The genetic architecture of common traits, including the number,
frequency, and effect sizes of inherited variants that contribute to individual
risk, has been long debated. Genome-wide association studies have identified
scores of common variants associated with type 2 diabetes, but in aggregate,
these explain only a fraction of heritability. To test the hypothesis that
lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES
consortia performed whole genome sequencing in 2,657 Europeans with and without
diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral
groups. To increase statistical power, we expanded sample size via genotyping
and imputation in a further 111,548 subjects. Variants associated with type 2
diabetes after sequencing were overwhelmingly common and most fell within
regions previously identified by genome-wide association studies. Comprehensive
enumeration of sequence variation is necessary to identify functional alleles
that provide important clues to disease pathophysiology, but large-scale
sequencing does not support a major role for lower-frequency variants in
predisposition to type 2 diabetes.
The hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is an immune system modulator and induces expression of the TLR coreceptor CD14. 1,25(OH)2D3 signals through the vitamin D receptor, a ligand-stimulated transcription factor that recognizes specific DNA sequences called vitamin D response elements. In this study, we show that 1,25(OH)2D3 is a direct regulator of antimicrobial innate immune responses. The promoters of the human cathelicidin antimicrobial peptide (camp) and defensin β2 (defB2) genes contain consensus vitamin D response elements that mediate 1,25(OH)2D3-dependent gene expression. 1,25(OH)2D3 induces antimicrobial peptide gene expression in isolated human keratinocytes, monocytes and neutrophils, and human cell lines, and 1,25(OH)2D3 along with LPS synergistically induce camp expression in neutrophils. Moreover, 1,25(OH)2D3 induces corresponding increases in antimicrobial proteins and secretion of antimicrobial activity against pathogens including Pseudomonas aeruginosa. 1,25(OH)2D3 thus directly regulates antimicrobial peptide gene expression, revealing the potential of its analogues in treatment of opportunistic infections.
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