Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK.
MRC Epidemiology Unit, University of Cambridge, Cambridge CB2 0QQ, UK.
J Clin Endocrinol Metab. 2023 Oct 18;108(11):e1394-e1402. doi: 10.1210/clinem/dgad263.
Vitamin D has been variably implicated in risk of developing type 1 diabetes based on cohorts of at-risk individuals. Emergent type 1 diabetes in childhood is putatively preceded by altered growth.
We explored whether polymorphisms in vitamin D metabolism genes modify risk of type 1 diabetes via effects on growth in a prospective, population-based cohort of infants.
The Cambridge Baby Growth Study enrolled newborns from Cambridgeshire, UK, for follow-up in infancy. In 612 infants, we genotyped single nucleotide polymorphisms in vitamin D metabolism genes that relate with type 1 diabetes: rs10741657 and rs12794714 in CYP2R1, rs12785878 in DHCR7, and rs10877012 in CYP27B1. Multivariate linear regression analyses tested associations between genotypes and anthropometric indices (weight, length, and skinfold thickness) or growth-related hormones (C-peptide, IGF-1, and leptin) in infancy.
Birth weight showed borderline associations with the diabetes risk-increasing alleles in CYP2R1, rs10741657 (β = -.11, P = .02) and rs12794714 (β = -.09, P = .04). The risk-increasing allele rs12794714 was also associated with higher IGF-1 levels at age 24 months (β = .30, P = .01). At age 3 months, the risk-increasing allele rs12785878 in DHCR7, known to negatively associate with 25-hydroxyvitamin D levels, showed a positive association with leptin levels (β = .23, P = .009), which was pronounced in girls (P = .004) vs boys (P = .7).
The vitamin D metabolism genes DHCR7 and CYP2R1 might influence infancy leptin and IGF-1 levels respectively. These findings open the possibility for a developmental role of vitamin D that is mediated by growth-related hormones with implications for the onset of type 1 diabetes autoimmunity.
基于高危人群队列的研究结果表明，维生素 D 对 1 型糖尿病的发病风险存在差异。儿童时期新发生的 1 型糖尿病据称是由生长改变引起的。
我们通过对英国剑桥郡的婴儿进行前瞻性、基于人群的队列研究，探讨维生素 D 代谢基因的多态性是否通过对生长的影响来改变 1 型糖尿病的发病风险。
剑桥婴儿生长研究招募了来自英国剑桥郡的新生儿进行婴儿期随访。在 612 名婴儿中，我们对维生素 D 代谢基因的单核苷酸多态性进行了基因分型，这些基因与 1 型糖尿病有关：CYP2R1 中的 rs10741657 和 rs12794714、DHCR7 中的 rs12785878 和 CYP27B1 中的 rs10877012。多变量线性回归分析测试了基因型与婴儿期人体测量指数（体重、身长和皮褶厚度）或与生长相关的激素（C 肽、IGF-1 和瘦素）之间的关联。
出生体重与 CYP2R1 中糖尿病风险增加的等位基因 rs10741657（β = -.11，P =.02）和 rs12794714（β = -.09，P =.04）呈边缘关联。风险增加的等位基因 rs12794714 也与 24 个月时 IGF-1 水平升高相关（β =.30，P =.01）。在 3 个月时，DHCR7 中与 25-羟维生素 D 水平负相关的已知风险增加的等位基因 rs12785878 与瘦素水平呈正相关（β =.23，P =.009），在女孩中更为显著（P =.004），而在男孩中则不显著（P =.7）。
维生素 D 代谢基因 DHCR7 和 CYP2R1 可能分别影响婴儿期的瘦素和 IGF-1 水平。这些发现为维生素 D 通过与生长相关的激素发挥发育作用的可能性提供了依据，这可能对 1 型糖尿病自身免疫的发病有影响。
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