Multilocus interactions at maternal tumor necrosis factor-α, tumor necrosis factor receptors, interleukin-6 and interleukin-6 receptor genes predict spontaneous preterm labor in European-American women

Ramkumar Menon, Digna R. Velez, Hyagriv Simhan, Kelli Ryckman, Lan Jiang, Poul Thorsen, Ida Vogel, Bo Jacobsson, Mario Merialdi, Scott M. Williams, Stephen J. Fortunato

Research output: Contribution to journalArticle

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Abstract

Objective: We hypothesize that genetic variations (single nucleotide polymorphisms-SNPs) in the tumor necrosis factor-α (TNF-α), TNF receptors (TNFRI and TNFRII), interleukin-6 (IL-6) and IL-6 receptor (IL-6R) genes predict high-risk status for spontaneous preterm birth (sPTB) in European-American women. In this study we examine the allelic and genotypic variations and the gene-gene interactions in the TNF-α, TNFRs, IL-6, and IL-6R genes in maternal DNA samples by using a case-control model. Study design: Maternal DNA from cases of sPTB after preterm labor (n = 101) and controls (normal term labor and delivery) (n = 321) were genotyped for SNPs in the TNF-α (6), TNFRI (6), TNFRII (7), IL-6 (5), and IL-6R (3) loci. SNPs were tested for both allele and genotype differences (cases vs controls) with the use of standard genetic epidemiologic methods. Multilocus interaction was assessed with multifactor dimensionality reduction analysis (MDR) to test all single and multilocus combinations for the ability to predict sPTB. Results: Few significant allelic and genotypic associations were detected between cases and controls in maternal DNA. Single locus analysis documented independent association of SNPs at -7294 (allele and genotype) of TNFRI and 24660 (genotype) TNFRII loci with sPTB. MDR revealed a significant 3 locus model that includes SNPs -3448 of TNF-α, -7227 of IL-6, and 33314 of IL-6R. This interactive model allowed the successful prediction of pre- to low-risk genotypes is 3.50 (95% CI 2.52-4.87, P < .001). Conclusion: This is the first report to document a multilocus interaction in sPTB that predicts 65.2% of the cases in a European-American sample. Although putatively significant associations with sPTB were seen at a few single locus sites in TNFRI and TNFRII, they were not as predictive as the 3-locus model produced by MDR, suggesting the use of multilocus analyses in gene association studies of complex disease such as sPTB.

Original languageEnglish (US)
Pages (from-to)1616-1624
Number of pages9
JournalAmerican Journal of Obstetrics and Gynecology
Volume194
Issue number6
DOIs
StatePublished - Jun 2006
Externally publishedYes

Fingerprint

Interleukin-6 Receptors
Premature Obstetric Labor
Tumor Necrosis Factor Receptors
Premature Birth
Interleukin-6
Tumor Necrosis Factor-alpha
Single Nucleotide Polymorphism
Mothers
Multifactor Dimensionality Reduction
Genes
Genotype
DNA
Alleles
Epidemiologic Methods
Interleukin-5

Keywords

  • Gene-gene interactions
  • Inflammatory cytokines
  • Multilocus models
  • Prematurity rate
  • Preterm delivery
  • White women

ASJC Scopus subject areas

  • Medicine(all)
  • Obstetrics and Gynecology

Cite this

Multilocus interactions at maternal tumor necrosis factor-α, tumor necrosis factor receptors, interleukin-6 and interleukin-6 receptor genes predict spontaneous preterm labor in European-American women. / Menon, Ramkumar; Velez, Digna R.; Simhan, Hyagriv; Ryckman, Kelli; Jiang, Lan; Thorsen, Poul; Vogel, Ida; Jacobsson, Bo; Merialdi, Mario; Williams, Scott M.; Fortunato, Stephen J.

In: American Journal of Obstetrics and Gynecology, Vol. 194, No. 6, 06.2006, p. 1616-1624.

Research output: Contribution to journalArticle

Menon, Ramkumar ; Velez, Digna R. ; Simhan, Hyagriv ; Ryckman, Kelli ; Jiang, Lan ; Thorsen, Poul ; Vogel, Ida ; Jacobsson, Bo ; Merialdi, Mario ; Williams, Scott M. ; Fortunato, Stephen J. / Multilocus interactions at maternal tumor necrosis factor-α, tumor necrosis factor receptors, interleukin-6 and interleukin-6 receptor genes predict spontaneous preterm labor in European-American women. In: American Journal of Obstetrics and Gynecology. 2006 ; Vol. 194, No. 6. pp. 1616-1624.
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abstract = "Objective: We hypothesize that genetic variations (single nucleotide polymorphisms-SNPs) in the tumor necrosis factor-α (TNF-α), TNF receptors (TNFRI and TNFRII), interleukin-6 (IL-6) and IL-6 receptor (IL-6R) genes predict high-risk status for spontaneous preterm birth (sPTB) in European-American women. In this study we examine the allelic and genotypic variations and the gene-gene interactions in the TNF-α, TNFRs, IL-6, and IL-6R genes in maternal DNA samples by using a case-control model. Study design: Maternal DNA from cases of sPTB after preterm labor (n = 101) and controls (normal term labor and delivery) (n = 321) were genotyped for SNPs in the TNF-α (6), TNFRI (6), TNFRII (7), IL-6 (5), and IL-6R (3) loci. SNPs were tested for both allele and genotype differences (cases vs controls) with the use of standard genetic epidemiologic methods. Multilocus interaction was assessed with multifactor dimensionality reduction analysis (MDR) to test all single and multilocus combinations for the ability to predict sPTB. Results: Few significant allelic and genotypic associations were detected between cases and controls in maternal DNA. Single locus analysis documented independent association of SNPs at -7294 (allele and genotype) of TNFRI and 24660 (genotype) TNFRII loci with sPTB. MDR revealed a significant 3 locus model that includes SNPs -3448 of TNF-α, -7227 of IL-6, and 33314 of IL-6R. This interactive model allowed the successful prediction of pre- to low-risk genotypes is 3.50 (95{\%} CI 2.52-4.87, P < .001). Conclusion: This is the first report to document a multilocus interaction in sPTB that predicts 65.2{\%} of the cases in a European-American sample. Although putatively significant associations with sPTB were seen at a few single locus sites in TNFRI and TNFRII, they were not as predictive as the 3-locus model produced by MDR, suggesting the use of multilocus analyses in gene association studies of complex disease such as sPTB.",
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AU - Menon, Ramkumar

AU - Velez, Digna R.

AU - Simhan, Hyagriv

AU - Ryckman, Kelli

AU - Jiang, Lan

AU - Thorsen, Poul

AU - Vogel, Ida

AU - Jacobsson, Bo

AU - Merialdi, Mario

AU - Williams, Scott M.

AU - Fortunato, Stephen J.

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N2 - Objective: We hypothesize that genetic variations (single nucleotide polymorphisms-SNPs) in the tumor necrosis factor-α (TNF-α), TNF receptors (TNFRI and TNFRII), interleukin-6 (IL-6) and IL-6 receptor (IL-6R) genes predict high-risk status for spontaneous preterm birth (sPTB) in European-American women. In this study we examine the allelic and genotypic variations and the gene-gene interactions in the TNF-α, TNFRs, IL-6, and IL-6R genes in maternal DNA samples by using a case-control model. Study design: Maternal DNA from cases of sPTB after preterm labor (n = 101) and controls (normal term labor and delivery) (n = 321) were genotyped for SNPs in the TNF-α (6), TNFRI (6), TNFRII (7), IL-6 (5), and IL-6R (3) loci. SNPs were tested for both allele and genotype differences (cases vs controls) with the use of standard genetic epidemiologic methods. Multilocus interaction was assessed with multifactor dimensionality reduction analysis (MDR) to test all single and multilocus combinations for the ability to predict sPTB. Results: Few significant allelic and genotypic associations were detected between cases and controls in maternal DNA. Single locus analysis documented independent association of SNPs at -7294 (allele and genotype) of TNFRI and 24660 (genotype) TNFRII loci with sPTB. MDR revealed a significant 3 locus model that includes SNPs -3448 of TNF-α, -7227 of IL-6, and 33314 of IL-6R. This interactive model allowed the successful prediction of pre- to low-risk genotypes is 3.50 (95% CI 2.52-4.87, P < .001). Conclusion: This is the first report to document a multilocus interaction in sPTB that predicts 65.2% of the cases in a European-American sample. Although putatively significant associations with sPTB were seen at a few single locus sites in TNFRI and TNFRII, they were not as predictive as the 3-locus model produced by MDR, suggesting the use of multilocus analyses in gene association studies of complex disease such as sPTB.

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KW - Inflammatory cytokines

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KW - Prematurity rate

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