Rafael Ríos

Dectin-1 and DC-SIGN Polymorphisms Associated with Invasive Pulmonary Aspergillosis Infection

The recognition of pathogen-derived structures by C-type lectins and the chemotactic activity mediated by the CCL2/CCR2 axis are critical steps in determining the host immune response to fungi. The present study was designed to investigate whether the presence of single nucleotide polymorphisms (SNPs) within DC-SIGN, Dectin-1, Dectin-2, CCL2 and CCR2 genes influence the risk of developing Invasive Pulmonary Aspergillosis (IPA). Twenty-seven SNPs were selected using a hybrid functional/tagging approach and genotyped in 182 haematological patients, fifty-seven of them diagnosed with proven or probable IPA according to the 2008 EORTC/MSG criteria. Association analysis revealed that carriers of the Dectin-1 rs3901533 T/T and Dectin-1 rs7309123 G/G genotypes and DC-SIGN rs4804800 G, DC-SIGN rs11465384 T, DC-SIGN 7248637 A and DC-SIGN 7252229 C alleles had a significantly increased risk of IPA infection (OR = 5.59 95%CI 1.37–22.77; OR = 4.91 95%CI 1.52–15.89; OR = 2.75 95%CI 1.27–5.95; OR = 2.70 95%CI 1.24–5.90; OR = 2.39 95%CI 1.09–5.22 and OR = 2.05 95%CI 1.00–4.22, respectively). There was also a significantly increased frequency of galactomannan positivity among patients carrying the Dectin-1 rs3901533_T allele and Dectin-1 rs7309123_G/G genotype. In addition, healthy individuals with this latter genotype showed a significantly decreased level of Dectin-1 mRNA expression compared to C-allele carriers, suggesting a role of the Dectin-1 rs7309123 polymorphism in determining the levels of Dectin-1 and, consequently, the level of susceptibility to IPA infection. SNP-SNP interaction (epistasis) analysis revealed significant interactions models including SNPs in Dectin-1, Dectin-2, CCL2 and CCR2 genes, with synergistic genetic effects. Although these results need to be further validated in larger cohorts, they suggest that Dectin-1, DC-SIGN, Dectin-2, CCL2 and CCR2 genetic variants influence the risk of IPA infection and might be useful in developing a risk-adapted prophylaxis.

Genetics and molecular epidemiology of multiple myeloma: The rationale for the IMMEnSE consortium (Review)

There is strong evidence suggesting the presence of a genetic component in the aetiology of multiple myeloma (MM). However no genetic risk factors have been unequivocally established so far. To further our understanding of the genetic determinants of MM risk, a promising strategy is to collect a large set of patients in a consortium, as successfully done for other cancers. In this article, we review the main findings in the genetic susceptibility and pharmacogenetics of MM and present the strategy of the IMMEnSE (International Multiple Myeloma rESEarch) consortium in contributing to determine the role of genetic variation in pharmacogenetics and in MM risk.

Impact of polymorphic variation at 7p15.3, 3p22.1 and 2p23.3 loci on risk of multiple myeloma

whole of the UK. Wales has been a pioneer in the process of haematology harmonization, as a result of the introduction of a national laboratory information management system for Wales, and is represented on the Pathology Harmony Haematology Sub-Group. Scotland is represented on the Pathology Harmony Committee and the Scottish representatives have supported the earlier changes in Clinical Chemistry. The process to date has not been as easy as might be envisaged; it has taken much effort to reach this stage of the project. The haematology sub-group is also working closely with the DH advisor for the National Laboratory Medicine Catalogue (NLMC) on the incorporation of the changes of nomenclature and units into the NLMC, the standard for pathology test requests and results reporting, under collaborative development by the RCPath, the Department of Health and NHS Connecting for Health. The future challenges will be to move on to other areas of standardization including the development of consensus reference intervals for FBC and expansion to other areas of haematology, e.g., Hb A2, haematinic assays, coagulation factor assays and leucocyte immunophenotyping. The issue of harmonized reference intervals for the extended FBC is not expected to be straightforward, given the variation seen with age, ethnic differences and physiological state, e.g., pregnancy. For harmonized reference intervals to be effective, they must be widely adopted and this will not happen without a pragmatic approach and majority agreement within haematology.

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

Compelling biological and epidemiological evidences point to a key role of genetic variants of the TERT and TERC genes in cancer development. We analyzed the genetic variability of these two gene regions using samples of 2,267 multiple myeloma (MM) cases and 2,796 healthy controls. We found that a TERT variant, rs2242652, is associated with reduced MM susceptibility (OR = 0.81; 95% CI: 0.72–0.92; p = 0.001). In addition we measured the leukocyte telomere length (LTL) in a subgroup of 140 cases who were chemotherapy‐free at the time of blood donation and 468 controls, and found that MM patients had longer telomeres compared to controls (OR = 1.19; 95% CI: 0.63–2.24; ptrend = 0.01 comparing the quartile with the longest LTL versus the shortest LTL). Our data suggest the hypothesis of decreased disease risk by genetic variants that reduce the efficiency of the telomerase complex. This reduced efficiency leads to shorter telomere ends, which in turn may also be a marker of decreased MM risk.

Comprehensive investigation of genetic variation in the 8q24 region and multiple myeloma risk in the IMMEnSE consortium.

Genome‐wide association studies (GWAS) have shown that the 8q24 region harbours multiple independent cancer susceptibility loci, even though it is devoid of genes. Given that no GWAS data are currently available for multiple myeloma (MM), we tested the hypothesis that genetic variants in this region could play a role in MM risk. We genotyped 20 single nucleotide polymorphisms of 8q24 in 1188 MM cases and 2465 controls and found a statistically significant (P = 0·0022) association between rs2456449 and MM risk. These data provide further evidence that the genetic variability in the 8q24 region is associated with cancer risk, particularly haematological malignancies.

Genetic variants and multiple myeloma risk: IMMEnSE validation of the best reported associations--an extensive replication of the associations from the candidate gene era.

Background: Genetic background plays a role in multiple myeloma susceptibility. Several single-nucleotide polymorphisms (SNP) associated with genetic susceptibility to multiple myeloma were identified in the last years, but only a few of them were validated in independent studies. Methods: With the aim to conclusively validate the strongest associations so far reported, we selected the polymorphisms rs2227667 (SERPINE1), rs17501108 (HGF), rs3136685 (CCR7), rs16944 (IL1B), rs12147254 (TRAF3), rs1805087 (MTR), rs1800629 (TNF-α), rs7516435 (CASP9), rs1042265 (BAX), rs2234922 (mEH), and rs1801133 (MTHFR). We genotyped them in 1,498 multiple myeloma cases and 1,934 controls ascertained in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium, and meta-analyzed our results with previously published ones. Results: None of the selected SNPs were significantly associated with multiple myeloma risk (P value range, 0.055–0.981), possibly with the exception of the SNP rs2227667 (SERPINE1) in women. Conclusions: We can exclude that the selected polymorphisms are major multiple myeloma risk factors. Impact: Independent validation studies are crucial to identify true genetic risk factors. Our large-scale study clarifies the role of previously published polymorphisms in multiple myeloma risk. Cancer Epidemiol Biomarkers Prev; 23(4); 670–4. ©2014 AACR.

Transplantation-Associated Thrombotic Microangiopathy in Patients Treated With Sirolimus and Cyclosporine as Salvage Therapy for Graft-Versus-Host Disease

Background: Transplantation-associated thrombotic microangiopathy (TA-TMA) is a rare complication of hematopoietic stem cell transplantation. Because sirolimus (SIR) and calcineurin inhibitor—either cyclosporine (CsA) or tacrolimus—have become more common as graft-versus-host disease (GVHD) prophylaxis, we are witnessing a higher frequency of this complication. Objective: To analyze the incidence, timing, and management of TA-TMA in patients who received the combination of CsA and SIR as therapy for uncontrolled GVHD in one single center. Methods: This was a retrospective analysis from February 2002 to June 2014 of the combination of SIR and CsA as salvage therapy in 61 patients with treatment-refractory or relapsed acute GVHD (n = 24) or chronic GVHD (n = 37) in a tertiary hospital. Results: A total of 61 patients received CsA and SIR as salvage therapy for acute (n = 16), late acute (n = 8), overlap syndrome (n = 22), or classic chronic (n = 15) GVHD. We identified 13 patients with TA-TMA (21.3%), and the status of GVHD was active in 11 of 13 patients. Only 1 patient showed high CsA levels, and 6 of 13 patients had very high concentrations of SIR in blood. We used an enzyme inducer in 6 patients, which proved effective in 3. Overall survival for TA-TMA patients was inferior compared to that for non TA-TMA patients at 12 months (42.9% vs 51.9%) and 24 months (34.3% vs 49.1%), although this difference was not significant. Conclusion: Prompt identification and good management of TA-TMA, with better control of GVHD, may contribute to a decrease in patient mortality that would result from this complication.

Polymorphisms in regulators of xenobiotic transport and metabolism genes PXR and CAR do not affect multiple myeloma risk: a case–control study in the context of the IMMEnSE consortium

The exposure to pesticides and toxic compounds in xenobiotic transport and metabolism genes has been shown to affect risk of developing multiple myeloma (MM). Therefore, we hypothesized that genetic variations in xenobiotic transport and metabolism regulator genes PXR (NR1I2) and CAR (NR1I3) could determine a difference in MM susceptibility. Ten tagging single-nucleotide polymorphisms (SNPs) for PXR and seven for the CAR genes were selected and genotyped in 627 MM cases and 883 controls collected in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium. None of the 17 SNPs investigated showed significant association with MM risk either alone or when combined in haplotypes. Significant SNP–SNP interactions were not found, neither with 58 previously genotyped polymorphisms in ABC transporters. We can therefore exclude that common genetic variants in the xenobiotic transport and metabolism regulator genes PXR and CAR affect MM risk.

Polymorphisms in xenobiotic transporters ABCB1 , ABCG2 , ABCC2 , ABCC1 , ABCC3 and multiple myeloma risk: a case–control study in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium

Polymorphisms in xenobiotic transporters ABCB1 , ABCG2 , ABCC2 , ABCC1 , ABCC3 and multiple myeloma risk: a case–control study in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium

Attractors with irrational rotation number

Let h : R-2 -> R-2 be a dissipative and orientation preserving homeomorphism having an asymptotically stable fixed point. Let U be the region of attraction and assume that it is proper and unbounded. Using Caratheodorys prime ends theory one can associate a rotation number, rho, to h(vertical bar U). We prove that any map in the above conditions and with rho is not an element of Q induces a Denjoy homeomorphism in the circle of prime ends. We also present some explicit examples of maps in this class and we show that, if the infinity point is accessible by an arc in U, rho is not an element of Q if and only if Per(h) = Fix(h) = {p}.