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Objectives Vitamin D deficiency was associated with obesity. However, the causal relationship remains controversial. We hypothesized that there would be family-based associations in both vitamin D deficient families and obese families for the SNPs associated with vitamin D deficiency, if vitamin D deficiency was a causal factor of obesity. We aimed to investigate the family-based association of SNPs in CYP27B1 with both vitamin D deficiency and obesity. Methods Four hundred and nineteen pedigrees containing 1505 rural individuals aged from 18 to 79 years in Henan Province of China were included in this study. Family-based associations of rs10877012 and rs4646536 in CYP27B1 with vitamin D deficiency and obesity were investigated. Serum 25(OH)D3 concentration Results It was shown that vitamin D deficiency was a risk factor of obesity (adjusted OR: 1.332, 95% CI: 1.042-1.703, P = 0.022). Furthermore, there were family-based associations for allele T of rs10877012 and allele T of rs4646536 in both vitamin D deficient families and obese families (P < 0.05). Both rs10877012 and rs4646536 were associated with serum 25(OH)D3 levels between siblings (P < 0.05), but not BMI (P > 0.05). In addition, there is linkage disequilibrium between rs10877012 and rs4646536 (D' = 1.0, r.sup.2 = 0.992). Conclusion Vitamin D deficiency may be a causal factor of obesity. Maintaining sufficient vitamin D is beneficial to obesity prevention. Vitamin D deficiency was associated with obesity. But their causal relationship is still controversial. CYP27B1 plays a direct role in circulating the concentration of 25(OH)D, which can be used to investigate causal relationships. In this study, allele T of rs10877012 and allele T of rs4646536 in CYP27B1 were family-based linked with both vitamin D deficiency and obesity. In addition, both rs10877012 and rs4646536 were associated with serum 25(OH)D.sub.3 levels between siblings but not BMI. Therefore, vitamin D deficiency may be a causal factor of obesity. Maintaining sufficient vitamin D is beneficial to obesity prevention., Author(s): Songcheng Yu [sup.1], Yinhua Feng [sup.1], Chenling Qu [sup.2], Wenqian Huo [sup.1], Zhenxing Mao [sup.1], Chongjian Wang [sup.1], Wenjie Li [sup.1], Xing Li [sup.1] Author Affiliations: (1) College of [...]