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Background: Evolutionarily conserved sequences likely have biological function., Methods: To determine whether variation in conserved sequences in non-coding DNA contributes to risk for human disease, we studied six conserved non-coding elements in the Th2 cytokine cluster on human chromosome 5q31 in a large Hutterite pedigree and in samples of outbred European American and African American asthma cases and controls., Results: Among six conserved non-coding elements (> 100 bp, > 70% identity; human-mouse comparison), we identified one single nucleotide polymorphism (SNP) in each of two conserved elements and six SNPs in the flanking regions of three conserved elements. We genotyped our samples for four of these SNPs and an additional three SNPs each in the IL13 and IL4 genes. While there was only modest evidence for association with single SNPs in the Hutterite and European American samples (P < 0.05), there were highly significant associations in European Americans between asthma and haplotypes comprised of SNPs in the IL4 gene (P < 0.001), including a SNP in a conserved non-coding element. Furthermore, variation in the IL13 gene was strongly associated with total IgE (P = 0.00022) and allergic sensitization to mold allergens (P = 0.00076) in the Hutterites, and more modestly associated with sensitization to molds in the European Americans and African Americans (P < 0.01)., Conclusion: These results indicate that there is overall little variation in the conserved non-coding elements on 5q31, but variation in IL4 and IL13, including possibly one SNP in a conserved element, influence asthma and atopic phenotypes in diverse populations.

Asthma affects nearly 14 million people worldwide and has been steadily increasing in frequency for the past 50 years. Although environmental factors clearly influence the onset, progression, and severity of this disease, family and twin studies indicate that genetic variation also influences susceptibility. Linkage of asthma and related phenotypes to chromosome 6p21 has been reported in seven genome screens, making it the most replicated region of the genome. However, because many genes with individually small effects are likely to contribute to risk, identification of asthma susceptibility loci has been challenging. In this study, we present evidence from four independent samples in support of HLA-G as a novel asthma and bronchial hyperresponsiveness susceptibility gene in the human leukocyte antigen region on chromosome 6p21, and we speculate that this gene might contribute to risk for other inflammatory diseases that show linkage to this region.

Background: Muscarinic acetylcholine receptors are members of the superfamily of G protein-coupled, 7 transmembrane- spanning proteins. They are important in the development of airway hyperresponsiveness. In the lung the M3 receptor, encoded by the cholinergic receptor muscarinic 3 gene, is present in airway smooth muscle and mediates smooth muscle contraction., Objective: We considered the cholinergic receptor muscarinic 3 gene as a possible candidate gene for bronchial asthma and initiated studies to identify polymorphisms in the promoter region., Method: We identified 4 single-nucleotide polymorphisms (-708A/G, -627G/C, -513C/A, and -492C/T) and 2 short tandem repeat polymorphisms, a tetranucleotide (CTTT)12-20 and a dinucleotide (GT)6-19 repeat., Results: None of the identified single nucleotide polymorphisms were significantly more frequent in asthmatic patients (n = 76) compared with in healthy control subjects (n = 81). Furthermore, there was no evidence for nonrandom transmission of short tandem repeat polymorphism haplotypes to individuals with asthma or bronchial hyperresponsiveness (P >.50) in a large Hutterite pedigree. However, there was significant nonrandom transmission of haplotypes to individuals with skin test reactivity to cockroach allergens (global transmission disequilibrium test: chi2 = 38.55, P =.013)., Conclusions: These results suggest a possible role for this gene in atopic disorders.