Abstract P451: Aircraft Noise Exposure As A Novel Risk Factor For Clonal Hematopoiesis Of Indeterminate Potential

Circulation ◽  
2020 ◽  
Vol 141 (Suppl_1) ◽  
Author(s):  
Jason M Collins ◽  
Alex Reiner ◽  
Joann E Manson ◽  
Alexander G Bick ◽  
Pradeep Natarajan ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Risk Factor ◽  
Postmenopausal Women ◽  
Peripheral Blood ◽  
Somatic Mutations ◽  
Noise Exposure ◽  
Aircraft Noise ◽  
Blood Draw ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis

Background: Although the etiology of clonal hematopoiesis of indeterminate potential (CHIP) remains unclear, CHIP-defining somatic mutations within hematopoietic stem cells appear to expand peripheral blood leukocyte populations, promote inflammation, and thereby increase cardiovascular disease (CVD) risk. Moreover, high noise exposures have been linked to chromosomal aberrations in bone marrow and DNA repair in peripheral blood leukocytes. We therefore examined the potential of aircraft noise exposure as a novel risk factor for CHIP. Methods: We leveraged cross-sectional data on 10,050 postmenopausal women without prior hematologic malignancy in a Women’s Health Initiative (WHI) ancillary study of 5,309 women with stroke and/or venous thromboembolic disease and 4,741 controls. We ascertained CHIP using Trans-Omics for Precision Medicine (TOPMed) whole-genome sequencing data, the GATK Mu TECT2 somatic variant caller, a pre-specified list of leukemogenic driver mutations in 74 genes, and a threshold variant allele frequency of > 0.02. In cooperation with the Federal Aviation Administration, we generated day-night-level (DNL) noise contours around 90 major U.S. airports using the Aviation Environmental Design Tool noise modelling software. The DNL imposes a penalty for nighttime noise exposure and is the primary means for assessing and regulating noise exposure in the U.S. We estimated geocoded participant address-specific, annual average DNL aircraft noise exposures in decibels (dB) from the contours on the day of blood draw and categorized individuals as exposed or non-exposed (DNL ≥ or < 45dB). We estimated the noise-related risk of CHIP as an odds ratio, 95% confidence interval (OR, 95% CI) using logistic regression before and after adjustment for age, race / ethnicity, case-control status, smoking, alcohol use, body mass index, physical activity, hearing loss, education, and neighborhood socioeconomic status. Results: Among this population of postmenopausal women (Mean age: 68.7 years; White: 82.1%; African American: 12.3%), 19.4% were exposed to aircraft noise, and 8.4% had CHIP. The age-adjusted CHIP proportion was higher among whites (8.1%) than African Americans (7.3%) and other racial/ethnic groups (6.4%). CHIP was also more common among women aged ≥ 70 years (11.5%) than those aged 60-69 years (7.5%) or 50-59 years (3.8%). Compared to non-exposed women, those exposed to aircraft noise were not at increased risk of CHIP: OR unadjusted (95% CI) = 0.95 (0.80, 1.14) and OR adjusted (95% CI) = 0.97 (0.81, 1.16). Results were insensitive to dichotomization of noise exposure at 55 dB and further exclusion of women with hearing loss. Conclusion: Our study found no evidence of an association between aircraft noise and CHIP suggesting that aircraft noise may not be a factor contributing to CHIP-defining somatic mutations linked to CVD.

scholarly journals High Prevalence of PPM1D Mutations in Therapy-Related AML/MDS Is Due to Context-Specific Clonal Hematopoiesis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 746-746
Author(s):  
Joanne Hsu ◽  
Tajhal Dayaram ◽  
Ayala Tovy ◽  
Etienne De Braekeleer ◽  
Mira Jeong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Peripheral Blood ◽  
Somatic Mutations ◽  
De Novo ◽  
Prognostic Significance ◽  
Specific Treatment ◽  
Chemotherapeutic Agents ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Fitness Advantage

Abstract Clonal hematopoiesis (CH) is a condition in which individual hematopoietic stem cells (HSCs) acquire a fitness advantage and contribute disproportionately to peripheral blood production. Somatic mutations in around 20 genes are recurrently associated with CH, with truncating mutations in PPM1D being among the most common. PPM1D encodes the WIP1 protein (Wildtype p53-Induced Phosphatase 1), which is upregulated by p53 during DNA damage and acts homeostatically to downregulate the DNA damage response (DDR). More recently, PPM1D mutations have been observed in the blood of individuals who had previously been exposed to chemotherapeutic agents for prior malignancies. The effect of PPM1D truncating mutations on hematopoiesis remains unclear, as does the precise mechanism by which PPM1D mutations confer a fitness advantage to hematopoietic stem and progenitor cells in CH. To explore the prevalence and features of PPM1D mutations in a focused subset of patients with prior chemotherapy exposure, we screened for PPM1D mutations in 156 patients with t-AML (n=77) and t-MDS (n=79) by targeted-capture deep sequencing of PPM1D and 295 cancer genes. Truncating mutations in PPM1D were detected in 31/156 cases (20%) with a mean VAF of 0.105 (range 0.02-0.48), making it the second most commonly mutated gene in t-AML/MDS after TP53 (29%). In contrast, PPM1D mutations were detected in only 0.5% of a matched de novo MDS/AML cohort, confirming a specific enrichment in therapy-related cases (Fig 1a). Notably, PPM1D-mutant CH was specifically associated with prior exposure to platinum agents (p=0.004) and etoposide (p=0.021). To investigate the mechanisms behind this clinical association, we created PPM1D truncating mutations in multiple cell lines using CRISPR-Cas9. The truncated WIP1 protein was highly stabilized, leading to a net hyperactive effect on the dephosphorylation of DDR pathway members including phospho-p53 and γH2AX. We next asked whether this translates to chemoresistance, by comparing the sensitivities of PPM1D-mutant and wild-type (WT) cells to various agents. PPM1D mutants were resistant to DNA-damaging agents such as cisplatin, etoposide and doxorubicin, but not to vincristine, a microtubule inhibitor, indicating enhanced survival in specific contexts. We then asked whether this conferred an advantage, by competing PPM1D-mutant and WT cells in vitro with multiple exposures. PPM1D mutants did not have an advantage at baseline or in the context of vincristine, but significantly outcompeted their WT counterparts when exposed to cisplatin, etoposide, and doxorubicin. Annexin V staining revealed that PPM1D mutants exhibit diminished apoptosis with DDR-inducing agents, explaining most of their competitive advantage. Co-treatment with a PPM1D inhibitor reversed this gain and may have clinical implications. To understand the in vivo parameters that impact PPM1D-mutant cell fitness, we next generated a novel Ppm1d truncated knock-in mouse model. Characterization of baseline hematopoiesis in the Ppm1d mutant mouse revealed no appreciable differences in lineage composition or proportion of hematopoietic progenitors. To analyze the factors that impact clonal evolution, we competed Ppm1d-mutant and WT cells in specific proportions in bone marrow transplantation. In the context of stress from transplantation alone, Ppm1d-mutant and WT HSCs remained at the same proportions as the initial transplant. Similarly, serial transplantation did not alter their relative contributions to peripheral blood production. In contrast, competitively transplanted mice treated with cisplatin demonstrated a striking selection for Ppm1d mutants in both the peripheral blood (Fig 1b) and LT-HSCs, suggesting that Ppm1d-mutant clones achieve greater fitness and gain a selective advantage under specific extrinsic stressors. This differs from CH-associated mutations in DNMT3A and TET2, where intrinsic characteristics such as enhanced self-renewal appear sufficient to drive clonal expansion. Broadly, this study highlights the significance of context-specificity underlying CH of different somatic mutations. Furthermore, these findings establish the prognostic significance of CH in the development of t-AML/MDS and demonstrate the importance of understanding specific treatment <-> mutation interactions to inform choices of therapeutic interventions in patients with primary cancers. Disclosures Vassiliou: Celgene: Research Funding; KYMAB: Consultancy, Equity Ownership.

scholarly journals Discovering the drivers of clonal hematopoiesis

2020 ◽  
Author(s):  
Oriol Pich ◽  
Iker Reyes-Salazar ◽  
Abel Gonzalez-Perez ◽  
Nuria Lopez-Bigas
Keyword(s):  
Positive Selection ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Cancer Genomics ◽  
Variant Calling ◽  
Selective Advantage ◽  
Cancer Genes ◽  
Driver Genes ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis

AbstractMutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) in certain conditions drive clonal hematopoiesis (CH). While some CH drivers have been identified experimentally or through epidemiological studies, the compendium of all genes able to drive CH upon mutations in HSCs is far from complete. We propose that identifying signals of positive selection in blood somatic mutations may be an effective way to identify CH driver genes, similarly as done to identify cancer genes. Using a reverse somatic variant calling approach, we repurposed whole-genome and whole-exome blood/tumor paired samples of more than 12,000 donors from two large cancer genomics cohorts to identify blood somatic mutations. The application of IntOGen, a robust driver discovery pipeline, to blood somatic mutations across both cohorts, and more than 24,000 targeted sequenced samples yielded a list of close to 70 genes with signals of positive selection in CH, available at http://www.intogen.org/ch. This approach recovers all known CH genes, and discovers novel candidates. Generating this compendium is an essential step to understand the molecular mechanisms of CH and to accurately detect individuals with CH to ascertain their risk to develop related diseases.

HLA Class I Allele-Lacking Hematopoietic Stem/Progenitor Cells Support Long-Term Clonal Hematopoiesis without Oncogenic Driver Mutations in Acquired Aplastic Anemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3894-3894
Author(s):  
Tatsuya Imi ◽  
Takamasa Katagiri ◽  
Kazuyoshi Hosomichi ◽  
Noriharu Nakagawa ◽  
Yoshitaka Zaimoku ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Progenitor Cells ◽  
Somatic Mutations ◽  
Hla Class I ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
Target Sequencing ◽  
Clonal Hematopoiesis ◽  
Oncogenic Driver

Abstract [Background] Clonal hematopoiesis is currently known to be common in patients with acquired aplastic anemia (AA). One of the most common abnormalities underlying clonal hematopoiesis in AA patients is copy-number neutral loss of heterozygosity (LOH) in the short of 6 chromosome (6pLOH) caused by acquired uniparental disomy. Hematopoietic stem/progenitor cells (HSPCs) having undergone 6pLOH are thought to evade attack by cytotoxic T lymphocytes (CTLs) specific to auto-antigens by lacking particular HLA-A alleles. These HSPCs then produce HLA class I allele-lacking [HLA(-)] leukocytes to support hematopoiesis in patients with AA patients in remission. Our recent study showed that HLA(-) granulocytes are detected in about 24% of newly-diagnosed AA patients, and the aberrant granulocytes often account for more than 95% of the total granulocytes and persist for many years. The sustainability of 6pLOH(+) HSPC clones suggests that these HSPCs may suffer from secondary somatic mutations that confer a proliferative advantage on them over normal HSPCs. Alternatively, 6pLOH(+) HSPCs may persist and continue to support hematopoiesis according to their inherent sustainability, just like the PIGA mutant HSPCs we previously described (Katagiri et al. Stem Cells, 2013). To test these hypotheses, we determined the sequences of genes associated with the clonal expansion of HSPCs in HLA(-) granulocytes. [Patients and Methods] Eleven AA patients whose percentages of HLA(-) granulocytes ranged 6.4%-99.8% (median 94.2%) of the total granulocyte population were chosen for this study. The patients (male/female, 5/6 and age 27-79 [median 53] years) had been diagnosed with severe (n=5) or non-severe (n=6) AA 2-25 [median 12.5] years earlier, and 7 and 4 patients achieved complete response and partial response, respectively after treatments with cyclosporine (CsA) alone (n=4), CsA+antithymocyte globulin (ATG, n=3), CsA+anabolic steroids (AS, n=2), AS+romiplostim (n=1), and AS alone (n=1). The lineage combinations of HLA(-) cells were granulocyte, monocytes, B cells and T cells (GMBT) in 6, GMB in 4 and GM in 1. HLA(-) and normal [HLA(+)] granulocytes were sorted from the blood leukocytes of the 11 patients and the DNA of each cell population as well as that of buccal mucosa cells was subjected to target sequencing of 61 myelodysplastic syndrome (MDS)-related genes with MiSeq. DNA samples from 5 patients including 4 patients whose HLA(-) cell percentages were greater than 95% were further analyzed by whole-exome sequencing (WES) using HiSeq. The percentage of 6pLOH(+) cells in the total granulocytes or sorted HLA(-) granulocytes were estimated using digital droplet PCR or deep sequencing of HLA alleles. [Results] Target sequencing of 8 of the 11 patients revealed somatic mutations in the HLA(-) granulocytes of 3 patients. HLA(-) granulocytes-specific mutations were found in DNMT3A, PRR5L, SMC3A, and LRCH1 (Table). The variant allele frequencies (VAF) of these mutations were far lower (5.1%-20%) than those of HLA(-) granulocytes that accounted for 95% of sorted cells. WES revealed 22 non-synonymous and 9 synonymous mutations in the HLA(-) granulocytes from 4 of the 5 patientsthat included 3 new patients and 2 patients whose samples were negative for mutations revealed by the target sequencing. The VAF of these mutations ranged from 20.7-52.5% (median 44.1%, Table). Very-high VAFs of several mutant genes suggested that these mutations occurred simultaneously with or soon after the occurrence of 6pLOH. A patient who achieved remission after romiplostim therapy without ATG showed various gene mutations that were thought to have occurred after 6pLOH. Despite of their highly biased hematopoiesis supported by single or few clones, recurrent or MDS-related oncogenic mutations were not detected in any of the 11 patients. Of note, the percentages of 6pLOH(+) cells in the sorted HLA(-) granulocytes were ≤75% (36.7%, 46%, 74%, and 75%) in 4 patients, indicating the presence of granulocytes lacking HLA-A alleles through mechanisms other than 6pLOH. [Conclusions] HLA(-) HSPCs caused by 6pLOH or other unknown mechanisms support long-term hematopoiesis without the development of oncogenic driver mutations that are associated with clonal hematopoiesis of MDS; as such, clonal hematopoiesis by 6pLOH(+) HSPCs may not portend a poor prognosis. Disclosures Nakao: Alexion Pharmaceuticals: Honoraria, Research Funding.

scholarly journals Effects of PARP Inhibitor Therapy on p53-Deficient Hematopoietic Stem and Progenitor Cell Fitness

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3275-3275
Author(s):  
Jeremy T Baeten ◽  
Irenaeus C.C. Chan ◽  
Daniel C. Link ◽  
Kelly L. Bolton
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Prior Exposure ◽  
Clinical Samples ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Fitness Advantage ◽  
Increased Risk ◽  
Bone Marrow Chimeras ◽  
The Impact

Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors are an important new class of anti-cancer therapies. Therapy-related myeloid neoplasia (tMN) has been reported following PARPi therapy and is associated with adverse outcomes. We have previously shown, in retrospective data, that prior chemotherapy increases the incidence of clonal hematopoiesis (CH), especially in DNA damage response (DDR) pathway genes including TP53, PPM1D, and CHEK2 and is associated with progression to tMN. In particular, patients who receive PARPi therapy are more likely to have CH compared to other therapies or untreated patients. In the IMPACT study of CH in 10,156 cancer patients, exposure to PARPi were more likely to have CH (33%) compared to untreated patients (16%). This was particularly pronounced for DDR gene mutations, with 25% of PARPi treated patients with DDR CH compared to 2% of untreated patients. In multivariate analysis accounting for demographics and exposure to other chemotherapy or radiation therapy, exposure to PARPi conferred an increased risk of DDR CH (OR = 3.6, 95% CI 1.5-8.5, p = 0.004). From these data, we hypothesize that mutations in DDR pathway genes provide a fitness advantage to hematopoietic stem/progenitor cells (HSPCs) following PARPi treatment, leading to clonal hematopoiesis. A major limitation, however of our previous work in retrospective clinical samples, is the inability to completely adjust for the confounding effect of prior exposure to cytotoxic therapy (in particular platinum therapies) and germline BRCA1/2 mutations; both which have been shown or hypothesized to increase the risk of tMN. To test whether PARPi exposure might provide a fitness advantage to HSPCs independent of prior exposure to other therapies, we first examined the response of CRISPR-gene edited TP53-/- MOLM13 cells to the PARPi Olaparib and, as a control, Cisplatin. As expected, TP53-/- cells had increased resistance to both agents, though the response was much more pronounced in Cisplatin-treated cells (Figure 1A,B). Next, we implemented a mouse model of TP53-mutant clonal hematopoiesis, by generating mixed bone marrow chimeras transplanted with a 1:9 ratio of wildtype (CD45.1) to TP53 R172H+/- (CD45.2) cells. The "baseline" contribution of TP53 R172H+/- (CD45.2) cells to peripheral blood leukocytes 8 weeks after transplantation was determined by flow cytometry. Mice were then randomized into the following three cohorts: 1) Cisplatin (6mg/kg on days 1, 8, and 15); 2) Olaparib (50mg/kg daily for 3 weeks); and 3) vehicle alone. Peripheral blood chimerism was assessed 3, 9, and 12 weeks after initiating treatment. In addition, the contribution of TP53 R172H+/- to lineage -Sca1 +Kit + (LSK) cells in the bone marrow was determined. Cisplatin treatment resulted in a significant increase in the contribution of TP53 R172H+ to peripheral blood total leukocytes, granulocytes, and bone marrow LSK cells (Figure 1C-E). In contrast, Olaparib treated mice showed no change in CD45 chimerism. From these results we conclude that p53-deficiency does not confer a strong fitness advantage to mouse HSPCs in response to PARPi treatment. This suggests that the strong association observed between prior PARPi therapy, CH and tMN in clinical cohorts may in part be due to the confounding effects of prior (often heavy) exposure to platinum-based therapy. However, the majority of patients receiving PARPi have germline heterozygous BRCA1/2 mutations that could be contributing to their hematopoietic response to PARPi therapy. Experiments are underway to test this possibility by analyzing mixed bone marrow chimeras carrying heterozygous mutations of both Brca1 and Trp53. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Evaluation and Management of Patients with Diabetes and Hearing Loss

2019 ◽  
Vol 40 (04) ◽  
pp. 308-314 ◽  
Author(s):  
Christopher Spankovich ◽  
Krishna Yerraguntla
Keyword(s):  
Diabetes Mellitus ◽  
Hearing Loss ◽  
Risk Factor ◽  
Noise Exposure ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Patients With Diabetes ◽  
Acquired Hearing Loss ◽  
Ototoxic Drugs

AbstractDiabetes mellitus is a significant risk factor for acquired hearing loss and tinnitus. Persons with diabetes (PWD) may present with hearing loss symptoms earlier in life than those without diabetes. Furthermore, diabetes may exacerbate risk for hearing loss related to noise exposure and ototoxic drugs. The purpose of this article is to provide recommendations for the prevention, screening, evaluation, and management of hearing loss in PWD.

scholarly journals 288 Hearing Loss as a Potentially Modifiable Risk Factor in People with Mild Cognitive Symptoms Attending a Specialist Memory Service

2019 ◽  
Vol 48 (Supplement_3) ◽  
pp. iii17-iii65
Author(s):  
Cathy McHale ◽  
Jennifer Sharkey ◽  
Tara Coughlan ◽  
Desmond O’Neill ◽  
Joshi Dookhy ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Risk Factor ◽  
Hearing Aids ◽  
Noise Exposure ◽  
Care Pathway ◽  
Pure Tone Audiometry ◽  
Modifiable Risk Factor ◽  
Speech Discrimination ◽  
Loss Assessment ◽  
Memory Assessment

Abstract Background People with mild hearing loss at age 50 are twice as likely to develop dementia increasing to a five times greater risk for those with severe hearing loss. The prevalence of dementia and hearing impairment increase with age. Intact hearing enables cognition, facilitates social interaction and enhances communication. Hearing loss, social isolation and dementia are commonly interwoven. We recently commenced routine audiology screening in our memory service. Methods Consecutive patients with mild cognitive impairment attending a tertiary memory assessment and support service were referred for full audiology screening. People were routinely referred on basis of cognitive diagnosis, and not on the basis of perceived hearing loss. Assessment included ENT history, otoscopy, tympanometry, pure tone audiometry and speech audiometry to determine the presence, type and amount of any hearing loss present. This included speech discrimination testing – a functional test to determine processing of 10 phonetically balanced words with 100% being an optimal response. Results 20 people (12 women), mean age 72.3 (range 57-87) were assessed. The majority had amnestic MCI 18/20 (90%). 9/20 (45%) patients subjectively complained of hearing loss. 7/20 (35%) had history of occupational noise exposure. 12/20 (60%) had occlusion due to ear wax. Hearing loss identified: Mild 8/20 (40%); Moderate to severe 7/20 (35%); with Normal hearing in 5/20 (25%). High frequency hearing loss was noted in 19/20 (95%). Speech discrimination score was impaired in those with hearing loss: mean 89.4% (range 66-100). 6/20 (30%) received referral for hearing aids. Conclusion This study highlights the importance of incorporating an assessment of auditory acuity as part of memory assessment and post-diagnostic care-pathway for people with mild cognitive complaints given the established impact hearing loss has on the future risk for cognitive decline. Hearing loss is frequently unidentified and is a clear modifiable risk factor to promote brain health.

scholarly journals Somatic mutations and clonal hematopoiesis in congenital neutropenia

Blood ◽  
2018 ◽  
Vol 131 (4) ◽  
pp. 408-416 ◽  
Author(s):  
Jun Xia ◽  
Christopher A. Miller ◽  
Jack Baty ◽  
Amrita Ramesh ◽  
Matthew R. M. Jotte ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Congenital Neutropenia ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Mutation Burden ◽  
Key Points

Key Points Hematopoietic stem/progenitor mutation burden is not increased in SCN. Clonal hematopoiesis due to mutations of TP53 is present in the majority of patients with SDS.

scholarly journals Telomere length in peripheral leukocytes is a sensitive marker for assessing genetic damage among workers exposed to isopropanol, lead and noise: the case of an electronics manufacturer

2021 ◽  
Vol 43 (1) ◽  
Author(s):  
Yao Lu ◽  
Xinxia Liu ◽  
Zhiqiang Zhao ◽  
Xiaoyan Ou ◽  
Yarui Yang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Telomere Length ◽  
Peripheral Blood ◽  
Protective Factor ◽  
Noise Exposure ◽  
Blood Lead ◽  
Regression Equation ◽  
Occupational Hazards ◽  
Genetic Damage ◽  
Exposed Workers

Abstract Background Workers in electronics manufacturers may be exposed to various occupational hazards such as isopropanol, lead, and noise. Telomeres are special segments of cap-like DNA protein complex at end of liner chromosomes in eukaryotic cells. Telomere length is a potential marker of genetic damage. The aim of this study is to evaluate the effect of occupational hazards on the relative telomere length (rTL) of peripheral blood cells of workers in an electronics manufacturer, and to explore whether relative telomere length could be a biomarker for assessing genetic damage in the electronics manufacturing industry. Methods We investigated a large-scale electronics manufacturer in the Pearl River Delta Region. We ultimately collected 699 qualified workers (248 with isopropanol exposure, 182 with lead exposure, 157 with noise exposure, and 112 controls). During physical examination of the workers, we gave them questionnaires to understand their health statuses and living habits. We also collected peripheral blood samples from these workers to test exposure levels and rTL in the leucocytes. Results The concentrations of air isopropanol in all monitored workshops was 25.3 mg/m3 and air lead smoke was 0.020 mg/m3. The maximum equivalent continuous A sound level noise exposure position was 82.2dB (A). All were lower than those in the Occupational Exposure Limits in Workplaces in China. Urinary acetone in the isopropanol exposed group was 1.04 (0, 1.50) mg/L, and cumulative urinary acetone was 1.48 (0, 5.09) mg-years/L. Blood lead levels (BLLs) were 28.57 (22.77, 37.06) µg/dL, and cumulative blood lead levels (CBLLs) were 92.75 (55.47, 165.13) µg-years/dL. rTL was different between occupational exposed workers and controls: rTL was 0.140 units (95 % CI: 0.022, 0.259) shorter in lead exposed workers and 0.467 units (95 % CI: 0.276–0.658) shorter in noise exposed workers compared to the controls. There is no statistical difference in rTL between isopropanol exposure workers and the controls. In order to elucidate the relationship between rTL and occupational hazards exposure, we divided the isopropanol exposure workers into three groups (0, ~1.43 mg/L, and >1.43 mg/L). None of the rTL difference was statistically significant among exposed workers at different uroacetone levels (P>0.05). The groups with ≥100 µg/dL blood lead had shorter rTL than the group with blood lead below 100 µg/dL (F=4.422, P=0.013). We incorporated age, gender, birthplace, race, education level, smoking, and alcohol consumption into the linear regression equation. Only blood lead concentration (X) was entered into the regression equation, yielding a multivariate linear regression equation of Y=0.397-0.124X (F=8.091, P=0.005). Workers with different hearing loss also had statistically significant differences in rTL (F=5.731, P=0.004). rTL was a protective factor for the occurrence of noise-induced hearing loss (NIHL). The longer the rTL, the lower the risk of NIHL [OR=0.64 (0.42, 0.98)]. Conclusions rTL was shorter in lead exposed workers and noise exposed workers, and it was a protective factor for the occurrence of the noise-induced hearing loss. Thus, rTL of peripheral blood may be a sensitive marker of genetic damage among workers in environments with lead and noise exposure.

scholarly journals Clonal Hematopoiesis Is Associated with Risk of Cardiovascular Disease in Individuals with Human Immunodeficiency Virus

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3277-3277
Author(s):  
Brian Wiley ◽  
Kristin Erlandson ◽  
Katherine Tassiopoulos ◽  
Yizhe Song ◽  
Rachel Presti ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Risk Factor ◽  
Research Funding ◽  
Case Control ◽  
Reverse Transcriptase Inhibitors ◽  
Blood Draw ◽  
Clonal Hematopoiesis ◽  
Increased Risk ◽  
Living With Hiv

Abstract Introduction An estimated 1.2 million individuals in the United States are living with HIV (www.hiv.gov). Thanks to modern antiretroviral therapies (ART), the life expectancies of individuals living with HIV now approach those of people without HIV (Marcus 2020). But with this, an increase in the proportion of deaths due to non-infectious causes has occurred including, predominately, cardiovascular disease (CVD). Multiple studies have shown that HIV infection is an independent risk factor for cardiovascular disease. This increased risk is multifactorial due to an increased prevalence of traditional CVD risk factors and HIV-specific risk factors including ART, chronic inflammation and immune activation (Hsue 2010). Clonal Hematopoiesis, characterized by the expansion of blood cells stemming from a mutant hematopoietic stem/progenitor cell (HSPCs) is an emerging risk factor for cardiovascular disease. Mechanistically, this is thought to be driven, at least in part, by CH-induced proinflammatory circulating leukocytes (Jaiswal 2017, Bick 2020). Recent data suggest that inflammatory states may also promote the expansion of DNMT3A and TET2 CH mutant HSPCs suggesting a potential feedback loop (Zheng 2019, King 2019). CH has been recently reported to be increased among individuals living with HIV (Dharan 2021). Whether CH is a risk factor for HIV-associated CVD is not known. Given evidence of an increased prevalence of CH among those with HIV, we hypothesized that CH would predict risk of CVD. Methods We performed a nested case-control study drawn from the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) observational study which was a long-term study of individuals with newly diagnosed HIV receiving ART (N=4,371). Cases who developed a cardiovascular event were matched to controls with no event based on age at blood draw and sex. Peripheral blood mononuclear cells (PMBCs) were isolated from the blood draw closest to the time of CVD event or time of censoring, for cases and controls respectively. Extracted DNA was subjected to whole exome sequencing (WES) at a median depth of 500x. We also included WES data from 267 children sequenced using the same platform as a technical panel of normal (PON). Mutation calling was performed using Mutect2, VarDict and Varscan2. We retained variants that met the following criteria: 1) passed by at least two callers 2) showed statistically significant higher variant allele fraction (VAF) compared to our PON 3) had VAF between 2-35% 4) at least 6 reads supporting the variant 5) passed additional post-calling filters for germline variants and sequencing artifacts 6) were annotated as a putative driver of CH based on previously defined criteria. Results Over 13 years of follow-up we observed 83 cardiovascular events: 4 cases of ASC, 14 of stroke, 25 of cerebrovascular accident, 37 of myocardial infarction, 2 of peripheral artery disease, and 1 heart failure. The mean age of our participants was 51.6 years, 81% were male, 35% percent were African-American, 17% were Hispanic and 2% were Asian. Among 161 participants (83 cases and 78 controls) we observed at least one CH mutation in 14% of participants (18% of cases and 10% of controls). The median VAF was 3.5% with 23 individuals harboring a median of 1 mutation (range 1-2). In a conditional logistic regression model adjusted for race, Atherosclerotic Cardiovascular Disease (ASCVD) Risk Score and stratified by case-control matched pairs, CH was significantly associated with CVD (OR=3.70, 95% CI 1.03-13.23 p=0.045). Because of the possible confounding effects of classes of ART therapy on the CH-CVD association, we explored whether the prevalence of CH differed based on prior exposure to ART sub-class(es). We did not observe differences in the frequency of CH among individuals with prior exposure to different ART regimens (Non-Nucleoside Reverse Transcriptase Inhibitors 14%, Nucleoside reverse transcriptase inhibitors 17%, Protease inhibitors 20%, Integrase inhibitors 18%) Conclusions Among individuals with HIV, CH is associated with a nearly four-fold increased risk of CVD. These findings highlight the relevance of CH to HIV-associated CVD and provide support for interventions targeting potential CH-induced pro-inflammatory states among patients with HIV. Disclosures Erlandson: Gilead Sciences: Consultancy, Research Funding; Viiv Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy. Bolton: bristol myers squibb: Research Funding.

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