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Genetic variants, immune function, and risk of pre-eclampsia among American Indians.

ABSTRACT: To determine the prevalence in an American Indian population of genetic variants with putative effects on immune function and determine if they are associated with pre-eclampsia (PE).In a study of 66 cases and 130 matched controls, six single nucleotide polymorphisms (SNP) with either previously demonstrated or postulated modulating effects on the immune system were genotyped. Allele frequencies and various genetic models were evaluated by conditional logistic regression in both univariate and multiply adjusted models.Although most genetic variants lacked evidence of association with PE, the minor allele of the CRP related, rs1205 SNP in a dominant model with adjustment for age at delivery, nulliparity, and body mass index, exhibited an odds ratio of 0.259 (95% CI of 0.08-0.81, P=0.020) in relation to severe PE (48 cases). The allelic prevalence of this variant was 46.1% in this population.Of the six SNPs related to immune function in this study, a functional variant in the 3'UTR of the CRP gene was shown to be associated with severe PE in an American Indian population.

SUBMITTER: Best LG

PROVIDER: S-EPMC3253256 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Genetic variants, immune function, and risk of pre-eclampsia among American Indians.

Best Lyle G LG Nadeau Melanie M Davis Kylie K Lamb Felicia F Bercier Shellee S Anderson Cindy M CM

American journal of reproductive immunology (New York, N.Y. : 1989) 20111017 2

<h4>Problem</h4>To determine the prevalence in an American Indian population of genetic variants with putative effects on immune function and determine if they are associated with pre-eclampsia (PE).<h4>Method of study</h4>In a study of 66 cases and 130 matched controls, six single nucleotide polymorphisms (SNP) with either previously demonstrated or postulated modulating effects on the immune system were genotyped. Allele frequencies and various genetic models were evaluated by conditional logi ...[more]

PMID: 22004660

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Project description:BackgroundThe 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.MethodsThis 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.ResultsA 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.ConclusionThe 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.

Project description:Background: Genetic research may inform underlying mechanisms for disparities in the burden of type 2 diabetes mellitus among American Indians. Our objective was to assess the association of genetic variants in cardiometabolic candidate genes with B cell dysfunction via HOMA-B, insulin resistance via HOMA-IR, and type 2 diabetes mellitus in the Strong Heart Family Study (SHFS). Methods and Results: We examined the association of variants, previously associated with cardiometabolic traits (?200,000 from Illumina Cardio MetaboChip), using mixed models of HOMA-B residuals corrected for HOMA-IR (cHOMA-B), log transformed HOMA-IR, and incident diabetes, adjusted for age, sex, population stratification, and familial relatedness. Center-specific estimates were combined using fixed effect meta-analyses. We used Bonferroni correction to account for multiple testing (P < 4.13 × 10-7). We also assessed the association between variants in candidate diabetes genes with these metabolic traits. We explored the top SNPs in an independent, replication sample from Southwestern Arizona. We identified significant associations with cHOMA-B for common variants at 26 loci of which 8 were novel (PRSS7, FCRL5, PEL1, LRP12, IGLL1, ARHGEF10, PARVA, FLJ16686). The most significant variant association with cHOMA-B was observed on chromosome 5 for an intergenic variant near PARP8 (rs2961831, P = 6.39 × 10-9). In the replication study, we found a signal at rs4607517 near GCK/YKT6 (P = 0.01). Variants near candidate diabetes genes (especially GCK and KCNQ1) were also nominally associated with HOMA-IR and cHOMA-B. Conclusion: We identified variants at novel loci and confirmed those at known candidate diabetes loci associations for cHOMA-B. This study also provided evidence for association of variants at KCNQ2, CTNAA2, and KCNQ1with cHOMA-B among American Indians. Further studies are needed to account for the high heritability of diabetes among the American Indian participants of the SHFS cohort.

Dataset Information

Genetic variants, immune function, and risk of pre-eclampsia among American Indians.

Publications

Genetic variants, immune function, and risk of pre-eclampsia among American Indians.

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