Germline genomic and phenomic landscape of clonal hematopoiesis in 323,112 individuals

Uddin, Md Mesbah; Yu, Zhi; Weinstock, Joshua S; Nakao, Tetsushi; Niroula, Abhishek; Urbut, Sarah; Koyama, Satoshi; Zekavat, Seyedeh M.; Paruchuri, Kaavya; Silver, Alexander J.; Mack, Taralynn; Wong, Megan; Haidermota, Sara; Bhattacharya, Romit; Jorshery, Saman Doroodgar; Raddatz, Michael A.; Honigberg, Michael C.; Hornsby, Whitney E.; Zhang, Martin Jinye; Sankaran, Vijay G.; Griffin, Gabriel K.; Gibson, Christopher J.; Kresge, Hailey A.; Ellinor, Patrick T.; Cho, Kelly; Sun, Yan V.; Wilson, Peter W.F.; Pyarajan, Saiju; Xu, Yaomin; Savona, Michael R.; Reiner, Alexander P.; Jaiswal, Siddhartha; Ebert, Benjamin L.; Bick, Alexander G.; Natarajan, Pradeep

doi:10.1101/2022.07.29.22278015

Cited by 7 publications

(8 citation statements)

References 96 publications

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“…16 CHIP was also recently assessed in participants of the UK Biobank by using exome sequencing data that have a limit of detection of ≈5% VAF, thus being at least 5-fold less sensitive than our method. 17,18 To enable a proper comparison with the UK Biobank prevalence rates, we adjusted for the sampling bias due to lower detection limit in our sample by downsampling our raw sequencing data to locus-specific exome sequencing coverage. We obtained the mean and SD of the coverage rates for each of the 32 genes that were present both in our panel and in the UK Biobank CHIP call (Table S2).…”

Section: Methodsmentioning

confidence: 99%

Prevalence and Therapeutic Implications of Clonal Hematopoiesis of Indeterminate Potential in Young Patients With Stroke

Mayerhofer

Strecker

Becker

et al. 2023

Stroke

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Background: Undetermined stroke etiology hampers optimal secondary prevention in a large proportion of young patients. We explored whether genetic screening for clonal hematopoiesis of indetermined potential (CHIP), a novel risk factor for stroke, could identify patients with myeloid precursor lesions or covert myeloid neoplasm requiring specific treatment. Methods: We performed targeted sequencing on 56 genes recurrently mutated in hematologic neoplasms in a prospective cohort of patients with acute brain ischemia between 18 and 60 years. CHIP prevalence was compared with age-matched healthy controls from the Nijmegen Biomedical Study (n=1604) and the UK Biobank (n=101 678). Patients with suspicion of high-risk CHIP or myeloid neoplasm were invited for further hematologic evaluation. Results: We included 248 consecutive patients (39% women) of whom 176 (71%) had cryptogenic stroke etiology. Fifty-one (21%) patients had CHIP, 3-fold more than in the general population (7.7% versus 2.6% for the Nijmegen Biomedical Study and 11.9% versus 4.1% for UK Biobank; P <0.001 for both). Patients with CHIP were older (median [interquartile range], 53 [50–59] versus 51 [41–56] years; P <0.001), had higher carotid intima-media thickness (0.68 [0.58–0.80] versus 0.59 [0.51–0.73] mm; P =0.009), and had higher burden of atherosclerosis (29.4% versus 16.7%; P =0.04). We invited 11 patients (4.4%) for further hematologic assessment, which in 7 led to the diagnosis of high-risk CHIP and in 2 to the new diagnosis of a myeloproliferative neoplasm with indication for cytoreductive therapy. Conclusions: Using genetic screening for myeloid disorders in patients with stroke of predominantly undetermined etiology, we found a 3-fold higher CHIP prevalence than in the general population. We identified high-risk CHIP and previously covert myeloproliferative neoplasms as potential stroke etiologies in 4.4% and 1% of patients, respectively. Our findings demonstrate the diagnostic and therapeutic yield of genetic screening in young patients with stroke. Future studies should investigate the role of CHIP for stroke recurrence and optimal secondary prevention.

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Section: Methodsmentioning

confidence: 99%

Prevalence and Therapeutic Implications of Clonal Hematopoiesis of Indeterminate Potential in Young Patients With Stroke

Mayerhofer

Strecker

Becker

et al. 2023

Stroke

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“…The opposite effect directions observed at the CD164 locus for incident DNMT3A and TET2 CH could explain this null association in overall CH. Previously we and others reported opposite associations at the TCL1A locus with prevalent DNMT3A and TET2 CH, leading to a null association with overall CH 1,[13][14][15] . This study found an association at the TCL1A locus with incident overall CH and TET2 CH but not with incident DNMT3A CH.…”

Section: Discussionmentioning

confidence: 58%

“…This could be due to lower statistical power, poor imputation quality, or true biological differences between prevalent and incident CH. The CD164 locus is an example of the latter, where this locus is strongly associated with prevalent CH [13][14][15] but lacks any association with incident CH. The opposite effect directions observed at the CD164 locus for incident DNMT3A and TET2 CH could explain this null association in overall CH.…”

Section: Discussionmentioning

confidence: 99%

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Long-term longitudinal analysis of 4,187 participants reveals new insights into determinants of incident clonal hematopoiesis

Uddin,

Saadatagah,

Niroula

et al. 2023

Preprint

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Clonal hematopoiesis (CH), characterized by blood cells predominantly originating from a single mutated hematopoietic stem cell, is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CH is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CH. We found that age at baseline, sex, and dyslipidemia significantly influence the incidence of CH, while ASCVD and other traditional risk factors for ASCVD did not exhibit such associations. Our study also revealed associations between germline genetic variants and incident CH, prioritizing genes in CH development. Our comprehensive longitudinal assessment yields novel insights into the factors contributing to incident CH in older adults.

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“… 35 CHIP mutations were defined according to a prespecified list of pathogenic variants in 74 genes known to be drivers of clonal hematopoiesis and myeloid malignancies, as detailed in Table S2 . 36 , 37 To minimize false‐positive CHIP calls, variants were kept for further curation only if the total read depth was ≥10, 35 , 38 the read depth for the alternate allele was ≥3, and there was ≥1 read in both forward and reverse directions supporting the alternate allele. 35 CHIP was defined as variant allele frequency (VAF) ≥2%.…”

Section: Methodsmentioning

confidence: 99%

Birth Weight Is Associated With Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Outcomes in Adulthood

Schuermans

Nakao

Ruan

et al. 2023

JAHA

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Background High and low birth weight are independently associated with increased cardiovascular disease risk in adulthood. Clonal hematopoiesis of indeterminate potential (CHIP), the age‐related clonal expansion of hematopoietic cells with preleukemic somatic mutations, predicts incident cardiovascular disease independent of traditional cardiovascular risk factors. Whether birth weight predicts development of CHIP later in life is unknown. Methods and Results A total of 221 047 adults enrolled in the UK Biobank with whole exome sequences and self‐reported birth weight were analyzed. Of those, 22 030 (11.5%) had low (<2.5 kg) and 29 292 (14.7%) high birth weight (>4.0 kg). CHIP prevalence was higher among participants with low (6.0%, P =0.049) and high (6.3%, P <0.001) versus normal birth weight (5.7%, ref.). Multivariable‐adjusted logistic regression analyses demonstrated that each 1‐kg increase in birth weight was associated with a 3% increased risk of CHIP (odds ratio, 1.03 [95% CI, 1.00–1.06]; P =0.04), driven by a stronger association observed between birth weight and DNMT3A CHIP (odds ratio, 1.04 per 1‐kg increase [95% CI, 1.01–1.08]; P =0.02). Mendelian randomization analyses supported a causal relationship of longer gestational age at delivery with DNMT3A CHIP. Multivariable Cox regression demonstrated that CHIP was independently and additively associated with incident cardiovascular disease or death across birth weight groups, with highest absolute risks in those with CHIP plus high or low birth weight. Conclusions Higher birth weight is associated with increased risk of developing CHIP in midlife, especially DNMT3A CHIP. These findings identify a novel risk factor for CHIP and provide insights into the relationships among early‐life environment, CHIP, cancer, and cardiovascular disease.

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Germline genomic and phenomic landscape of clonal hematopoiesis in 323,112 individuals

Cited by 7 publications

References 96 publications

Prevalence and Therapeutic Implications of Clonal Hematopoiesis of Indeterminate Potential in Young Patients With Stroke

Prevalence and Therapeutic Implications of Clonal Hematopoiesis of Indeterminate Potential in Young Patients With Stroke

Long-term longitudinal analysis of 4,187 participants reveals new insights into determinants of incident clonal hematopoiesis

Birth Weight Is Associated With Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Outcomes in Adulthood

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