Clonal hematopoiesis in elderly twins: concordance, discordance and mortality

Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is defined by mutations in myeloid cancer-associated genes with a variant allele frequency of at least 2%. Recent studies have suggested a possible genetic predisposition to CH. To further explore this phenomenon, we conducted a population-based study of 594 twins from 299 pairs aged 73-94 years, all with more than 20 years follow-up. We sequenced DNA from peripheral blood with a customized 21 genes panel at a median coverage of 6179X. The casewise concordance rates for mutations were calculated to assess genetic predisposition. Mutations were identified in 214 (36%) of the twins. Whereas 20 twin pairs had mutations within the same genes, the exact same mutation was only observed in two twin pairs. No significant difference in casewise concordance between monozygotic and dizygotic twins were found for any specific gene, subgroup or CHIP mutations overall and no significant heritability could be detected. In pairs discordant for CHIP mutations, we tested if the affected twin died before the unaffected twin, as a direct measurement of the association of having CH when controlling for familial factors. A total of 127 twin pairs were discordant for carrying a mutation, and in 61 (48%) cases the affected twin died first, p=0.72. Overall, we did not find a genetic predisposition to CHIP mutations in this twin study. The previously described negative association of CHIP mutations on survival, could not be confirmed in a direct comparison among twin pairs that were discordant for CHIP mutations.