneous labor, ultrasound‐confirmed fetal abnormality, insulin‐dependent diabetes mellitus, multiple pregnancy	yes	mother	‘+970’	N
IL1R2	51	Boston, white, black, Hispanic	300 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	Y
IL1RN	56	North Carolina, white and black	95 cases, 105 controls	<37 wks	multiple gestation, medical complications, induction of labor	yes	mother	VNTR ‘intron2’	Y
IL1RN	57	Switzerland, white	25 cases, 166 controls	<37 wks	none indicated	yes, analyzed separately	mother	VNTR ‘intron2’	Y
IL1RN	58	New York, white, black, Hispanic	30 cases, 192 controls	<37 wks	<15 years old, antibiotics within 4 weeks of collection, multiple gestation, cervical cerclage, previous late‐gestation pregnancy loss, placenta previa, isoimmunization, other medical complications	unknown	mother	VNTR ‘intron2’	Y
IL1RN	50	Australian, white	202 cases, 185 controls	<35 wks	autoimmune disease, preeclampsia, in vitro fertilization, uterine malformation, placental abruption, nonspontaneous labor, ultrasound‐confirmed fetal abnormality, insulin‐dependent diabetes mellitus, multiple pregnancy	yes	mother	‘+11100’	N
IL1RN	51	Boston, white, black, Hispanic	305 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
IL2	31	North Carolina, white and black	black: 67 cases, 238 controls; white: 69 cases, 336 controls	<37 wks	medically indicated, induction	yes	mother	‘−385’	N
IL4	31	Australian, white	202 cases, 185 controls	<35 wks	autoimmune disease, preeclampsia, in vitro fertilization, uterine malformation, placental abruption, nonspontaneous labor, ultrasound‐confirmed fetal abnormality, insulin‐dependent diabetes mellitus, multiple pregnancy	yes	mother	‘−590’	Y
IL4	53	New York, white, black, Hispanic	73 mothers, 148 infants (either twins or triplets)	<37 wks	none indicated	yes	both	‘−590’	Y
IL4	51	Boston, white, black, Hispanic	306 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
IL6	54	German, white	infants: 909 case, 491 control; Mothers: 466 cases, 281 control	<37 wks	none indicated	yes	both	‘174G promoter’	Y
IL6	55	Pennsylvania, white and black	black: 12 cases, 46 controls; white: 39 cases, 110 controls	<34 wks	cervical cerclage, vaginal bleeding, preeclampsia, diabetes mellitus, collagen vascular disease	no	mother	‘−174’	Y
IL6	31	North Carolina, white and black	black: 67 cases, 238 controls; white: 69 cases, 336 controls	<37 wks	medically indicated, induction	yes	mother	‘−237’	G×E only
IL6	33	Nashville, white and black	black: 50 cases, 223 controls; white: 77 cases, 184 controls	<36 wks	mixed race, excluded term births treated for preterm labor or intraamniotic infection from controls, excluded cases with PPROM, multiple gestations, preeclampsia, fetal abnormalities, medical complications such as gestational diabetes, surgeries during pregnancies	no	mother	5 LD SNPs	G×E only
IL6	30	Nashville, white and black	black: 50 cases, 223 controls; white: 77 cases, 184 controls	<36 wks	mixed race, excluded term births treated for preterm labor or intraamniotic infection from controls, excluded cases with PPROM, multiple gestations, preeclampsia, fetal abnormalities, medical complications such as gestational diabetes, surgeries during pregnancies	no	mother	LD SNPs	N
IL6	50	Australian, white	202 cases, 185 controls	<35 wks	autoimmune disease, preeclampsia, in vitro fertilization, uterine malformation, placental abruption, nonspontaneous labor, ultrasound‐confirmed fetal abnormality, insulin‐dependent diabetes mellitus, multiple pregnancy	yes	mother	‘−174’	N
IL6R	30	Nashville, white and black	black: 50 cases, 223 controls; white: 77 cases, 184 controls	<36 wks	mixed race, excluded term births treated for preterm labor or intraamniotic infection from controls, excluded cases with PPROM, multiple gestations, preeclampsia, fetal abnormalities, medical complications such as gestational diabetes, surgeries during pregnancies	no	mother	LD SNPs	G×G only
IL6R	33	Nashville, white and black	black: 50 cases, 223 controls; white: 77 cases, 184 controls	<36 wks	mixed race, excluded term births treated for preterm labor or intraamniotic infection from controls, excluded cases with PPROM, multiple gestations, preeclampsia, fetal abnormalities, medical complications such as gestational diabetes, surgeries during pregnancies	no	mother	6 LD SNPs	Y
IL8	51	Boston, white, black, Hispanic	307 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
IL8	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘−251 A/T’	N
IL10	50	Australian, white	202 cases, 185 controls	<35 wks	autoimmune disease, preeclampsia, in vitro fertilization, uterine malformation, placental abruption, nonspontaneous labor, ultrasound‐confirmed fetal abnormality, insulin‐dependent diabetes mellitus, multiple pregnancy	yes	mother	‘−1082, −819, −592’	Y
IL10	51	Boston, white, black, Hispanic	308 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
IL10	53	New York, white, black, Hispanic	73 mothers, 148 infants (either twins or triplets)	<37 wks	none indicated	yes	both	‘−1082’	N
IL10RA	51	Boston, white, black, Hispanic	309 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
IL11	51	Boston, white, black, Hispanic	310 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
IL12A	51	Boston, white, black, Hispanic	311 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
IL18	51	Boston, white, black, Hispanic	312 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
LTA	31	North Carolina, white and black	black: 67 cases, 238 controls; white: 69 cases, 336 controls	<37 wks	medically indicated, induction	yes	mother	‘IVS1+90’, ‘IVS1−82’	Y
LTA	51	Boston, white, black, Hispanic	313 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
LTA	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	T26N	N
CSF3	51	Boston, white, black, Hispanic	302 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
IFNGR1	51	Boston, white, black, Hispanic	303 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
TGFB1	50	Australian, white	202 cases, 185 controls	<35 wks	autoimmune disease, preeclampsia, in vitro fertilization, uterine malformation, placental abruption, nonspontaneous labor, ultrasound‐confirmed fetal abnormality, insulin‐dependent diabetes mellitus, multiple pregnancy	yes	mother	‘−800, −509’	N
MBL2	50	Australian, white	202 cases, 185 controls	<35 wks	autoimmune disease, preeclampsia, in vitro fertilization, uterine malformation, placental abruption, nonspontaneous labor, ultrasound‐confirmed fetal abnormality, insulin‐dependent diabetes mellitus, multiple pregnancy	yes	mother	‘−550, 221, Arg52Cys, Gly54Asp, Gly57Glu’	Y
MBL2	59	Austria, white	102 cases, 102 controls	<36 wks	none indicated	unknown	child	‘−550, 221, Arg52Cys, Gly54ASp, Gly57Glu’	Y
TNFRSF6	60	New York, white, black, Hispanic	119 mothers, 238 infants (either twins or triplets)	<37 wks	none indicated	yes, analyzed separately	both	‘−670’	PPROM only
TNFRSF6	50	Australian, white	202 cases, 185 controls	<35 wks	autoimmune disease, preeclampsia, in vitro fertilization, uterine malformation, placental abruption, nonspontaneous labor, ultrasound‐confirmed fetal abnormality, insulin‐dependent diabetes mellitus, multiple pregnancy	yes	mother	‘−1377, −670’	N
CD14	29	NY, white, black, Hispanic	110 mother‐infant pairs	<37 wks	intrauterine demise, <24 weeks, uterine abnormalities, cervical incompetence, history of endocrine or immunosuppressive disorders, HIV‐positive	yes, analyzed separately	both	‘−159’	PROM only, G×G
CD14	54	German, white	909 preterm infants, 491 control infants; 466 preterm mothers, 281 control mothers	<37 wks	none indicated	yes	both	‘159T’	N
TLR2	61	Dutch, white	200 preterm infants, 105 term infants	<37 wks	multiple pregnancies, preeclampsia	yes	child	‘T −16934A, Arg753Gln’	Y
TLR2	71	German, white	910 preterm infants, 491 control infants; 466 preterm mothers, 281 control mothers	<37 wks	none indicated	yes	both	‘Arg753Gln’	N
TRL4	62	Finland, white	440 preterm infants, 351 control infants; 74 preterm mothers, 20 control mothers	<35 wks	none indicated	yes	both	‘Asp299Gly, Thr399Ile’	Y
TLR4	61	Dutch, white	201 preterm infants, 105 term infants	<37 wks	multiple pregnancies, preeclampsia	yes	child	‘Thr399Ile’	N
TRL4	63	Philadelphia and Detroit, black	131 PPROM cases, 246 controls	<37 wks	multiple gestation, induced labor, malformations	yes	child	‘Ala896Gly’	N
TRL4	71	German, white	911 preterm infants, 491 control infants; 466 preterm mothers, 281 control mothers	<37 wks	none indicated	yes	both	‘896G’	N
ALOX5AP	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	rs1769874, ‘SQ13S32’, ‘SQ13S25’	N
NOD2	63	Philadelphia and Detroit, black	131 PPROM cases, 246 controls	<37 wks	multiple gestation, induced labor, malformations	yes	child	‘2936insC’	PPROM only
NOD2	71	German, white	912 preterm infants, 491 control infants; 466 preterm mothers, 281 control mothers	<37 wks	none indicated	yes	both	‘3020insC’	N
Remodeling of connective tissues
MMP1	64	Philadelphia and Detroit, black	179 PPROM cases, 235 controls	<37 wks	multiple gestation, induced labor, malformations	yes	child	‘−1607’	PROM only
MMP9	65	Philadelphia and Detroit, black	74 PPROM cases, 215 controls	<37 wks	multiple gestation, fetal abnormalities, medical complications requiring labor induction	yes	mother	‘−1562’, CA repeat (−208 to−185)	PROM only
PLAT	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘−7351 C/T’	N
SERPINH1	66	Pennsylvania, black	244 PROM cases, 358 controls	<37 wks	multiple gestations, fetal abnormalities, trauma, connective tissue diseases, medical complications of pregnancy	yes, only PROM	mother	‘−656’	Y
SERPINH1	66	Pennsylvania, black	92 PPROM cases, 184 controls	<37 wks	multiple gestations, fetal abnormalities, trauma, connective tissue diseases, medical complications of pregnancy	yes, only PROM	mother	‘−656’	Y
SLC23A1	67	North Carolina, white and black	black: 129 cases, 237 controls; white: 142 cases, 335 controls	<37 wks	none indicated	yes	mother	haplotype‐tagging SNPs	N
SLC23A2	67	North Carolina, white and black	black: 129 cases, 237 controls; white: 142 cases, 335 controls	<37 wks	none indicated	yes	mother	haplotype‐tagging SNPs	Y
Premature uterine contraction
ADRB2	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘Gln27Glu’	Y
ADRB2	68	unknown	159 total mother‐infant pairs	unknown	unknown	unknown	mother, child	‘Gly16Arg, Gln27Glu’	Y
ADRB2	69	New York, Hispanic	28 preterm mothers, 251 term mothers	<37 wks	multiple gestations, chorioamnionitis, uterine malformation, abnormal placental implantation, fetal abnormalities, history or evidence of drug abuse	unknown	mother	‘Gly16Arg, Gln27Glu’	Y
DRD2	51	Boston, white, black, Hispanic	317 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
PDE4D	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	rs12188950	N
PTGER2	51	Boston, white, black, Hispanic	319 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
PTGES	51	Boston, white, black, Hispanic	320 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
PTGFR	51	Boston, white, black, Hispanic	321 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
Placental function
F2	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘G20210A’	N
F2	71	German, white	Mothers: 507 cases, 278 controls; Infants: 593 VLBW, 278 controls	<37 wks, <1500 g	none indicated	yes	both	‘G20210A’	N
F5	51	Boston, white, black, Hispanic	300 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	Y
F5	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘Arg506Gln’	N
F5	71	German, white	507 preterm mothers, 278 term mothers; 593 VLBW infants, 278 term	<37 wks, <1500 g	none indicated	yes	both	‘Arg506Gln’	N
F7	71	German, white	mothers: 507 cases, 278 controls; infants: 593 VLBW, 278 controls	<37 wks, <1500 g	none indicated	yes	both	‘121indel’	Y
F7	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘−323 INDEL, Arg353Gln’	N
F13A1	71	German, white	mothers: 507 cases, 278 controls; infants: 593 VLBW, 278 controls	<37 wks, <1500 g	none indicated	yes	both	‘Val43Leu’	Y
NOS2A	51	Boston, white, black, Hispanic	300 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	Y
NOS2A	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘−231 c/t’	Y
NOS3	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘−922 a/g’, E298D, 690 CT	Y
NOS3	51	Boston, white, black, Hispanic	315 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
FGB	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘Gln27Glu, Arg448Lys’	N
TFPI	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘−33 T/C’	N
PROC	51	Boston, white, black, Hispanic	314 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
ANXA5	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘1 C/T’	N
ADD1	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘Gly460Trp’	N
EPCR/PROCR	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘4600 A/G’	N
SERPINE1	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘675 4g/5g’, 11053 g/t	N
SERPINB2	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘Asn120Asp, Asn40Lys, Ser423Cys’	N
THBD	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘Gly127Ala’	Y
VEGF	70	Greece, white	54 cases, 79 menopausal women as controls	<37 wks	no induction, had to have evidence of regular contractions before 37 weeks	unknown	mother	‘−634’ G/C, 936 C/T	Y
Response to environmental toxins
ADH1C	51	Boston, white, black, Hispanic	322 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
PON1	73	China, Han Chinese	92 case trios, 114 control trios	28–37 wks	birth defects	unknown	child	‘Gln192Arg’	Y
PON1	72	UK, white	3266 total, population cohort	<37 wks?	none indicated	unknown	mother	‘Gln192Arg’	Y
PON2	73	China, Han Chinese	92 case trios, 114 control trios	28–37 wks	birth defects	unknown	child	‘Ala148Gly, Ser311Cys’	Y
OPRM1	51	Boston, white, black, Hispanic	301 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	Y
GSTT1	74	Pennsylvania, white and black	51 case, 904 control mother/infant pairs	<37 wks and <2500 g	>2500 g and preterm, term and LBW/SGA	unknown	both	‘null’	Y
CYP1A1	74	Pennsylvania, white and black	52 case, 904 control mother/infant pairs	<37 wks and <2500 g	>2500 g and preterm, term and LBW/SGA	unknown	both	‘*1−*3’	N
CYP2E1	74	Pennsylvania, white and black	53 case, 904 control mother/infant pairs	<37 wks and <2500 g	>2500 g and preterm, term and LBW/SGA	unknown	both	‘*1, *5B’	N
GSTM1	74	Pennsylvania, white and black	54 case, 904 control mother/infant pairs	<37 wks and <2500 g	>2500 g and preterm, term and LBW/SGA	unknown	both	‘null’	N
NAT2	74	Pennsylvania, white and black	55 case, 904 control mother/infant pairs	<37 wks and <2500 g	>2500 g and preterm, term and LBW/SGA	unknown	both	‘fast/slow’	N
Fetal stress pathway
CRHBP	51	Boston, white, black, Hispanic	316 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
Functional loss of progesterone
PGR	51	Boston, white, black, Hispanic	318 cases, 458 controls	<37 wks?	none indicated	unknown	mother	LD SNPs	N
Other
CBS	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘Leu278Thr’	N
MTHFR	52	Australian, white	443 infants with cerebral palsy, 883 infants without cerebral palsy	<37 wks	none indicated	unknown	child	‘677 c/t’	N
MTHFR	80	North Carolina, white and black	black: 67 cases, 238 controls; white: 69 cases, 336 controls	<37 wks	medically indicated, induction	yes	mother	‘677, 1298’	N
MTHFR	81	Danish, white	unknown	<37 wks?	unknown	?	diabetic mother	‘−677’ c/t	N
MTR	80	North Carolina, white and black	black: 67 cases, 238 controls; white: 69 cases, 336 controls	<37 wks	medically indicated, induction	yes	mother	‘2756’	N
MTRR	80	North Carolina, white and black	black: 67 cases, 238 controls; white: 69 cases, 336 controls	<37 wks	medically indicated, induction	yes	mother	‘66’	Y
SHMT1	80	North Carolina, white and black	black: 67 cases, 238 controls; white: 69 cases, 336 controls	<37 wks	medically indicated, induction	yes	mother	‘1420’	Y, G×E
PPARG	82	Northern Ireland, white	two cohorts of 382, 620 singleton births	<37 wks?	none indicated	unknown	child	‘Pro12Ala’	Y

PPROM‐preterm premature rupture of membranes, LD‐linkage disequilibrium, SNP‐single nucleotide polymorphism, VNTP‐variable number tandem repeat, VLBW‐very low birth weight, LBW‐low birth weight, SGA‐small for gestational age

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