Levy, H., Raby, B. A., Lake, S., Tantisira, K. G., Kwiatkowski, D., Lazarus, R., Silverman, E. K., Richter, B., Klimecki, W. T., Vercelli, D., Martinez, F. D., & Weiss, S. T. (2005). Association of defensin β-1 gene polymorphisms with asthma. Journal of Allergy and Clinical Immunology, 115(2), 252-258.
PMID: 15696078;Abstract:
Background: Defensins are antimicrobial peptides that may take part in airway inflammation and hyperresponsiveness. We characterized the genetic diversity in the defensin β-1 (DEFB1) locus and tested for an association between common genetic variants and asthma diagnosis. Methods: To identify single nucleotide polymorphisms (SNPs), we resequenced this gene in 23 self-defined European Americans and 24 African Americans. To test whether DEFB1 genetic variants are associated with asthma, we genotyped 4 haplotype-tag SNPs in 517 asthmatic and 519 control samples from the Nurses' Health Study (NHS) and performed a case-control association analysis. To replicate these findings, we evaluated the DEFB1 polymorphisms in a second cohort from the Childhood Asthma Management Program. Results: Within the NHS, single SNP testing suggested an association between asthma diagnosis and a 5′ genomic SNP (g.-1816 T>C; P = .025) and intronic SNP (IVS+692 G>A; P = .054). A significant association between haplotype (Adenine, Cytosine, Thymine, Adenine [ACTA]) and asthma (P = .024) was also identified. Associations between asthma diagnosis and both DEFB1 polymorphisms were observed in Childhood Asthma Management Program, a second cohort: g.-1816 T>C and IVS+692 G>A demonstrated significant transmission distortion (P = .05 and .007, respectively). Transmission distortion was not observed in male subjects. The rare alleles (-1816C and +692A) were undertransmitted to offspring with asthma, suggesting a protective effect, contrary to the findings in the NHS cohort. Similar effects were evident at the haplotype level: ACTA was undertransmitted (P = .04) and was more prominent in female subjects (P = .007). Conclusion: Variation in DEFB1 contributes to asthma diagnosis, with apparent gender-specific effects.
Bolt, A. M., Byrd, R. M., & Klimecki, W. T. (2010). Autophagy is a biological target of arsenic. Arsenic in Geosphere and Human Diseases, As 2010 - 3rd International Congress: Arsenic in the Environment, 291-292.
Levy, H., Raby, B. A., Lake, S., Tantisira, K. G., Kwiatkowski, D., Lazarus, R., Silverman, E. K., Richter, B., Klimecki, W. T., Vercelli, D., Martinez, F. D., & Weiss, S. T. (2005). Association of defensin beta-1 gene polymorphisms with asthma. The Journal of allergy and clinical immunology, 115(2), 252-8.
Defensins are antimicrobial peptides that may take part in airway inflammation and hyperresponsiveness.
Webster, R. B., Rodriguez, Y., Klimecki, W. T., & Vercelli, D. (2007). The human IL-13 locus in neonatal CD4+ T cells is refractory to the acquisition of a repressive chromatin architecture. Journal of Biological Chemistry, 282(1), 700-709.
PMID: 17090525;Abstract:
The Th2 cytokine IL-13 is a major effector molecule in human allergic inflammation. Notably, IL-13 expression at birth correlates with subsequent susceptibility to atopic disease. In order to characterize the chromatin-based mechanisms that regulate IL-13 expression in human neonatal CD4+ T cells, we analyzed patterns of DNase I hypersensitivity and epigenetic modifications within the IL-13 locus in cord blood CD4+ T cells, naive or differentiated in vitro under Th1- or Th2-polarizing conditions. In naive CD4+ T cells, hypersensitivity associated with DNA hypomethylation was limited to the distal promoter. Unexpectedly, during both Th1 and Th2 differentiation, the locus was extensively remodeled, as revealed by the formation of numerous HS sites and decreased DNA methylation. Obvious differences in chromatin architecture were limited to the proximal promoter, where strong hypersensitivity, hypomethylation, and permissive histone modifications were found selectively in Th2 cells. In addition to revealing the locations of putative cis-regulatory elements thatmaybe required to control IL-13 expression in neonatal CD4+ T cells, our results suggest that differential IL-13 expression may depend on the acquisition of a permissive chromatin architecture at the proximal promoter in Th2 cells rather than the formation of locus-wide repressive chromatin in Th1 cells. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.
Kripke, D. F., Klimecki, W. T., Nievergelt, C. M., Rex, K. M., Murray, S. S., Shekhtman, T., Tranah, G. J., Loving, R. T., Lee, H., Rhee, M. K., Shadan, F. F., Poceta, J. S., Jamil, S. M., Kline, L. E., & Kelsoe, J. R. (2014). Circadian polymorphisms in night owls, in bipolars, and in non-24-hour sleep cycles. Psychiatry investigation, 11(4), 345-62.
People called night owls habitually have late bedtimes and late times of arising, sometimes suffering a heritable circadian disturbance called delayed sleep phase syndrome (DSPS). Those with DSPS, those with more severe progressively-late non-24-hour sleep-wake cycles, and those with bipolar disorder may share genetic tendencies for slowed or delayed circadian cycles. We searched for polymorphisms associated with DSPS in a case-control study of DSPS research participants and a separate study of Sleep Center patients undergoing polysomnography. In 45 participants, we resequenced portions of 15 circadian genes to identify unknown polymorphisms that might be associated with DSPS, non-24-hour rhythms, or bipolar comorbidities. We then genotyped single nucleotide polymorphisms (SNPs) in both larger samples, using Illumina Golden Gate assays. Associations of SNPs with the DSPS phenotype and with the morningness-eveningness parametric phenotype were computed for both samples, then combined for meta-analyses. Delayed sleep and "eveningness" were inversely associated with loci in circadian genes NFIL3 (rs2482705) and RORC (rs3828057). A group of haplotypes overlapping BHLHE40 was associated with non-24-hour sleep-wake cycles, and less robustly, with delayed sleep and bipolar disorder (e.g., rs34883305, rs34870629, rs74439275, and rs3750275 were associated with n=37, p=4.58E-09, Bonferroni p=2.95E-06). Bright light and melatonin can palliate circadian disorders, and genetics may clarify the underlying circadian photoperiodic mechanisms. After further replication and identification of the causal polymorphisms, these findings may point to future treatments for DSPS, non-24-hour rhythms, and possibly bipolar disorder or depression.