Two Variants of the C-Reactive Protein Gene Are Associated with Risk of Pre-Eclampsia in an American Indian Population

Background: The etiology of pre-eclampsia (PE) is unknown; but it is accepted that normal pregnancy represents a distinctive challenge to the maternal immune system. C-reactive protein is a prominent component of the innate immune system; and we previously reported an association between PE and the CRP polymorphism, rs1205. Our aim was to explore the effects of additional CRP variants. The IBC (Cardiochip) genotyping microarray focuses on candidate genes and pathways related to the pathophysiology of cardiovascular disease. Methods: This study recruited 140 cases of PE and 270 matched controls, of which 95 cases met criteria as severe PE, from an American Indian community. IBC array genotypes from 10 suitable CRP SNPs were analyzed. A replication sample of 178 cases and 427 controls of European ancestry was also genotyped. Results: A nominally significant difference (p value <0.05) was seen in the distribution of discordant matched pairs for rs3093068; and Bonferroni corrected differences (P<0.005) were seen for rs876538, rs2794521, and rs3091244. Univariate conditional logistic regression odds ratios (OR) were nominally significant for rs3093068 and rs876538 models only. Multivariate logistic models with adjustment for mother's age, nulliparity and BMI attenuated the effect (OR 1.58, P = 0.066, 95% CI 0.97–2.58) for rs876538 and (OR 2.59, P = 0.050, 95% CI 1.00–6.68) for rs3093068. An additive risk score of the above two risk genotypes shows a multivariate adjusted OR of 2.04 (P = 0.013, 95% CI 1.16–3.56). The replication sample also demonstrated significant association between PE and the rs876538 allele (OR = 1.55, P = 0.01, 95% CI 2.16–1.10). We also show putative functionality for the rs876538 and rs3093068 CRP variants. Conclusion: The CRP variants, rs876538 and rs3093068, previously associated with other cardiovascular disease phenotypes, show suggestive association with PE in this American Indian population, further supporting a possible role for CRP in PE

The proportion of PAFs in ranges for TMCC and HapMap populations.

<p>The proportion of PAFs in ranges for TMCC and HapMap populations.</p

Plot of TMCC vs HapMap CEU PAFs.

<p>Plot of TMCC vs HapMap CEU PAFs.</p

Univariate, conditional logistic regression analysis of factors associated with pre-eclampsia.

<p>Univariate, conditional logistic regression analysis of factors associated with pre-eclampsia.</p

Multivariate, conditional logistic regression analysis of factors associated with pre-eclampsia and severe pre-eclampsia.

<p>*Covariates showing univariate significance, plus age, which interacts with nulliparity.</p

Characteristics of matched cases and controls.

<p>*41/201 indicates 41 minor alleles (T in this case) and 201 major alleles for a total of 242.</p><p>**Differences in allele frequency evaluated with Chi square test.</p><p>***Differences between means evaluated with paired t test.</p><p>****Differences between discrete variables evaluated with McNemar's Chi square test.</p