Racial disparity in pathophysiologic pathways of preterm birth based on genetic variants - PubMed (original) (raw)

Racial disparity in pathophysiologic pathways of preterm birth based on genetic variants

Ramkumar Menon et al. Reprod Biol Endocrinol. 2009.

Abstract

Objective: To study pathophysiologic pathways in spontaneous preterm birth and possibly the racial disparity associating with maternal and fetal genetic variations, using bioinformatics tools.

Methods: A large scale candidate gene association study was performed on 1442 SNPs in 130 genes in a case (preterm birth < 36 weeks) control study (term birth > 37 weeks). Both maternal and fetal DNA from Caucasians (172 cases and 198 controls) and 279 African-Americans (82 cases and 197 controls) were used. A single locus association (genotypic) analysis followed by hierarchical clustering was performed, where clustering was based on p values for significant associations within each race. Using Ingenuity Pathway Analysis (IPA) software, known pathophysiologic pathways in both races were determined.

Results: From all SNPs entered into the analysis, the IPA mapped genes to specific disease functions. Gene variants in Caucasians were implicated in disease functions shared with other known disorders; specifically, dermatopathy, inflammation, and hematological disorders. This may reflect abnormal cervical ripening and decidual hemorrhage. In African-Americans inflammatory pathways were the most prevalent. In Caucasians, maternal gene variants showed the most prominent role in disease functions, whereas in African Americans it was fetal variants. The IPA software was used to generate molecular interaction maps that differed between races and also between maternal and fetal genetic variants.

Conclusion: Differences at the genetic level revealed distinct disease functions and operational pathways in African Americans and Caucasians in spontaneous preterm birth. Differences in maternal and fetal contributions in pregnancy outcome are also different between African Americans and Caucasians. These results present a set of explicit testable hypotheses regarding genetic associations with preterm birth in African Americans and Caucasians.

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Figures

Figure 1

Top disease and disorder functions determined by IPA to be overrepresented by focus genes. Panel A, Caucasian mothers and their fetuses; panel B, African American mothers and their fetuses. Dark blue bars, maternal; light blue, fetal. The p-value for a given diseases and disorder annotation is calculated by the IPA software using Fishers Exact Test taking into account the number of focus genes that participate in that process in relation the total number of genes associated with that process in the IPA knowledgebase.

Figure 2

Top ranking gene/protein networks determined by IPA analysis in Caucasian maternal (net work score 34) and fetal (net work score 38). Panel A, maternal networks; panel B, fetal networks. Solid lines show direct interaction (binding/physical contact); dashed line, indirect interaction supported by the literature but possibly involving one or more intermediate molecules that have not been investigated definitively. Molecular interactions involving only binding are connected with a solid line (no arrowhead) since directionality cannot be inferred. Focus genes: pink color, met criteria for case-control comparison for genotype at p ≤ 0.05; red, met criteria for case-control comparison for genotype at p ≤ 0.001; grey, indicating one or more SNP was analyzed in our data set but case-control comparison did not meet p ≤ 0.05; no color – additional interconnected genes generated algorithmically by IPA, i.e., proteins, or complexes, including new potential biomarkers. * indicates that there was more than one SNP probe for this gene tested and the most significant was placed into the analysis.

Figure 3

Second ranking gene/protein networks determined by IPA analysis in Caucasian maternal (net work score 32) and fetal (net work score 29). Panel A, maternal networks; panel B, fetal networks. Solid lines show direct interaction (binding/physical contact); dashed line, indirect interaction supported by the literature but possibly involving one or more intermediate molecules that have not been investigated definitively. Molecular interactions involving only binding are connected with a solid line (no arrowhead) since directionality cannot be inferred. Focus genes: pink color, met criteria for case-control comparison for genotype at p ≤ 0.05; red, met criteria for case-control comparison for genotype at p ≤ 0.001; grey, indicating one or more SNP was analyzed in our data set but case-control comparison did not meet p ≤ 0.05; no color – additional interconnected genes generated algorithmically by IPA, i.e., proteins, or complexes, including new potential biomarkers. * indicates that there was more than one SNP probe for this gene tested and the most significant was placed into the analysis.

Figure 4

Third ranking Gene/protein networks determined by IPA analysis in Caucasian maternal (net work score 16) and fetal (net work score 13). Panel A, maternal networks; panel B, fetal networks. Solid lines show direct interaction (binding/physical contact); dashed line, indirect interaction supported by the literature but possibly involving one or more intermediate molecules that have not been investigated definitively. Molecular interactions involving only binding are connected with a solid line (no arrowhead) since directionality cannot be inferred. Focus genes: pink color, met criteria for case-control comparison for genotype at p ≤ 0.05; red, met criteria for case-control comparison for genotype at p ≤ 0.001; grey, indicating one or more SNP was analyzed in our data set but case-control comparison did not meet p ≤ 0.05; no color – additional interconnected genes generated algorithmically by IPA, i.e., proteins, or complexes, including new potential biomarkers. * indicates that there was more than one SNP probe for this gene tested and the most significant was placed into the analysis.

Figure 5

Top ranking gene/protein networks determined by IPA analysis in African Americans maternal (net work score 33) and fetal (net work score 40). Panel A, maternal networks; panel B, fetal networks. Solid lines show direct interaction (binding/physical contact); dashed line, indirect interaction supported by the literature but possibly involving one or more intermediate molecules that have not been investigated definitively. Molecular interactions involving only binding are connected with a solid line (no arrowhead) since directionality cannot be inferred. Focus genes: pink color, met criteria for case-control comparison for genotype at p ≤ 0.05; red, met criteria for case-control comparison for genotype at p ≤ 0.001; grey, indicating one or more SNP was analyzed in our data set but case-control comparison did not meet p ≤ 0.05; no color – additional interconnected genes generated algorithmically by IPA, i.e., proteins, or complexes, including new potential biomarkers. * indicates that there was more than one SNP probe for this gene tested and the most significant was placed into the analysis.

Figure 6

Second ranking gene/protein networks determined by IPA analysis in African Americans maternal (net work score 25) and fetal (net work score 15). Panel A, maternal networks; panel B, fetal networks. Solid lines show direct interaction (binding/physical contact); dashed line, indirect interaction supported by the literature but possibly involving one or more intermediate molecules that have not been investigated definitively. Molecular interactions involving only binding are connected with a solid line (no arrowhead) since directionality cannot be inferred. Focus genes: pink color, met criteria for case-control comparison for genotype at p ≤ 0.05; red, met criteria for case-control comparison for genotype at p ≤ 0.001; grey, indicating one or more SNP was analyzed in our data set but case-control comparison did not meet p ≤ 0.05; no color – additional interconnected genes generated algorithmically by IPA, i.e., proteins, or complexes, including new potential biomarkers. * indicates that there was more than one SNP probe for this gene tested and the most significant was placed into the analysis.

Figure 7

Third ranking Gene/protein networks determined by IPA analysis in Caucasian maternal (net work score 18) and fetal (net work score 13). Panel A, maternal networks; panel B, fetal networks. Solid lines show direct interaction (binding/physical contact); dashed line, indirect interaction supported by the literature but possibly involving one or more intermediate molecules that have not been investigated definitively. Molecular interactions involving only binding are connected with a solid line (no arrowhead) since directionality cannot be inferred. Focus genes: pink color, met criteria for case-control comparison for genotype at p ≤ 0.05; red, met criteria for case-control comparison for genotype at p ≤ 0.001; grey, indicating one or more SNP was analyzed in our data set but case-control comparison did not meet p ≤ 0.05; no color – additional interconnected genes generated algorithmically by IPA, i.e., proteins, or complexes, including new potential biomarkers. * indicates that there was more than one SNP probe for this gene tested and the most significant was placed into the analysis.

Figure 8

Fourth ranking Gene/protein networks determined by IPA analysis in Caucasian maternal (net work score 15) and fetal (net work score 13). Panel A, maternal networks; panel B, fetal networks. Solid lines show direct interaction (binding/physical contact); dashed line, indirect interaction supported by the literature but possibly involving one or more intermediate molecules that have not been investigated definitively. Molecular interactions involving only binding are connected with a solid line (no arrowhead) since directionality cannot be inferred. Focus genes: pink color, met criteria for case-control comparison for genotype at p ≤ 0.05; red, met criteria for case-control comparison for genotype at p ≤ 0.001; grey, indicating one or more SNP was analyzed in our data set but case-control comparison did not meet p ≤ 0.05; no color – additional interconnected genes generated algorithmically by IPA, i.e., proteins, or complexes, including new potential biomarkers. * indicates that there was more than one SNP probe for this gene tested and the most significant was placed into the analysis.

Figure 9

Legends used in network diagrams (figures 2–8).

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