CONTEXT: Obesity is associated with short telomere length. The cause of this association is unknown.

OBJECTIVE: We hypothesized that genetically increased body mass index (BMI) is associated with telomere length shortening and that low-grade inflammation might contribute through elevated C-reactive protein.

SETTING AND DESIGN: We studied 45,069 individuals from the Copenhagen General Population Study with measurements of leukocyte telomere length, BMI, and C-reactive protein in a Mendelian randomization study. Using the three obesity-associated polymorphisms FTO rs9939609, MC4R rs17782313, and TMEM18 rs6548238, and the CRP promoter polymorphism rs3091244 in instrumental variable analyses, we estimated the associations between genetically increased BMI and telomere length and between genetically increased C-reactive protein and telomere length.

RESULTS: In multivariable-adjusted observational analyses, telomere length decreased with seven base pairs (95% confidence interval, -9--5) per unit increase in BMI, and further adjustment for C-reactive protein attenuated this association to -5 base pairs (-8--3). In accordance, instrumental variable analysis showed a non-significant telomere length shortening of six base pairs (-37-25) per unit increase in genetically determined BMI. Furthermore, in observational analyses, telomere length decreased with nine base pairs (-16--2) for a doubling in C-reactive protein, supported by the instrumental variable analyses showing a corresponding genetically determined decrease of 66 base pairs (-124--7).

CONCLUSIONS: High BMI is associated with short telomere length observationally. This might possibly be mediated through elevated C-reactive protein, given that genetically elevated C-reactive protein levels are associated with short telomere length.