Common genetic variation in the CYP2R1 gene, which was associated with higher levels of

Table 1: Characteristics of the study population

Table 1: Characteristics of the study population No. (%) or mean ± SD Offspring Controls Characteristic n = 1038 n = 461 p value Age, yr 59.5 ± 6.3 58.9 ± 7.0 0.09 Female 574 (55.4) 257 (55.7) 0.9 Body mass index 25.2 ± 3.5 25.4 ± 3.5 0.3 Vitamin D intake Via habitual food intake, µg/d 3.92 ± 1.9 3.87 ± 1.7 0.7 Multivitamin supplements 298 (28.7) 120 (26.0) 0.3 Vitamin D supplements 35 (3.4) 16 (3.5) 0.9 Creatinine, mmol/L 80.7 ± 12.0 82.0 ± 12.8 0.09 Disease history Diabetes mellitus 28 (2.7) 29 (6.3) 0.001 Hypertension 192 (18.5) 110 (23.9) 0.02 Myocardial infarction 16 (1.5) 11 (2.4) 0.3 Stroke 17 (1.7) 8 (1.7) 0.9 Malignant disease 77 (7.4) 30 (6.5) 0.4 Medication use Diabetes medication 10 (1.2) 14 (3.7) 0.004 Antihypertensive drugs 127 (15.0) 82 (21.4) 0.006 Lipid lowering agents 63 (7.5) 37 (8.7) 0.2

Note: SD = standard deviation.

risk of death, cardiovascular disease and cognitive decline. Because of limitations in the design of these studies, it was not possible to infer a causal relation between vitamin D and outcome. In the case of mortality, low serum vitamin D levels might be a marker of frailty, because ill patients are expected to spend less time outdoors and may have inadequate nutrition. A similar phenomenon might be involved in the proposed relation between low vitamin D and the onset of cardio- vascular disease, in which, for example, BMI and low physical activity (which influences vitamin D levels, via lower exposure to sun light) might be residual confounding factors.4,14 A doubtful causal association between vitamin D and health out- comes is supported by clinical trials showing a lack of reduction in cardiovascular disease and mortality after vitamin D supplementation.8

vitamin D, was significantly underrepresented (p = 0.04) among offspring compared with controls (Table 4). The allele frequencies of the common genetic variants were in Hardy–Weinberg equilib- rium. The difference in serum levels of vitamin D between the offspring and controls persisted when the 3 genotypes were included as covariates in the statistical model (offspring 61.4 nmol/mL; controls 63.9 nmol/L; p = 0.001).

Interpretation

We found that the offspring of nonagenarians who had at least 1 nonagenarian sibling had lower levels of vitamin D than controls, independent of possible confounding factors and SNPs associated with vita- min D levels. We also found that the offspring had a lower frequency of common genetic variants in the CYP2R1 gene; a common genetic variant of this gene predisposes people to high vitamin D lev- els. These findings support an association between low vitamin D levels and familial longevity.

levels were not associated with disease history. We found that the offspring of nonagenarian sib- lings, who had a lower prevalence of cardiovas- cular diseases and a lower mortality rate com- pared to controls,9,10 had lower levels of vitamin D. The difference in vitamin D levels between offspring and their partners was not explained by any of the potential confounding factors that we investigated. Our results might indicate that low

has various functions, including bone mineraliza- tion, differentiation of immune cells, and inhibi- tion of proliferation and angiogenesis in cancer.2 Cross-sectional and longitudinal studies have linked low serum levels of vitamin D to a higher

Table 2: Vitamin D and parathyroid hormone levels in offspring and controls

Mean (95% CI) Offspring Controls Variable n = 1038 n = 461 p value 25(OH) vitamin D,* nmol/L Model 1† 64.3 (63.1– 65.4) 68.5 (66.0–71.1) 0.002 Model 2‡ 64.3 (63.1– 65.4) 68.4 (66.0–71.0) 0.002 Sensitivity analyses Supplement users excluded§ 64.3 (63.1–65.4) 68.4 (66.0– 1.0) 0.002 Matched analysis¶ 64.5 (61.4–69.5) 70.0 (65.6–74.7) 0.001 Sun exposure adjusted** 67.7 (62.7–73.1) 72.0 (66.4–78.2) 0.02 Parathyroid hormone,†† pg/mL Model 1† 39.2 (38.5–39.9) 39.6 (38.1–41.0) 0.7 Model 2‡ 39.3 (38.6–40.0) 39.3 (37.8–40.7) 0.9 Sensitivity analyses Supplement users excluded§ 39.3 (38.6–40.0) 39.3 (37.8–40.7) 0.9 Matched analysis¶ 37.4 (35.0–39.9) 39.1 (36.5–41.6) 0.049

*Vitamin D presented as geometric means with 95% CI. †Model 1: adjusted for sex and age. ‡Model 2: model 1 plus adjustment for body mass index, month of the year blood was drawn, habitual vitamin D intake via food, use of multivitamin supplements, use of vitamin D supplements, and creatinine level. §Used model 2 for analysis; included 727 offspring and 332 controls who did not use multivitamin and/or vitamin D supplements. ¶Used model 2 for analysis; included 430 offspring and 430 controls, who were partners. **Used model 2 for analysis, with additional adjustment for tanning bed use and sun exposure; included 279 offspring and 275 controls. ††Parathyroid hormone levels presented as means with 95% CI.

parathyroid hormone and by low levels of cal- cium and phosphorus. We do not know whether the lower levels of 25(OH) vitamin D observed in the offspring will also result in lower levels of the active hormone 1,25(OH) vitamin D. We 2 found that serum parathyroid hormone levels were lower in offspring in the analyses restricted to only couples, but not in the other analyses.

levels of vitamin D are associated with an increased propensity to reach a very old age.