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

ICAR: endoscopic skull‐base surgery

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Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

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

Association testing of HLA B–C haplotypes with psoriasis and HIV-1 control.

<p>The B*57:01–C*06:02 haplotype is highly enriched in both psoriasis and HIV-1 control patients. The limited sample size of the HIV cohort precludes the detection of smaller effects. Only haplotypes with p<0.01 are shown.</p

Proposed model of relationship between psoriasis and HIV-1 control.

<p>Human ancestors encountered retroviruses similar to HIV-1, leading to positive selection for viral control alleles such as B*57. Individuals who develop psoriasis are enriched for viral control alleles that are aberrantly activated by environmental triggers or unknown skin antigens (possibly sharing homology to HIV-1 epitopes). When individuals with psoriasis become infected with HIV-1, they mount vigorous cytotoxic T cell and natural killer cell immune responses leading to secretion of pro-inflammatory cytokines which worsens the psoriasis. The genetic determinants for psoriasis and HIV-1 control are overlapping, but not identical.</p

Top ten classical HLA alleles associated with psoriasis, and comparison to HIV-1 controllers as published in [15].

<p>Alleles marked with † have an independent effect on HIV-1 control. A high degree of similarity is observed between psoriasis and HIV-1 control with respect to the magnitude and direction of the associated alleles. P values and ORs for psoriasis samples were adjusted by ancestry, gender, and cohort. ORs greater than 1.0 correspond to psoriasis susceptibility and control of HIV-1, whereas ORs less than 1.0 correspond to decreased psoriasis susceptibility and lack of virologic control. NS, not significant.</p

Association of rs67384697 with psoriasis and conditional analysis on HLA-C*06:02 and B*57:01.

<p>rs67384697, a G/del SNP located in the 3′UTR of HLA-C, has been shown to modulate HLA-C expression levels by affecting the binding of microRNA hsa-miR-148 to its target site <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002514#pgen.1002514-Kulkarni1" target="_blank">[37]</a>. rs67384697 is associated with HIV-1 control independent of the classical HLA-alleles HLA-B*5701 and HLA-B*27:05.</p

Association testing of extended class I and II HLA haplotypes with psoriasis and HIV-1 control.

<p>The B*57:01–C*06:02–DQA1*02:01–DQB1*03:03–DRB1*07:01 haplotype is highly enriched in both psoriasis and HIV-1 control patients. Note: HLA-DQA1 was not genotyped in the HIV cohort, thus the frequencies reflect HLA B –C–DQB1–DRB1 haplotypes. Only haplotypes with p<0.01 are shown.</p

HLA class I alleles identified by stepwise logistic regression as independently associated with psoriasis.

<p>HLA class I alleles identified by stepwise logistic regression as independently associated with psoriasis.</p