Reference
Complete the bibliographic reference for the article according to AJE format.

Annells, MF, Hard, PH, Mullighan CG et al. Interleukins-1, -4, -6, -10, tumor necrosis factor, transforming growth factor-[beta], FAS, and mannose-binding protein C gene polymorphisms in Australian women: Risk of preterm birth. Am J Obstet Gynecol  2004:191;2056-67

Category of HuGE information
Specify the types of information (from the list below) available in the article:

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

1. Gene-disease association

Study hypotheses or purpose
The authors study hypotheses or main purpose for conducting the study

The purpose of this study was to examine the relationship between preterm birth and 22 single nucleotide polymorphisms in genes that encode cytokines and mediators of apoptosis and host defense.

Gene(s)
Identification of the following:

1. Gene name
2. Chromosome location
3. Gene product/function
4. Alleles
5. OMIM #
6. GDPInfo link

1. Gene name: TNF tumor necrosis factor
2. Chromosomes location: 6p21.3
3. Gene product/function:
4. Alleles: G+488A,G -238A, G-308A
5. OMIM#: 191160
6. Go to GDPInfo Genes A-Z result

1. Gene name: IL6 Interleukin 6
2. Chromosome location: 7p21
3. Gene product/function:
4. Allele: C-176G
5. OMIM#: 147620
6. Go to GDPInfo Genes A-Z result

1. Gene name: IL1A Interleukin 1 alpha
2. Chromosome location: 2q14
3. Gene product/function:
4. Allele: -889
5. OMIM#: 147760
6. Go to GDPInfo Genes A-Z result

1. Gene name: IL1B
2. Chromosome location: 2q14
3. Gene product/function:
4. Allele: +3962, -511
5. OMIM#: 147720
6. Go to GDPInfo Genes A-Z result

1. Gene name: IL-1 type 1 receptor IL1R1
2. Chromosome location: 147810
3. Gene product/function:
4. Allele: +970
5. OMIM#: 2q12
6. Go to GDPInfo Genes A-Z result

1. Gene name: IL4 Interleukin 4
2. Chromosome location:5q31.1
3. Gene product/function:
4. Allele: (-590)
5. OMIM#:147780
6. Go to GDPInfo Genes A-Z result

1. Gene name: IL10 Interleukin 10
2. Chromosome location:1q31-q32
3. Gene product/function:
4. Allele: -1082, -819, -592
5. OMIMGene product/function:: 124092
6. Go to GDPInfo Genes A-Z result

1. Gene name: FAS FAS (tumor necrosis factor receptor superfamily, member 6), alias is TNFRSF6
2. Chromosome location: 10q24.1
3. Gene product/function:
4. Allele: (-1377, -670)
5. OMIM: 134637
6. Go to GDPInfo Genes A-Z result

1. Gene Names: IL-1 receptor antagonist IL1RN
2. Chromosome location:2q14.2
3. Gene product/function:
4. Allele: (+11100)
5. OMIM#: 147679
6. Go to GDPInfo Genes A-Z result

1. Gene name:TGFB1 transforming growth factor, beta-1
2. Chromosome location: 19q13.1
3. Gene product/function:
4. Allele: -800, -509
5. OMIM#: 190180
6. Go to GDPInfo Genes A-Z result

1. Gene name: MBL2 lectin, mannose-binding, soluble,2
2. Chromosome location: 10q11.2-q21
3. Gene product/function:
4. Allele: -550, -221, codon 52 [Arg-Cys], codon 54 [Gly-Asp], codon 57 [Gly-Glu]),4
5. OMIM#: 154545
6. Go to GDPInfo Genes A-Z result

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

• Age
• Primagravida
• Smoking
• Drug use
• Alcohol use
• Chorioamnionitis
• Endometritis

Health outcome(s)
Identification of the major health outcome(s) studied

Perterm birth (PTB), stratified as 20-28 and 29-34 weeks gestation
Preterm premature rupture of membranes (PPROM)

1. Case-control
2. Cohort 
3. Cross-sectional
4. Descriptive or case series
5. Clinical trial
6. Population screening

1. Case Control

Case definition
For study designs 2, 3, and 6, the following are defined, where available:

1. Case selection criteria
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants

1. Disease case definition: Spontaneous labor and delivery between 20-35 weeks gestation.

2. Exclusion criteria: Diagnosis with an auto-immune disease, preeclampsia, in virto fertilization treatment, uterine malformation, placental abruption, non-spontaneous labor, ultrasound-confirmed fetal abnormality, insulin-dependent diabetes, or multiple pregnancy.

3. Gender: Female

4. Race/ethnicity: All were white and of European descent

5. Age: Participants had to be at least 18 at the time of enrollment.

6. Time period: not stated

7. Geographic location: Women treated at Women's and Children's Hospital, North Adelaide South Australia

8. Number of participants: 202 (68% of total eligible)

Control definition  
For study design 1, the following are defined, if available. 

1. Control selection criteria
2. Matching variables
3. Exclusion criteria 
4. Gender
5. Race/ethnicity
6. Age
7. Time period
8. Geographic location
9. Number of participants

1. Control selection criteria: No history of PTB and at least one term birth (>37 weeks).
2. Matching variables: Not Stated
3. Exclusion criteria: History of PTB. Diagnosis with an auto-immune disease, preeclampsia, in virto fertilization treatment, uterine malformation, placental abruption, non-spontaneous labor, ultrasound-confirmed fetal abnormality, insulin-dependent diabetes, or multiple pregnancy.
4. Gender: Female
5. Race/ethnicity: All were white and of European descent
6. Age: Participants had to be at least 18 at the time of enrollment.
7. Time period: not stated
8. Geographic location: Women who attended the antenatal clinic
9. Number of participants: 185 (88% of total eligible)

1. Environmental factor
2. Exposure assessment
3. Exposure definition
4. Number of participants with exposure data (%
   of total eligible)

1. Environmental factor: See above
2. Exposure assessment: self-reported and medical records
3. Exposure definition:
4. Number of Participants with exposure data: Not stated

1. Environmental factor: Data were collected on environmental factors listed above, which were included in multivariate models; however, gene-environment interactions were not assessed.

1. Gene
2. DNA source
3. Methodology
4. Number of participants genotyped (% of total eligible) 

1. Genes:
   TNF (+488, -238, -308)
   IL6 (-174)-
   IL1A (-889), IL1B (+3962, -511)
   IL-1 type 1 receptor IL1R1 (+970)
   IL4 (-590)
   IL10 (-1082, -819, -592)
   TNFRSF6 (-1377, -670)
   IL-1 receptor antagonist IL1RN (+11100)
   TGFB1 (-800, -509)
   MBL2 (-550, -221, codon 52 [Arg-Cys], codon 54 [Gly-Asp], codon 57 [Gly-Glu]),4
2. DNA source: Not stated, although presumed to be peripheral blood

3. Genotyping method: Blinded blood samples were genotype by PCR-SSP and PCR haplotyping.

4. Number of participants genotyped: 100% [Looks from Table II as if genotypes were available for all 185 cases and 202 controls.]

Univariate analysis was done for each of the polymorphisms, followed by stepwise backwards multiple logistic regression analysis with a model that included smoking, alcohol use, substance use, IL1B+3962A, IL10-GCC and TGFB1-GT. When the model was corrected for using the Bonferroni correction no results remained significant.

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

2. Gene-disease association
    > View table 3

The authors conclude that polymorphisms that modulate the immune response might have a role in preterm birth and PPROM.

Comments
Provide additional insight, including methodologic issues and/or concerns about the study

The literature suggests that PTB might be the result of an abundant inflammatory response. In such a model, multiple genetic susceptibilities and environmental exposures would act together to result in increased preterm birth risk. These authors have the data to address components of this hypothesis by examining the effects multiple pro-inflammatory polymorphisms and environmental exposures on the risk of preterm birth. However, the analysis presented here does not examine the combined impact of multiple polymorphisms and/or environmental exposures that have the same biological effect. One could examine the effects of one, two and three pro-inflammatory polymorphism and environmental exposures on the risk of preterm birth. Analyzing the data in this way may show strong combinatory effects of pro-inflammatory cytokines and/or environmental exposure on the risk of PTB. In addition to the combinatorial analysis, future studies are needed to examine the effects of the fetal genotype as well as additional racial and ethnic groups.