1. Genome-wide association study on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a risk locus
Anni A V Antikainen, et al. Cardiovasc Res. 2021 Jan 21;117(2):600-612. doi: 10.1093/cvr/cvaa045.
Aims: Diabetes is a known risk factor for coronary artery disease (CAD). There is accumulating evidence that CAD pathogenesis differs for individuals with type 1 diabetes (T1D). However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing CAD susceptibility, especially in T1D, to examine the function of these discoveries and to study the role of the known risk loci in T1D. Methods and results: We performed the largest genome-wide association study to date for CAD in T1D, comprising 4869 individuals with T1D (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 [odds ratio (OR) = 1.32, P = 1.50 × 10-8], and rs6055069 on DEFB127 promoter (OR = 4.17, P = 2.35 × 10-9), with consistent results in survival analysis. The CDKN2B-AS1 variant replicated (P = 0.04) when adjusted for diabetic kidney disease in three additional T1D cohorts (cases/controls: 434/3123). Furthermore, we explored the function of the lead discoveries with a cardio-phenome-wide analysis. Among the eight suggestive loci (P < 1 × 10-6), rs70962766 near B3GNT2 associated with central blood pressure, rs1344228 near CNTNAP5 with intima media thickness, and rs2112481 on GRAMD2B promoter with serum leucocyte concentration. Finally, we calculated genetic risk scores for individuals with T1D with the known susceptibility loci. General population risk variants were modestly but significantly associated with CAD also in T1D (P = 4.21 × 10-7). Conclusion: While general population CAD risk loci had limited effect on the risk in T1D, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with CAD in individuals with T1D. The novel finding on β-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility, and CAD, although pending on future confirmation.
2. Expression of human beta defensin 4 in genetically modified keratinocytes enhances antimicrobial activity
Andrea K Smiley, Jason Gardner, Jennifer M Klingenberg, Alice N Neely, Dorothy M Supp J Burn Care Res. 2007 Jan-Feb;28(1):127-32. doi: 10.1097/BCR.0b013E31802C88FD.
Defensins are cationic peptides of the innate host defense system with antimicrobial activity against many of the microorganisms commonly found in burn units. Beta defensins are variably expressed in the epithelia of skin and other organs. Human beta defensin 4 reportedly has antimicrobial activity against Pseudomonas aeruginosa and is not normally expressed in intact skin. Genetic modification was used to ectopically express human beta defensin 4 in cultured primary epidermal keratinocytes. Keratinocytes expressing human beta defensin 4 showed significantly elevated antimicrobial activity against clinically-isolated P. aeruginosa compared with controls. These results suggest that genetic modification of keratinocytes can increase their resistance to microbial contamination. Bioengineered skin replacements containing human beta defensin 4-modified keratinocytes may be useful for transplantation to contaminated burn wounds.
3. Equine beta-defensin-1: full-length cDNA sequence and tissue expression
Elizabeth G Davis, Yongming Sang, Frank Blecha Vet Immunol Immunopathol. 2004 May;99(1-2):127-32. doi: 10.1016/j.vetimm.2003.12.010.
beta-Defensins are cysteine-rich endogenously produced antimicrobial peptides that play an important role in innate immune defense. Although, previous investigations have identified beta-defensins in several mammalian species, no reports have identified equine beta-defensins. Using a strategy of database searching for expressed sequence tags (EST) we identified putative expression of equine beta-defensins in hepatic tissue. Based on this information, sequence specific primers were designed for the equine gene enabling the identification of the full-length cDNA sequence of equine beta-defensin-1. Comparative analyses showed that equine beta-defensin-1 has 46-52% amino-acid identity with other beta-defensins, sharing the greatest identity with porcine beta-defensin-1. Complete conservation of cysteine residues was maintained between the species evaluated, and RT-PCR analysis revealed diverse mRNA tissue expression for equine beta-defensin-1. These data extend the repertoire of equine antimicrobial peptides and expand our understanding of equine innate immunity.
