Alex Reiner @fredhutch, @AlexBickMDPhD, and I are excited to share our new preprint, “Correlates and Consequences of Clonal Hematopoiesis Expansion Rate: A 15-Year Longitudinal Study of 6,986 Women” 1/n

Many thanks to our wonderful co-authors @JosephBreeyear @rheumrob @toddledwards @genepiman_giri @JDMosley_Moses @rodendm @AlexBickMDPhD and to the amazing participants who generously provided genetic and clinical data. 7/n

We propose using routine lab values – 1) the discrepancy between measured glucose and estimated glucose from HbA1c (“glucose gap”) and 2) red cell distribution width (marker of hemolysis) to identify those who may benefit from G6PD genotyping. Mind the gap! 4/n

But, what can clinicians do about this? Genotyping data is not readily accessible nor widespread. We sought to solve this problem using >100k people in the UK Biobank, NIH All of Us, the Million Veterans Program, and Vanderbilt BioVU. 3/n

@JosephBreeyear @toddledwards @genepiman_giri @JackieHellwege recently showed that a single SNP in ~10% of US African ancestry individuals (G6PD p.Val68Met) causes systematic underestimation of HbA1c and under-treatment/diagnosis of diabetes. Data in @NEJM found this as well. 2/n

RT @AlexBickMDPhD: I am honored to be elected to @the_asci! I am deeply grateful for the support from my incredible trainees and mentors @V…

Thank you so much to Alex Reiner and @AlexBickMDPhD for their mentorship, the participants of the Women’s Health Initiative, and our amazing team of coauthors. @M_Mesbah_Uddin @taralynn_mack @drkunzhao @jaiswalmdphd @DrPinkalDesai @pnatarajanmd @mchonig @jacobkitzman 11/11

We also had measured LTL at 2 timepoints! With this data, we saw that the clonal expansion rate of TET2 CHIP was associated with faster telomere shortening. We can now confirm @NakaoTetsushi's Mendelian Randomization results using measured data! 9/n

We then investigated measured leukocyte telomere length (LTL). Shorter baseline telomere length predicts incident PP1MD CHIP. In December, a paper in @Blood reported that pathogenically short telomere biology disorders were associated with PPM1D CHIP: 8/n

Some variants had gene-specific associations. As expected, rs2887399 in TCL1A limits TET2 clonal expansion. But we also found a novel association between rs11868362 in MSI2 which specifically limits ASXL1 clonal expansion (a small sample size but warrants further study).  6/n

We did not have power to do a GWAS, so we looked at variants which affect CHIP prevalence in the largest CHIP GWAS by Kessler et al in 2022 @DNApriori to see how they may alter clonal expansion rate. Manhattan plot shown here. 5/n

So, what happened to clones over ~15 years? Among ~4k mutations detected at baseline (VAF ≥ 0.5%), 50% progressed to CHIP (VAF ≥ 2%) at follow-up. Most small CHIP clones remained stable or progress to CHIP. 4/n

We investigated correlates of clonal expansion in nearly 7,000 women in the Women’s Health Initiative. We performed targeted sequencing to detect CHIP mutations at 2 timepoints, as described by @M_Mesbah_Uddin et al in 2022. Our lower limit of detection was 0.5%. 3/n

Many have shown that larger clonal hematopoiesis clones are worse than smaller ones. We hypothesize that faster-growing clones must also be worse since they will create larger clones. So, we want to study what factors influence clonal expansion rate... 2/n

@DecorteJoseph @MeilerLab Congrats Joe!!