SUN-823 - Genetic Variants of the Vitamin D Pathway and Their Impact on the Clinicalpresentation of Sporadic Primary Hyperparathyroidism

Genetic variants of the vitamin D pathway may alter enzyme activity and protein affinity,
affecting 25-hydroxyvitamin D (25OHD) levels, as demonstrated by mendelian
randomization (1,2). Severity of primary hyperparathyroidism (PHP) clinical presentations
are usually linked to low 25OHD (3) .

Objectives: to assess whether vitamin D pathway gene polymorphisms are related to
PHP manifestations.

Methods: This preliminary analysis included 251 PHP patients and 244 controls.
Genes encoding 25-hydroxylase (CYP2R1), 1-alpha-hydroxylase (CYP27B1), 7-
dehydrocholesterol reductase (DHCR7) and vitamin D-binding protein (Gc) were
genotyped by qPCR with allelic discrimination assays. Logistic regression used a
hierarchical modeling approach. Significance was set at p ≤ 0.05.

Results: Most participants were women (87.7%) and Caucasian (59.2%). Groups were
similar for sex, ethnicity and age, and all polymorphisms met Hardy-Weinberg
equilibrium. Genotype distribution did not differ between groups. Among PHP patients,
however, DHCR7, CYP2R1 and CYP27B1 polymorphisms correlated with disease
severity. CYP2R1 variants were associated with the presence of osteoporosis. The AA
genotype showed higher osteoporosis prevalence than other genotypes (81% vs
54.8%; OR 3.5 [95% CI 1.14–10.77]; p=0.029). Univariate regression showed that age
at diagnosis, PTH levels and CYP2R1 polymorphism were positively associated with
osteoporosis, while BMI was inversely associated. In multivariate analysis, CYP2R1
polymorphism, age at diagnosis and BMI remained independent predictors. Besides,
DHCR7 polymorphisms were linked to age at diagnosis, and CYP27B1 to total calcium
and PTH. Patients with DHCR7 GG genotype were diagnosed younger (59.8 ±10.3 vs
62.7 ±10.9 years; p=0.045). Carriers of the CYP27B1 T allele had higher
concentrations of total calcium (11.4 [10.4–19.1] vs 11.2 [10–18.8] mg/dL; p=0.039) and
PTH (162.8 [63.8–1982] vs 140.2 [51.4–2374] pg/mL; p=0.015).

Conclusion: This preliminary analysis indicates that vitamin D pathway variants may
influence PHP severity. The AA variant of 25-hydroxylase gene CYP2R1 increased
osteoporosis risk 3.5-fold, while 7-dehydrocholesterol reductase (DHCR7) and 1-alpha-
hydroxylase (CYP27B1) variants were associated with age at diagnosis, calcium and
PTH levels.

References
(1)- Berry DJ, et al. Evaluation of genetic markers as instruments for Mendelian
randomization studies on vitamin D. PLoS One. 2012;7(5):e37465
(2) - Karrow NA, et al. Genetic Variants Influencing Individual Vitamin D Status.
Nutrients. 2025 Aug 19;17(16):2673. 
(3) - Silverberg SJ. Vitamin D deficiency and primary hyperparathyroidism. J Bone Miner
Res. 2007 Dec;22 Suppl 2:V100-4.

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