Variants in the gene encoding C3 are associated with asthma and related phenotypes among African Caribbean families

Abstract

Proinflammatory and immunoregulatory products from C3 play a major role in phagocytosis, respiratory burst, and airways inflammation. C3 is critical in adaptive immunity; studies in mice deficient in C3 demonstrate that features of asthma are significantly attenuated in the absence of C3. To test the hypothesis that the C3 gene on chromosome 19p13.3-p13.2 contains variants associated with asthma and related phenotypes, we genotyped 25 single nucleotide polymorphism (SNP) markers distributed at intervals of B1.9 kb within the C3 gene in 852 African Caribbean subjects from 125 nuclear and extended pedigrees. We used the multiallelic test in the family-based association test program to examine sliding windows comprised of 2-6 SNPs. A five-SNP window between markers rs10402876 and rs366510 provided strongest evidence for linkage in the presence of linkage disequilibrium for asthma, high log[total IgE], and high log[IL-13]/[log[IFN-g] in terms of global P-values (P ¼ 0.00027, 0.00013, and 0.003, respectively). A three-SNP haplotype GGC for the first three of these markers showed best overall significance for the three phenotypes (P ¼ 0.003, 0.007, 0.018, respectively) considering haplotype-specific tests. Taken together, these results implicate the C3 gene as a priority candidate controlling risk for asthma and allergic disease in this population of African descent.

The Clinical and Environmental Determinants of Airway Transcriptional Profiles in Allergic Asthma

“…The association of complement component 3 (C3) expression with airflow obstruction and asthma is consistent with results from several mouse and human studies. C3-deficient mice show diminished airway hyperresponsiveness after allergen challenge (18), and C3 single-nucleotide polymorphism genotype associations with asthma have been identified in Japanese and AfricanCaribbean populations (19,20). The observed decreased expression of C3 in individuals with asthma (vs. individuals without asthma) might seem to contradict what would be expected for a condition associated with heightened inflammation.…”

Complement Activation Pathways: A Bridge between Innate and Adaptive Immune Responses in Asthma

“…Moreover, in support of the opposing roles of C3 and C5 in animal studies, Hasegawa and coworkers have recently reported an association between a single nucleotide polymorphism (SNP, 4896C/T) in the C3 gene and atopic asthma in both children and adults in a Japanese population, whereas SNPs in the human C5 gene are associated with protection against both childhood and adult asthma (37). Similarly, Barnes and colleagues have found a significant association between a 3-SNP haplotype in the C3 gene and asthma, IgE levels and the ratio of IFN-␥/IL-13 levels in serum in an Afro-Caribbean population (38). Interestingly, the frequency of these SNPs is high, suggesting that these polymorphisms may have conferred evolutionary advantage in the past and perhaps in protection from parasitic infections.…”

Macrophage migration inhibitory factor in acute lung injury: expression, biomarker, and associations

“…However, sliding SNP windows allows making a comprehensive screening of the region considered. As an example, Barnes et al 48 showed that a haplotype of C3 gene associated with asthma susceptibility would not have been identified if the sliding SNP window approach had not been utilized. Thus, although our results may be a false positive, the associated haplotypes span overlapping regions in European and African Americans, giving consistency to the association.…”