Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies.

The highly variable pharmacokinetics of tacrolimus can hamper the optimal management of kidney transplant patients. This variability has been attributed to the genetic polymorphism of CYP3A5 6986A>G, but the evidence is not clear. We conducted a meta-analysis of studies evaluating the effect of CYP3A5 polymorphism on kidney transplant recipients with tacrolimus plasma concentration divided by daily dose per body weight (C/D) and clinical outcomes. We searched in MEDLINE and EMBASE. We found evidence suggesting a significantly lower C/D among CYP3A5*1 allele carriers compared with carriers of the CYP3A5*3/*3 genotype at weeks 1 and 2, and months 1, 3, 6 and 12. We demonstrated that the expresser genotype might have higher risk of acute rejection and chronic nephrotoxicity. In conclusion, CYP3A5 6986A>G polymorphism can affect tacrolimus pharmacokinetics and the incidence of acute rejection and chronic nephrotoxicity on kidney transplant recipients. Patients at high risk of developing tacrolimus-related complications could be detected even before their kidney transplant.

CTL responses of high functional avidity and broad variant cross-reactivity are associated with HIV control.

Cytotoxic T lymphocyte (CTL) responses targeting specific HIV proteins, in particular Gag, have been associated with relative control of viral replication in vivo. However, Gag-specific CTL can also be detected in individuals who do not control the virus and it remains thus unclear how Gag-specific CTL may mediate the beneficial effects in some individuals but not in others. Here, we used a 10mer peptide set spanning HIV Gag-p24 to determine immunogen-specific T-cell responses and to assess functional properties including functional avidity and cross-reactivity in 25 HIV-1 controllers and 25 non-controllers without protective HLA class I alleles. Our data challenge the common belief that Gag-specific T cell responses dominate the virus-specific immunity exclusively in HIV-1 controllers as both groups mounted responses of comparable breadths and magnitudes against the p24 sequence. However, responses in controllers reacted to lower antigen concentrations and recognized more epitope variants than responses in non-controllers. These cross-sectional data, largely independent of particular HLA genetics and generated using direct ex-vivo samples thus identify T cell responses of high functional avidity and with broad variant reactivity as potential functional immune correlates of relative HIV control.

Association of Helicobacter pylori-related distal gastric cancer with the HLA class II gene DQB10602 and cagA strains in a southern European population.

BACKGROUND: Distinct human leukocyte antigen (HLA)-DQ genes have been associated with an increased or reduced risk for gastric cancer, but its association with Helicobacter pylori status is controversial. In the present study we evaluated the influence of host HLA DQA1 and DQB1 loci, H. pylori genotype, and socio-economic factors on predicting H. pylori-associated distal gastric cancer in a southern European population. MATERIAL AND METHODS: In a prospective case-control (1 : 2) study, 42 patients with H. pylori-associated distal gastric cancer were matched by age (+/-5 years) and gender to 84 patients with H. pylori-associated benign gastroduodenal disease (controls). The level of education received, smoking status, alcohol consumption, origin and familial history of gastric cancer were registered at inclusion. HLA DQA1 and DQB1 typing and H. pylori genotyping were determined from endoscopic gastric mucosal biopsies. RESULTS: Compared with control patients, a positive association with cagA(+) strains (p < .002) and a negative association with vacA-s2 strains (p < .02) was found in patients with distal gastric cancer. At the DQB1 locus, the (*)0602 allele was more frequent in distal gastric cancer than in controls (26.2% vs. 4.8%; p < .005). After correction for multiple comparisons (exact multiple regression analysis) the cagA(+) status and the DQB1(*)0602 allele were associated with an increased distal gastric cancer risk (OR 3.7; 95% CI = 1.33-12.26 and OR 4.82; 95% CI = 1.24-19.83, respectively) whereas the vacA-s2 status was associated with a decreased risk (OR 0.33; 95% CI = 0.10-0.94). CONCLUSION: Our findings suggest that in the H. pylori-infected southern European population, the cagA genotype and the HLA-DQB1(*)0602 gene confer an increased risk for distal gastric cancer.