Association analysis identifies ZNF750 regulatory variants in psoriasis

<p>Abstract</p> <p>Background</p> <p>Mutations in the <it>ZNF750 </it>promoter and coding regions have been previously associated with Mendelian forms of psoriasis and psoriasiform dermatitis. <it>ZNF750 </it>encodes a putative zinc finger transcription factor that is highly expressed in keratinocytes and represents a candidate psoriasis gene.</p> <p>Methods</p> <p>We examined whether <it>ZNF750 </it>variants were associated with psoriasis in a large case-control population. We sequenced the promoter and exon regions of <it>ZNF750 </it>in 716 Caucasian psoriasis cases and 397 Caucasian controls.</p> <p>Results</p> <p>We identified a total of 47 variants, including 38 rare variants of which 35 were novel. Association testing identified two <it>ZNF750 </it>haplotypes associated with psoriasis (p < 0.05). We also identified an excess of rare promoter and 5'untranslated region (UTR) variants in psoriasis cases compared to controls (p = 0.041), whereas there was no significant difference in the number of rare coding and rare 3' UTR variants. Using a promoter functional assay in stimulated human primary keratinocytes, we showed that four <it>ZNF750 </it>promoter and 5' UTR variants displayed a 35-55% reduction of <it>ZNF750 </it>promoter activity, consistent with the promoter activity reduction seen in a Mendelian psoriasis family with a <it>ZNF750 </it>promoter variant. However, the rare promoter and 5' UTR variants identified in this study did not strictly segregate with the psoriasis phenotype within families.</p> <p>Conclusions</p> <p>Two haplotypes of <it>ZNF750 </it>and rare 5' regulatory variants of <it>ZNF750 </it>were found to be associated with psoriasis. These rare 5' regulatory variants, though not causal, might serve as a genetic modifier of psoriasis.</p

Psoriasis Patients Are Enriched for Genetic Variants That Protect against HIV-1 Disease

An important paradigm in evolutionary genetics is that of a delicate balance between genetic variants that favorably boost host control of infection but which may unfavorably increase susceptibility to autoimmune disease. Here, we investigated whether patients with psoriasis, a common immune-mediated disease of the skin, are enriched for genetic variants that limit the ability of HIV-1 virus to replicate after infection. We analyzed the HLA class I and class II alleles of 1,727 Caucasian psoriasis cases and 3,581 controls and found that psoriasis patients are significantly more likely than controls to have gene variants that are protective against HIV-1 disease. This includes several HLA class I alleles associated with HIV-1 control; amino acid residues at HLA-B positions 67, 70, and 97 that mediate HIV-1 peptide binding; and the deletion polymorphism rs67384697 associated with high surface expression of HLA-C. We also found that the compound genotype KIR3DS1 plus HLA-B Bw4-80I, which respectively encode a natural killer cell activating receptor and its putative ligand, significantly increased psoriasis susceptibility. This compound genotype has also been associated with delay of progression to AIDS. Together, our results suggest that genetic variants that contribute to anti-viral immunity may predispose to the development of psoriasis

A linkage map of human chromosome 15 with an average resolution of 2 cM and containing 55 polymorphic microsatellites

We have constructed a 2.0 centiMorgan (cM) resolution genetic linkage map for chromosome 15q that contains 55 polymorphic satellites and 3 RFLPs that have placed on the map with odds for order of at least 1,000:1. Genotypes from 67 polymorphic loci (64 polymorphic microsatellites) were used to construct the map. Nine genes are included in the 1,000:1 map and 37 markers have heterozygosities of at least 70%. The sex-equal map length is 128 cM and the largest genetic interval is 11 cM (15.5 cM on the female map). The female and male map lengths are 150 cM and 106 cM, respectively. The map was constructed with 'MultiMap' and is based on the CEPH reference pedigrees and includes over 12,000 new genotypes. A sub-set of 12 markers spanning the length of the linkage map were genotyped in a somatic cell hybrid panel with breakpoints that divided 15q into five segments. Cytogenetic placement agreed with the linkage positions for each of the microsatellites tested with the exception of one (ACTC) which failed to give consistent results. Ten spontaneous new mutations were identified from a subset of 42 polymorphic microsatellites (out of a total of 20,420 transmissions), giving an apparent observed spontaneous mutation rate of 5 x 10(-4) per locus. An integrated map of chromosome 15q was also constructed with the microsatellite markers described here and previously genotyped RFLP-based markers. The sex average map spans 144.7 cM with an average distance between unique map locations of 3.5 cM and a maximum intermarker distance of 11.5 cM. These genetic linkage maps can be considered baseline maps for 15q which will be useful for physical mapping and the localization of disease genes and other genes of interest