Twin Study Finds No Genetic Predisposition to Clonal Hematopoiesis

In a study published in Blood, researchers found no concordance in somatic clonal hematopoiesis (CH) mutations in a cohort of older twins, indicating that there is no genetic predisposition to CH of indeterminate potential (CHIP), as previous research has suggested. There also was no observed difference in mortality between twin pairs that were discordant for CHIP mutations.

While the link between CHIP, defined by mutations in myeloid cancer–associated genes with a variant allele frequency of at least 2%, and hematologic cancer “is evident,” Jakob Werner Hansen, MD, PhD, from the University of Copenhagen and the Danish Stem Cell Center, and co-authors explained, “it is unknown why some aging individuals develop CHIP while others do not.”

To clarify whether CHIP mutations arise from a common genetic ancestor or are a result of shared environmental exposures, the authors conducted a study of 299 elderly twin pairs. Participants were prospectively followed for more than 20 years as part of the Longitudinal Study of Aging Danish Twins (LSADT). Per LSADT protocol, twin pairs donated blood and completed questionnaires about smoking and other lifestyle factors.

Investigators performed targeted DNA sequencing from peripheral blood collected at study entry from the 598 twins with a customized 21-gene panel at a median coverage of 6179X. Four twins were excluded from the study due to poor sequencing quality, and their corresponding twin was removed from the concordance analyses, which then included a total of 295 twin pairs.

The median age at study start was 77 years (range = 73-94 years), and 256 (43%) and 338 (57%) were monozygotic and dizygotic twins, respectively. Follow-up was at least 20 years for all patients.

Sequencing revealed a total of 286 mutations in 15 known, recurrent CHIP genes, distributed among 214 twins (36%). Some twins carried more than one mutation, the authors reported, with a maximum of three mutations detected in one individual. They also noted that the proportion of individuals with a CHIP mutation increased with age, ranging from 29% at age 75 to more than 64% in the group older than 85 years.

The most commonly mutated gene was DNMT3A, observed in 104 twins, followed by TET2, which was mutated in 81 twins. In total, DTA mutations accounted for 79.4% of all the mutations observed in this cohort.

Twins with CHIP mutations were older than the nonmutated twins (p<0.001), and CHIP mutations were equally distributed among monozygotic and dizygotic twins.

Next, the investigators calculated the casewise concordance rates for carrying a mutation in any of the 21 examined genes to assess genetic predisposition. Twenty twin pairs had mutations within the same genes; however, the exact same mutations (involving the exact same base exchange) were only observed among two twin pairs:

  • an SRSF2 mutation in one dizygotic twin pair
  • a DNMT3A mutation in a monozygotic twin pair

Therefore, the concordance rate was 0.40 for both monozygotic and dizygotic twins.

At the end of study follow-up (August 2018), 96% of the study population had died. After adjustment for age, sex, and tobacco use, CHIP mutation carriers had a “borderline significantly” increased mortality risk, compared with those without mutations (hazard ratio [HR] = 1.17; 95% CI 0.97-1.40; p=0.096).

Looking at the type of mutation (DTA or other mutations), the researchers found that only DTA mutations had a negative impact on survival (HR for overall survival = 1.21; 95% CI 1.01-1.45; p=0.035). “It is still not clear why DTA genes are so frequently mutated during aging, and it has been speculated whether this may be caused by a genetic predisposition,” the authors noted. “However, we did not find any indication of a genetic predisposition to CH in the study.”

Also, in the 127 twin pairs who were discordant for CH, the affected twin died before the unaffected twin in nearly half of the cases (n=61; 48%; p=0.72).

“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,” the authors reported.

In addition, the researchers did not observe any association between the presence of CHIP and the development of hematologic cancers among the 27 patients who developed a malignancy during follow-up. Still, twins with CHIP had an increased risk of developing “unspecified cytopenia” (p=0.05), but this association needs to be validated in other cohorts.

The results of this analysis are limited by the no complete blood counts were performed at the time of blood collection, so it was not possible to assess the potential correlation. Also, the study only included twins older than 73 years, “where CH is a common phenomenon,” the authors wrote. “By investigating only elderly twins, we may theoretically have missed a genetic predisposition to CH appearing in younger individuals.”

The authors report no relevant conflicts of interest.

Reference

Hansen JW, Pedersen DA, Larsen LA, et al. Clonal hematopoiesis in elderly twins: concordance, discordance and mortality. Blood. 2019 October 24. [Epub ahead of print]