In men with autoimmune thyroid disease, a common variant located upstream of the IL12B coding region may influence whether patients present with Graves' disease or Hashimoto's disease.
As part of its efforts to identify genes affecting the risk of type I diabetes (T1D), the Type I Diabetes Genetics Consortium commissioned an extensive survey of variants associated with genes reported earlier to have an association with disease susceptibility. In this report, we present the analysis of a set of single-nucleotide polymorphisms (SNPs) within and flanking the IL12B gene, which encodes the p40 subunit of the cytokines interleukin (IL)-12 and IL-23. No SNP showed individually significant association in the population as a whole. Nevertheless, subjects stratified according to genotype at the earlier reported SNP in the IL12B 3 0 UTR, rs3212227, confirmed small, but significant, differences in age of disease onset with a relative hazard ¼ 0.88 (P ¼ 0.005). The protective effect of rs3212227 allele 2 was gender specific (P ¼ 0.004 overall and P ¼ 0.0003 when unaffected siblings were considered). Among females, the 2.2 genotype was more protective, with relative hazard ¼ 0.75. We conclude that while there was no major effect of IL12B polymorphisms on T1D susceptibility in the entire study group, they have an impact on a subset of at-risk individuals.
Complement control proteins (CCPs) contain repeated protein domains, short consensus repeats (SCRs), which must be relevant to diverse functions such as complement activation, coagulation, viral binding, fetal implantation, and self-nonself recognition. Although SCRs share some discontinuous and imperfect motifs, there are many variable positions and indels making classification in subfamilies extremely difficult. Using domain-by-domain phylogenetic analysis, we have found that most domains can be classified into only 11 subfamilies, designated a, b, c, d, e, f, g, h, i, j, or k and identified by critical residues. Each particular CCP is characterized by the order of representatives of the subfamilies. Human complement receptor 1 (CR1) has ajefbkd repeated four times and followed by ch. The classification crosses CCPs and indicates that a particular CCP is a function of the mix of SCRs. The aje set is a feature of several CCPs including human CR1 and DAF and murine Crry and appears to be associated with the success or failure of implantation inter alia. This approach facilitates genomic analysis of available sequences and suggests a framework for the evolution of CCPs. Units of duplication range from single SCRs, to septamers such as efbkdaj, to extensive segments such as MCP-CR1L. Imperfections of duplication with subsequent deletion have contributed to diversification.
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