Genetic admixture in three mexican mestizo populations based on D1S80 and HLA‐DQA1 Loci

This study compares genetic polymorphisms at the D1S80 and HLA‐DQA1 loci in three Mexican Mestizo populations from three large states (Nuevo León, Jalisco, and the Federal District). Allele frequency distributions are relatively homogenous in the three samples; only the Federal District population shows minor differences of the HLA‐DQA1 allele frequencies compared with the other two. In terms of genetic composition, these Mestizo populations show evidence of admixture with predominantly Spanish‐European (50–60%) and Amerindian (37–49%) contributions; the African contribution (1–3%) is minor. Together with the observation that in Nuevo León, the admixture estimates based on D1S80 and HLA‐DQA1, are virtually the same as those reported earlier from blood group loci, suggests that DNA markers, such as D1S80 and HLA‐DQA1 are useful for examining genetic homogeneity/heterogeneity across Mestizo populations of Mexico. The inverse relationship of the proportion of gene diversity due to population differences (G_st) to within population gene diversity (H_s) is also consistent with theoretical predictions, supporting the use of these markers for population genetics studies. Am. J. Hum. Biol. 14:257–263, 2002. © 2002 Wiley‐Liss, Inc.     

Hemodiafiltration With Endogenous Reinfusion Improved Microinflammation and Endothelial Damage Compared With Online‐Hemodiafiltration: A Hypothesis Generating Study

Hemodiafiltration with endogenous reinfusion (HFR) after ultrafiltrate passage through a resin cartridge combines adsorption, convection, and diffusion. Our prospective single‐center crossover study compared HFR and online‐hemodiafiltration (OLHDF) effects on two uremic toxins and 13 inflammatory, endothelial status, or oxidative stress markers. After an 8‐week run‐in period of high‐flux hemodialysis, 17 eligible stable dialysis patients (median age 65 years, 10 male) without overt clinical inflammation were scheduled for four 8‐week periods in the sequence: HFR/OLHDF/HFR/OLHDF. Relative to OLHDF, HFR was associated with greater indoxyl sulfate removal and lesser abnormalities in all other study variables, namely circulating interleukin‐6, tumor necrosis factor‐alpha, proportions of activated proinflammatory (CD14+CD16+, CD14++CD16+) monocytes, endothelial progenitor cells, apoptotic endothelial microparticles, vascular endothelial growth factor, vascular cellular adhesion molecule, angiopoietins 2 and 1, annexin V, and superoxide dismutase. Differences were significant (P < 0.05) in median values of 13/15 variables. Study period comparisons were generally consistent with dialysis technique comparisons, as were data from the subgroup completing all study periods (n = 9). Our investigation provides hypothesis‐generating results suggesting that compared with OLHDF, HFR improves protein‐bound toxin removal, inflammatory and endothelial status, and oxidative stress.     

Genetic data on three complex STRs (ACTBP2, D21S11 and HUMFIBRA/FGA) in the Galician population (NW Spain)

The allele frequency distributions of three complex STRs, ACTBP2 (SE33), D21S11 and HUMFIBRA/ FGA in the population of Galicia were investigated. Analysis was carried out under denaturing conditions and fluorescent detection in the ALF DNA sequencer and typing was made by comparison with sequenced allelic ladders. No significant deviations from Hardy-Weinberg equilibrium were observed. No significant differences were found between our data and other Caucasian population data. ACTBP2 seems to be one of the most informative and polymorphic STRs. Received: 5 October 1998 / Received in revised form: 18 December 1998     

Association of PDCD1 with susceptibility to systemic lupus erythematosus

Objective

The A allele of the PD1.3 single‐nucleotide polymorphism (SNP) on the programmed cell death gene PDCD1 was markedly more frequent in patients with systemic lupus erythematosus (SLE) than in unaffected controls in a recent study involving large sets of Swedish, European American, and Mexican families. This study sought to determine the role of PDCD1 in susceptibility to SLE in the Spanish population.

Methods

Seven PDCD1 SNPs were studied in 518 SLE patients and 800 healthy control subjects who had been recruited in 5 distant towns spanning continental Spain. Patients and controls were of Spanish ancestry. The diagnosis of SLE was in accordance with the American College of Rheumatology updated classification criteria.

Results

The A allele of the PD1.3 polymorphism was significantly less frequent in Spanish female patients with SLE than in Spanish female controls (9.0% versus 13.0%, odds ratio 0.67, 95% confidence interval 0.50–0.89). This difference was consistent across the 5 sets of samples grouped by town of recruitment. The other PDCD1 SNPs were not associated with SLE susceptibility. The haplotype structure of PDCD1 in the Spanish controls was different from that reported in other healthy control populations.

Conclusion

Our results confirm the association of PDCD1 with susceptibility to SLE, but the findings show a lack of involvement of the PD1.3 SNP, which is contrary to the role of the PD1.3 A allele observed previously. These contradictory results probably reflect population differences in the haplotype structure of the PDCD1 locus. More research focusing on new polymorphisms and identifying associations in other populations will be needed to clarify the role of PDCD1 in SLE susceptibility.

     

The resolvin D1 receptor GPR32 transduces inflammation resolution and atheroprotection

Chronic inflammation is a hallmark of atherosclerosis and results from an imbalance between proinflammatory and proresolving signaling. The human GPR32 receptor, together with the ALX/FPR2 receptor, transduces biological actions of several proresolving mediators that stimulate resolution of inflammation. However, since no murine homologs of the human GPR32 receptor exist, comprehensive in vivo studies are lacking. Using human atherosclerotic lesions from carotid endarterectomies and creating a transgenic mouse model expressing human GPR32 on a Fpr2×ApoE double-KO background (hGPR32_myc×Fpr2^–/–×Apoe^–/–), we investigated the role of GPR32 in atherosclerosis and self-limiting acute inflammation. GPR32 mRNA was reduced in human atherosclerotic lesions and correlated with the immune cell markers ARG1, NOS2, and FOXP3. Atherosclerotic lesions, necrotic core, and aortic inflammation were reduced in hGPR32_mycTg×Fpr2^–/–×Apoe^–/– transgenic mice as compared with Fpr2^–/–×Apoe^–/– nontransgenic littermates. In a zymosan-induced peritonitis model, the hGPR32_mycTg×Fpr2^–/–×Apoe^–/– transgenic mice had reduced inflammation at 4 hours and enhanced proresolving macrophage responses at 24 hours compared with nontransgenic littermates. The GPR32 agonist aspirin-triggered resolvin D1 (AT-RvD1) regulated leukocyte responses, including enhancing macrophage phagocytosis and intracellular signaling in hGPR32_mycTg×Fpr2^–/–×Apoe^–/– transgenic mice, but not in Fpr2^–/–×Apoe^–/– nontransgenic littermates. Together, these results provide evidence that GPR32 regulates resolution of inflammation and is atheroprotective in vivo.     

Postmortem genetic testing should be recommended in sudden cardiac death cases due to thoracic aortic dissection

Background

Acute thoracic aortic dissections and ruptures, the main life-threatening complications of the corresponding aneurysms, are an important cause of sudden cardiac death. Despite the usefulness of the molecular diagnosis of these conditions in the clinical setting, the corresponding forensic field remains largely unexplored. The main goal of this study was to explore and validate a new massive parallel sequencing candidate gene​ assay as a diagnostic tool for acute thoracic aortic dissection autopsy cases.

Materials and methods

Massive parallel sequencing of 22 thoracic aortic disease candidate genes performed in 17 cases of thoracic aortic dissection using AmpliSeq and Ion Proton technologies. Genetic variants were filtered by location, type, and frequency at the Exome Aggregation Consortium and an internal database and further classified based on the American College of Medical Genetics and Genomics (ACMG) recommendations published in 2015. All prioritized results were confirmed by traditional sequencing.

Results

From the total of 10 potentially pathogenic genetic variants identified in 7 out of the 17 initial samples, 2 of them were further classified as pathogenic, 2 as likely pathogenic, 1 as possibly benign, and the remaining 5 as variants of uncertain significance, reaching a molecular autopsy yield of 23%, approximately.

Conclusions

This massive parallel sequencing candidate gene approach proved useful for the molecular autopsy of aortic dissection sudden cardiac death cases and should therefore be progressively incorporated into the forensic field, being especially beneficial for the anticipated diagnosis and risk stratification of any other family member at risk of developing the same condition.

     

Deletion of LCE3C and LCE3B is a susceptibility factor for psoriatic arthritis: A study in Spanish and Italian populations and meta‐analysis

Objective

The LCE3C_LCE3B‐del variant is associated with psoriasis and rheumatoid arthritis. Its role in psoriatic arthritis (PsA) is unclear, however, as shown by 3 recent studies with contradictory results. In order to investigate whether LCE3C_LCE3B‐del constitutes a risk factor for PsA susceptibility, we first tested this variant in patients with PsA from Spanish and Italian populations and then performed a meta‐analysis including the previous case–control studies.

Methods

We genotyped LCE3C_LCE3B‐del and its tag single‐nucleotide polymorphism (SNP), rs4112788, in an original discovery cohort of 424 Italian patients with PsA and 450 unaffected control subjects. A Spanish replication cohort consisting of 225 patients with PsA and 469 control subjects was also genotyped. A meta‐analysis considering 7,758 control subjects and 2,325 patients with PsA was also performed.

Results

We observed a significant association between PsA and the LCE3C_LCE3B‐del tag SNP in the Italian and Spanish cohorts, with an overall corrected P value of 0.00019 and a corresponding odds ratio of 1.35 (95% confidence interval 1.14–1.59). Stratified analyses by subphenotype indicated a stronger association for patients with oligoarticular disease. Meta‐analysis including data from all previous published studies confirmed an association of PsA with the LCE3C_LCE3B‐del tag SNP.

Conclusion

LCE3C_LCE3B‐del is a susceptibility factor for PsA, confirming the existence of a shared risk factor involving the epidermal skin barrier in autoimmune disorders.

     

Short communication: high effectiveness of etravirine in routine clinical practice in treatment-experienced HIV type 1-infected patients

The effectiveness of etravirine has not been thoroughly investigated in routine clinical practice, where adherence rates and the heterogeneous nature of patients differ from the clinical trial setting. We evaluated the effectiveness of rescue regimens containing etravirine and the factors associated with treatment response. Multicenter retrospective cohort of all consecutive patients was recruited in a routine clinical practice setting. Patients were taking rescue regimens containing etravirine plus an optimized background regimen. The primary endpoint was the percentage of patients with HIV-1 RNA <50 copies/ml at week 48. The secondary endpoints were those factors associated with treatment response to etravirine. Endpoints were evaluated using univariate and multivariate analysis. A total of 122 patients were included with a median viral load of 11,938 (1055-55,500) copies/ml at baseline. The most frequent drugs in the backbone were darunavir/ritonavir in 98 (80.3%) patients and raltegravir in 76 (62.3%). In the full dataset analysis, 73% (89/122; 95% CI, 64-81%) of patients responded to treatment at week 48; in the on-treatment analysis, 82% (89/109; 95% CI, 71-87%) responded. The factors associated with treatment failure to etravirine [HR (95% CI)] were baseline CD4(+) T cell count <200 cells/mm(3) [2.45 (1.17-5.16)] and use of raltegravir [0.47 (0.22-0.99)] and darunavir [0.45 (0.21-0.98)] as backbone drugs. Skin rash was the only adverse event directly related to etravirine and led to withdrawal in three patients (2.5%). In routine clinical practice, rescue ETR-containing regimens are well tolerated and achieve rates of virological suppression higher than those observed in its pivotal clinical trials, especially when combined with darunavir and raltegravir.     

Association study of 44 candidate genes with depressive and anxiety symptoms in post-partum women

The post-partum period is a time of extreme vulnerability for a whole spectrum of psychiatric disorders. Delivery may be considered an important risk factor in genetically susceptible women. Five hundred and eight SNPs in 44 genes at candidate pathways putatively related to mood changes after delivery were genotyped in a multicenter cohort of 1804 women from Spain. Participants completed two scales at 2-3 days, 8 weeks, and 32 weeks post-partum, the Edinburgh Post-partum Depression Scale (EPDS) and the Spielberger State-Trait Anxiety Inventory (STAI). Those women who scored 9 or more on EPDS were evaluated for major depression using the Diagnostic Interview for Genetics Studies (DIGS) adapted for post-partum depression. Association with major depression was assessed using likelihood ratio tests under a codominant genotype model. Association with scale scores was tested using linear mixed models to take into account repeated measures over time. Two intronic SNPs, one at the serotonin transporter gene (SLC6A4) and another at dopa decarboxylase (DDC), were significantly associated to STAI anxiety scores after multiple testing correction (nominal P = 0.0000513 and 0.000097, respectively). In addition, post hoc analysis at the unphased haplotype level using nominal significant SNPs revealed an association with a combination of three SNPs at protein kinase C, beta (PRKCB) with major depression, significant after multiple testing correction (nominal global P = 0.0001596). In conclusion, we detected a role of SLC6A4 in mood changes after stressful events, and revealed new putative associations involving DDC and PRKCB. Therefore, these genes deserve further investigation to confirm these results.