Levels of 25-hydroxyvitamin D in familial longevity: the Leiden Longevity Study

Raymond Noordam MSc, Anton J.M. de Craen PhD, Pardis Pedram MD MSc, Andrea B. Maier MD PhD, Simon P. Mooijaart MD PhD, Johannes van Pelt PhD, Edith J. Feskens PhD, Martinette T. Streppel PhD, P. Eline Slagboom PhD, Rudi G.J. Westendorp MD PhD, Marian Beekman PhD, Diana van Heemst PhD



Competing interests: None declared.

Background: Low levels of 25(OH) vitamin D are associated with various age-related dis- eases and mortality, but causality has not been determined. We investigated vitamin D levels in the offspring of nonagenarians who had at least one nonagenarian sibling; these off- spring have a lower prevalence of age-related diseases and a higher propensity to reach old age compared with their partners.

Results: The offspring had significantly lower levels of vitamin D (64.3 nmol/L) compared with controls (68.4 nmol/L; p = 0.002), independent of possible confounding factors. There was no dif- ference in the levels of parathyroid hormone between groups. Compared with controls, the offspring had a lower frequency of a genetic variant in the CYP2R1 gene (rs2060793) (p = 0.04). The difference in vitamin D levels between offspring and controls persisted over the 2 most prevalent genotypes of this SNP.

This article has been peer reviewed.

Methods: We assessed anthropometric character- istics, 25(OH) vitamin D levels, parathyroid hor- mone levels, dietary vitamin D intake and nucleotide polymorphisms (SNPs) associated vitamin D levels. We included offspring (n = of nonagenarians who had at least one nonage- narian sibling, and the offsprings’ partners (n 461; controls) from the Leiden Longevity We included age, sex, body mass index, during which blood sampling was dietary and supplemental vitamin D intake, creatinine levels as possible confounding factors.

Interpretation: Compared with controls, the off- spring of nonagenarians who had at least one nonagenarian sibling had a reduced frequency of a common variant in the CYP2R1 gene, which predisposes people to high vitamin D levels; they also had lower levels of vitamin D that persisted over the 2 most prevalent genotypes. These results cast doubt on the causal nature of previ- ously reported associations between low levels of vitamin D and age-related diseases and mortality.

ciation between serum levels of 25(OH) vitamin D and familial longevity. We assessed vitamin D levels in the offspring of nonagenarian siblings whom we have previously shown to have a lower prevalence of cardiovascular diseases and lower mortality compared to age- and environmental- matched controls.9,10 We also assessed whether genetic variation in 3 genes11 was associated with 25(OH) vitamin D levels among the offspring of nonagenarians who had at least 1 nonagenarian sibling, and their partners.

in the inhibition of proliferation and angiogenesis in cancer.2 Low serum levels of 25- hydroxyvitamin D3 (25[OH] vitamin D) are associated with increased mortality, cardiovascu- lar disease, diabetes mellitus, cancer, multiple sclerosis, allergy, asthma, infection, depression, mental illness and musculoskeletal pain.3–6 How- ever, because of design limitations, previous stud- ies have not been able to infer causality.7 A meta- analysis that included 51 studies and more than 30 000 individuals in each treatment group showed no reduction in all-cause or cardiovascu- lar mortality with vitamin D supplementation,8 suggesting that low serum levels of vitamin D are a consequence rather than a cause of disease.

Methods

Study design

The Leiden Longevity Study was designed to identify genetic and phenotypic markers related to familial longevity. A total of 421 families were recruited, consisting of long-lived white siblings, offspring and the offspring’s partners. Families were only included if at least 2 long-lived siblings were still alive and met the age criteria (≥ 89 yr

Vitamin D status is routinely assessed by mea- surement of serum concentration of the prohor- mone 25(OH) vitamin D, which is the most stable and abundant metabolite of vitamin D in circula- tion. In the current study, we investigated the asso-

Statistical analyses

for men; 91 yr for women).10 There was no selection based on health conditions or demo- graphic characteristics. Nonagenarian siblings had a 41% lower mortality risk compared with spo- radic nonagenarians.9 Because it is difficult to include proper controls for this age group, the nonagenarian’s offspring were asked to participate and serve as cases, because they have an increased propensity to reach old age.10 The offsprings’ part- ners were asked to participate in the study as envi- ronment-matched controls of a similar age because they tended to be similar for many of the environmental factors that might influence vita- min D levels.

The levels of 25(OH) vitamin D were not nor- mally distributed; thus, we log transformed the data. We categorized the data by month during which blood was drawn. Tanning bed use was categorized into never, 1–5 times per year, and 6–10 times per year.

We compared data for the offspring and con- trols using linear regression models. Because serum vitamin D levels are influenced by age, sex, body mass index (BMI), month of the year (as a measure of the available sun), supplemental intake (vitamin D and multivitamin use) and kidney function (measured by serum creatinine level), we considered these factors to be possible confound- ing factors, and we included them as covariates in the multivariate linear regression model.

The Leiden Longevity Study was approved by the medical ethics committee of the Leiden University Medical Center. Written informed consent was obtained from all participants.