Contributions
Abstract: EP1064
Type: E-Poster Presentation
Session title: Myeloproliferative neoplasms - Biology & Translational Research
Background
Age-related clonal haematopoiesis (CH) is a risk factor for atherosclerotic cardiovascular disease (CVD) and all-cause mortality. Chronic kidney disease (CKD) is a worldwide health problem associated with an elevated risk of CVD, but the relationship between CH and CKD is unknown.
Aims
To assess the relationship between CH and CKD in UK Biobank, a prospective, population-based cohort of UK subjects aged 40-69 years recruited between 2006-10.
Methods
We focused on subjects with both genomewide SNP array and WES data (n=200,361; median age = 58y, median follow up = 11y). Array allelic intensities were used to infer mosaic chromosome abnormalities (mCA), which were categorized as myeloid, lymphoid or other based on known cytogenetic associations. Likely somatic driver mutations were extracted from WES variant calls (DeepVariant) based on VAF, recurrency in COSMIC, CADD pathogenicity score and a binomial test against the mean VAF. Estimated Glomerular Filtration Rate (eGFR) was calculated using CKD-EPI formula using cystatin-C (eGFR.cys), creatinine (eGFR.creat), or both (eGFR.creat.cys). 10,144 participants were considered ineligible for analysis due to end stage kidney disease (n=211), any eGFR score <15 (n=20) or missing biochemistry measures (n=9,913) at study entry. Linear and logistic regression models were used with kidney function defined as (i) a binary trait (CKD, eGFR <60; control, eGFR ≥60) or (ii) a continuous trait. A Cox proportional hazard model was used to assess the risk of developing adverse outcomes defined by death, myocardial infarction or stroke. All P values were corrected for false discovery rate
Results
CH, defined as the presence of any mCA and/or somatic mutation, was identified in 5,449 (2.9%) eligible subjects. CH was negatively associated with eGFR.cys (OR=0.44, P=5.9x10-5), but not other eGFR scores, when tested as a continuous variable and was specifically associated with CKD defined by eGFR.cys <60 (n=5,449/185,038, OR=1.02, P=1.2x10-8). Focusing on CH defined by mCA only (n=1,918), eGFR.cys was associated with myeloid mCA (n=176, OR=0.01, P=5.9x10-5) and not lymphoid (n=229, P=0.13) or other mCA (n=1495, P=0.18). Similarly, for CH defined by somatic mutations (n=3,686), the association with eGFR.cys was due myeloid-malignancy related genes (n=3323, OR=0.26, P=1.2x10-7), particularly JAK2 V617F (n=139, OR=6.5x10-4, P=1.6x10-9) and TET2 (n=788, OR=0.13, P=9.5x10-5) but not DNMT3A or ASXL1. The link between myeloid malignancy and CKD is well established, and was replicated in our series, which included participants with a myeloid malignancy diagnosed prior to or within a year of study entry (n=320, OR= 3.9x10-3, P=7.0x10-12). Excluding these cases and also those with any prior history of CVD (n=8,459), we confirmed that myeloid CH was associated with adverse outcomes during follow up (RR=1.57, n=338/3,078, P=1.1x10-12) compared to myeloid CH-free participants (n=9174/176,944). For subjects who had CKD, the risk of adverse outcomes was higher: RR=2, n=1,186/6,991 P=7.6x10-78 compared to CKD free participants (n=8326/173,031). Within the CKD group, the risk was further increased for subjects with myeloid CH (RR=1.63, n=59/226, P=1.5x10-3) compared to those who were myeloid-CH free (n=1,127/6,765).
Conclusion
CH, and specifically myeloid CH, is associated with CKD defined by eGFR.cys. Myeloid CH promotes adverse outcomes in CKD, highlighting the importance of the interaction between intrinsic and extrinsic factors to define the health risk associated with CH.
Keyword(s): Clonality
Abstract: EP1064
Type: E-Poster Presentation
Session title: Myeloproliferative neoplasms - Biology & Translational Research
Background
Age-related clonal haematopoiesis (CH) is a risk factor for atherosclerotic cardiovascular disease (CVD) and all-cause mortality. Chronic kidney disease (CKD) is a worldwide health problem associated with an elevated risk of CVD, but the relationship between CH and CKD is unknown.
Aims
To assess the relationship between CH and CKD in UK Biobank, a prospective, population-based cohort of UK subjects aged 40-69 years recruited between 2006-10.
Methods
We focused on subjects with both genomewide SNP array and WES data (n=200,361; median age = 58y, median follow up = 11y). Array allelic intensities were used to infer mosaic chromosome abnormalities (mCA), which were categorized as myeloid, lymphoid or other based on known cytogenetic associations. Likely somatic driver mutations were extracted from WES variant calls (DeepVariant) based on VAF, recurrency in COSMIC, CADD pathogenicity score and a binomial test against the mean VAF. Estimated Glomerular Filtration Rate (eGFR) was calculated using CKD-EPI formula using cystatin-C (eGFR.cys), creatinine (eGFR.creat), or both (eGFR.creat.cys). 10,144 participants were considered ineligible for analysis due to end stage kidney disease (n=211), any eGFR score <15 (n=20) or missing biochemistry measures (n=9,913) at study entry. Linear and logistic regression models were used with kidney function defined as (i) a binary trait (CKD, eGFR <60; control, eGFR ≥60) or (ii) a continuous trait. A Cox proportional hazard model was used to assess the risk of developing adverse outcomes defined by death, myocardial infarction or stroke. All P values were corrected for false discovery rate
Results
CH, defined as the presence of any mCA and/or somatic mutation, was identified in 5,449 (2.9%) eligible subjects. CH was negatively associated with eGFR.cys (OR=0.44, P=5.9x10-5), but not other eGFR scores, when tested as a continuous variable and was specifically associated with CKD defined by eGFR.cys <60 (n=5,449/185,038, OR=1.02, P=1.2x10-8). Focusing on CH defined by mCA only (n=1,918), eGFR.cys was associated with myeloid mCA (n=176, OR=0.01, P=5.9x10-5) and not lymphoid (n=229, P=0.13) or other mCA (n=1495, P=0.18). Similarly, for CH defined by somatic mutations (n=3,686), the association with eGFR.cys was due myeloid-malignancy related genes (n=3323, OR=0.26, P=1.2x10-7), particularly JAK2 V617F (n=139, OR=6.5x10-4, P=1.6x10-9) and TET2 (n=788, OR=0.13, P=9.5x10-5) but not DNMT3A or ASXL1. The link between myeloid malignancy and CKD is well established, and was replicated in our series, which included participants with a myeloid malignancy diagnosed prior to or within a year of study entry (n=320, OR= 3.9x10-3, P=7.0x10-12). Excluding these cases and also those with any prior history of CVD (n=8,459), we confirmed that myeloid CH was associated with adverse outcomes during follow up (RR=1.57, n=338/3,078, P=1.1x10-12) compared to myeloid CH-free participants (n=9174/176,944). For subjects who had CKD, the risk of adverse outcomes was higher: RR=2, n=1,186/6,991 P=7.6x10-78 compared to CKD free participants (n=8326/173,031). Within the CKD group, the risk was further increased for subjects with myeloid CH (RR=1.63, n=59/226, P=1.5x10-3) compared to those who were myeloid-CH free (n=1,127/6,765).
Conclusion
CH, and specifically myeloid CH, is associated with CKD defined by eGFR.cys. Myeloid CH promotes adverse outcomes in CKD, highlighting the importance of the interaction between intrinsic and extrinsic factors to define the health risk associated with CH.
Keyword(s): Clonality