Citations

Key Points Eosinophils recruited to the airways in response to A fumigatus sensitization and challenge degranulate in response to virus infection. Activated eosinophils are antiviral and promote survival from an otherwise lethal respiratory virus infection.

Abstract A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76–0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75–0.95; P = 0.006). Considering a multiple-testing–corrected significance threshold of P < 2.5 × 10−5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79–0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852–61. ©2013 AACR.

AbstractBackground & AimsChronic kidney disease (CKD) after liver transplant (LT) is associated with increased long‐term mortality. The impact of gender on CKD before and after LT is unknown. To further define risk factors and analyse gender differences in the incidence and progression of CKD after liver transplant.MethodsFour hundred and fifty‐five consecutive adult primary solitary LT recipients were included. Iothalamate clearance tests performed over time were analysed.ResultsMean age was 51.4 ± 10.4 years with 63% males. A percentage of 29.1% of females and 21.1% of males had a GFR<60 ml/min/1.73 m2 and 10.2% of females and 5.9% of males had GFR<30 ml/min/1.73 m2 prior to transplant. At 1 year, 52.6% of recipients tested (69.6% females, 43.0% males) had GFR<60 ml/min/1.73 m2 and 7.3% (11.6% females, 4.9% males) had GFR<30 ml/min/1.73 m2. Pre‐LT GFR<60 ml/min/1.73 m2 [OR 3.28, (1.76–6.10), P ≤ 0.001], female gender (OR 2.96, (1.72–5.10), P < 0.001) and age [OR 1.09, (1.05–1.12), P < 0.001] were independently predictive of stage ≥3 CKD at 1 year post‐LT. Female gender [OR 2.52, (1.25–4.71), P = 0.004], age [OR 1.05, (1.02–1.08), P = 0.003] and NASH [OR 2.95, (1.06–8.21), P = 0.039] were independently predictive of ≥stage 3 CKD at 5 years post‐LT. Pre‐LT diabetes was associated with stage 4 CKD at 5 years [OR 2.91, (1.33–6.36), P = 0.008] post‐LT.ConclusionsIn addition to age and pre‐LT CKD, female gender and NASH are independent predictors of ≥stage 3 CKD post‐LT. Gender‐based approaches to optimize modifiable risk factors are needed to improved post‐transplant renal function.

Abstract Ovarian cancer is a clinically and molecularly heterogeneous disease. The driving forces behind this variability are unknown. Here, we report wide variation in the expression of the DNA cytosine deaminase APOBEC3B, with elevated expression in the majority of ovarian cancer cell lines (three SDs above the mean of normal ovarian surface epithelial cells) and high-grade primary ovarian cancers. APOBEC3B is active in the nucleus of several ovarian cancer cell lines and elicits a biochemical preference for deamination of cytosines in 5′-TC dinucleotides. Importantly, examination of whole-genome sequence from 16 ovarian cancers reveals that APOBEC3B expression correlates with total mutation load as well as elevated levels of transversion mutations. In particular, high APOBEC3B expression correlates with C-to-A and C-to-G transversion mutations within 5′-TC dinucleotide motifs in early-stage high-grade serous ovarian cancer genomes, suggesting that APOBEC3B-catalyzed genomic uracil lesions are further processed by downstream DNA "repair" enzymes including error-prone translesion polymerases. These data identify a potential role for APOBEC3B in serous ovarian cancer genomic instability. Cancer Res; 73(24); 7222–31. ©2013 AACR.

Objective Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end‐stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene ( APOL1 ) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk. Methods APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN‐ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression. Results Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN‐ESRD cases than in SLE non‐nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN‐ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE‐ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10 −9 ), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10 −6 ). The age‐, sex‐, and admixture‐adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ∼2 years earlier among individuals with APOL1 risk genotypes ( P = 0.01). Conclusion APOL1 G1/G2 alleles strongly impact the risk of LN‐ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN‐ESRD in African Americans.