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

Vitamin D is produced in the skin in response to ultraviolet B rays and can also be obtained from food and supplements. In the liver, vitamin D is converted to 25(OH) vitamin D, which is later converted in the kidneys to the active hormone that regulates calcium metabolism (1,25 dihydroxy - vitamin D [1,25(OH) vitamin D]). Vitamin D sta- 2 tus is routinely assessed by the measurement of the serum concentration of 25(OH) vitamin D, which is the most stable and abundant metabolite of vita- min D in circulation; this metabolite reflects both vitamin D intake and endogenous production. Because levels of the active hormone 1,25(OH) 2 vitamin D do not correlate well with overall vita- min D status, levels of this metabolite are not con- sidered clinically useful.1

Genetically determined differences may exist in vitamin D metabolism. Indeed, the CYP2R1 gene plays a role in the conversion of vitamin D to 25(OH) vitamin D. However, although the allele frequency of a common genetic variant in this gene was underrepresented in the offspring, the difference in serum vitamin D levels between offspring and controls persisted when we con- trolled for this genetic variant.

Literature on other potential mechanisms explaining our findings is scarce. We speculate that offspring might have a higher expression of the

The synthesis of 1,25(OH) vitamin D is 2 tightly regulated and is stimulated by serum

Table 3: 25(OH) Vitamin D levels in offspring and controls, by genotype

25(OH) Vitamin D (nmol/L); mean (95% CI) SNP, locus Offspring Controls p value* < 0.001† rs2060793, CYP2R1 Wildtype/wildtype 61.8 (59.9–63.8) 68.7 (65.7–71.8) < 0.001 Wildtype/variant 64.7 (62.7–66.6) 68.3 (65.7–71.0) 0.03 Variant/variant 69.4 (65.8–73.3) 72.9 (68.4–77.6) 0.2 rs2282679, GC < 0.001† Wildtype/wildtype 67.2 (65.2–69.0) 72.8 (70.2–75.6) 0.001 Wildtype/variant 62.6 (60.6–64.7) 66.1 (63.4–68.9) 0.05 Variant/variant 53.1 (50.1–56.1) 60.3 (55.9–65.0) 0.04 rs3829251, NADSYN1 0.8† Wildtype/wildtype 63.8 (62.2–65.2) 68.6 (66.4–70.7) 0.001 Wildtype/variant 64.8 (62.1–67.6) 70.1 (66.3–74.2) 0.05 Variant/variant 62.4 (55.4–70.2) 68.3 (59.9–78.5) 0.3

Note: CI = confidence interval, SNP = single nucleotide polymorphism. * Analyses were adjusted for age, sex, body mass index, month of the year that blood was drawn (except rs3829251, because the number of participants with the variant/variant genotype was too low), vitamin D use, multivitamin supplement use, and habitual vitamin D intake per day. †Pooled p value (offspring and controls) of the association between the genetic variant and vitamin D level.

Table 4: Comparison of genetic variation associated with vitamin D between offspring and controls

Minor allele frequency Single nucleotide Gene or Minor Offspring Controls polymorphism locus Location allele n = 1038 n = 461 p value rs2282679 GC 4q13.3 C 0.263 0.270 0.6 rs3829251 NADSYN1 11q13.4 A 0.154 0.163 0.6 rs2060793 CYP2R1 11p15.2 A 0.371 0.418 0.04

Analyses were adjusted for age, sex and familial relationship. Note: CYP2R1 = cytochrome P450, family 2, subfamily R, polypeptide 1; GC = group specific component (vitamin D binding protein); NADSYN1 = nicotinamide adenine dinucleotide synthetase 1.

morbidity than sporadic nonagenarians: the Leiden Longevity Study. J Am Geriatr Soc

;

:

-

Schoenmaker M, de Craen AJ, de Meijer PH, et al. Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study. Eur J Hum Genet

;

:

-

Ahn J, Yu K, Stolzenberg-Solomon R, et al. Genome-wide asso- ciation study of circulating vitamin D levels. Hum Mol Genet

;

:

-

Verkleij-Hagoort AC, de Vries JH, Stegers MP, et al. Validation of the assessment of folate and vitamin B

intake in women of repro- ductive age: the method of triads. Eur J Clin Nutr

;

:

-

Deelen J, Beekman M, Uh HW, et al. Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited. Aging Cell

;

:

-

Nadir MA, Szwejkowski BR, Witham MD. Vitamin D and car- diovascular prevention. Cardiovasc Ther

;

:e

-

Kurosu H, Yamamoto M, Clark JD, et al. Suppression of aging in mice by the hormone klotho. Science

;

:

-

Medici D, Razzaque MS, Deluca S, et al. FGF-

-Klotho sig- naling stimulates proliferation and prevents vitamin D–induced apoptosis. J Cell Biol

;

:

-

Tsujikawa H, Kurotaki Y, Fujimori T, et al. Klotho, a gene related to a syndrome resembling human premature aging, func- tions in a negative regulatory circuit of vitamin D endocrine sys- tem. Mol Endocrinol

;

:

-

Semba RD, Cappola AR, Sun K, et al. Plasma klotho and mor- tality risk in older community-dwelling adults. J Gerontol A Biol Sci Med Sci

;

:

-

Semba RD, Cappola AR, Sun K, et al. Plasma klotho and cardio- vascular disease in adults. J Am Geriatr Soc

;

:

-

Semba RD, Cappola AR, Sun K, et al. Relationship of low plasma klotho with poor grip strength in older community-dwelling adults: the I

HIANTI study. Eur J Appl Physiol

;

:

-

Cyganek K, Mirkiewicz-Sieradzka B, Malecki MT, et al. Clinical risk factors and the role of VDR gene polymorphisms in diabetic retinopathy in Polish type

diabetes patients. Acta Diabetol

;

:

-

Tworowska-Bardzinska U, Lwow F, Kubicka E, et al. The vitamin D receptor gene Bs

polymorphism is not associated with anthropometric and biochemical parameters describing metabolic syndrome in postmenopausal women. Gynecol Eendocrinol

;

:

-

Zmuda JM, Cauley JA, Ferrell RE. Molecular epidemiology of vitamin D receptor gene variants. Epidemiol Rev

;

:

-