Obtaining VitD from food sources is ideal, but this is usually tough due to the there are so scarce foods that naturally include VitD. Daily supplementation may be appropriate to preserve a constant serum level of 25(OH)D, though compliance with a daily regimen can be a big challenge in some cases (58). Taking a high-dose of VitD3 (50,000IU per week) is recommended for hypovitaminosis D therapy [40], so in the present trial, we administrated 9 high-dose VitD capsules (50,000IU cholecalciferol per week). To identify novel and hidden determinants that explain the individual variations in the response to the VitD supplementation, we applied a best data mining model. Results of present study highlight the importance of cardiometabolic risk factors in characterization of response to VitD intervention.
In adolescents girl we found that basal level- and age-dependent increment serum 25(OH)D following the use of supplements. Rahmanian et al. reported that baseline serum VitD amounts and geographical region are determinant of the magnitude of responsiveness to supplementation [41]. Recently, a systematic review and meta-analysis of randomized controlled trials (RCTs) revealed that baseline 25(OH)D concentration and age were significant determinants of changes in 25(OH)D concentration following VitD treatment [42]. The inverse association between baseline levels of S-25(OH)D and changes in 25(OH)D in response to VitD intervention may be due to the a negative feedback of 25-hydroxylase activity [43]. Aging has commonly reported to be related with decreased circulating values of 25(OH)D [44, 45]. Although, other evidences announced that aging has low considerable or no effect on response to supplementation [46-49]. The reason for the contradictory findings is the mean age of the volunteers is different between studies.
With our model, the 29.3% increase in serum 25(OH)D following VitD supplementation can be predicted if anthropometric parameters including WHR, NC, WC, wrist circumference, and HC levels are known.
Accumulating evidence shows an inverse relationship between S-25(OH)-D and all indices of adiposity, including weight, BMI, percent body fat, WC and WHR. For instance, the BW, BMI, and WC of the women with ≥90 nmol/l S-25(OH)D were significantly lower compared to women with <90 nmol/l S-25(OH)D subjects. But, the HC and the WHR were not differed between both groups[50]. Furthermore, Tamer and co-researchers found that serum 25(OH)D levels were inversely associated with BMI, WC and WHR (r = –0.48, p<0.0001; r = –0.48, p<0.0001 and r=–0.31, p<0.05, respectively). The authors concluded that hypovitaminosis D in lacking of diabetes type 1 and hyperparathyroidism may be associated with obesity/abdominal obesity[51]. Similarly Vilarrasa et al by using bivariate correlation analysis reported that the S-25(OH)D levels was inversely correlated with BMI (r=–0.43, p=0.001) and WHR (r=–0.40, p=0.001) [52]. In a population-based study in elderly, higher BMI, and WC were significantly related with lower S-25(OH)D (standardized β values=–0.136, and –0.137, respectively; P < 0.05), after adjustment for possible confounders [53].
One of the explanation for the relationship between obesity and lower VitD levels is because of the higher capability of VitD storage in the fat tissue or the interaction with autocrine elements generated via adipose tissues[54, 55]. But, the reverse of causal inference of higher BMI in the attenuating of VitD status was not proven [56]. It is also suggested that the higher serum 25(OH)D conversion to 1,25(OH)2D found in obese cases [57] may be increased in obese individuals with low serum 25(OH)D concentrations versus obese subjects with higher concentrations causing to great 25(OH)D consumption.
In agreement with our findings, results from previous studies which using classical linear statistical methods highlighted the hallmark of anthropometric indices in variance of S-25(OH)-D levels post-supplementation. Previous reports from particular age groups highlighted a significant role for BW for prediction of variation in 25(OH)D levels after intervention [58-60] even compared to body fat mass [58]. Blum and co-workers reported that magnitude of increasing in serum value of 25(OH)D concentration in response to supplementation negatively related with BW, BMI, central body fat, and waist round in elderly [61]. Twelve-week VitD supplementation in healthy overweight and obese female led to statistically significant reduction in body fat mass compared to the placebo group, however, BW and WC did not change significantly in intervention and placebo groups. A significant inverse association between variations in S-25(OH) levels and body fat mass was found (r =-0.319, P = 0.005) [62].
WC and WHR are the most prevalent representative measures of visceral adipose tissue. But, WHR may be a superior predictor of CVD risk as HC is inversely related with the evolution of cardio-metabolic risk factors [63-65]. An interesting and novel finding of our algorithm is the independent, relationship of VitD responsiveness with WC and WHR. Pasco and colleagues observed that women with a normal WC were 1.5–fold more likely compared to women with a higher WC to have high S-25(OH)D (OR=1.46 , 95% CI:1.02–20.8; p = 0.038) [66].
NC was identified as the third significant predictor that independently affected the response of S-25(OH)D to VitD supplementation in current study. NC, as an indicator of upper body subcutaneous fat distribution suggested having potential for using as identification of overweight/obese individuals. From the anatomical standpoint, upper-body subcutaneous adipose tissue is a unique fat storage situated in a separate section compared with visceral adipose tissue. Systemic free fatty acid amounts are mainly ascertained via upper-body subcutaneous fat, indicating that this fat storage may involve in risk of CVD [67, 68]. NC as a neck fat is a very simple, convenient and reliable alternative measure of obesity and may even be an better independent marker of metabolic risk versus BMI and WC[69, 70].
Wrist circumference measurement being easy-to-detect, and noninvasive may be a good surrogate to analyze bone metabolism because it is an simple to measure the skeletal frame without being significantly confounded via variation in body fat and perturbing factors [71].
Unlike other anthropometrics, it have high reproducibility due to it does not need multiple repeated assessments for precision and reliability[72]. Wrist circumference could be proposed as a novel anthropometric measurement for prediction of insulin resistance, metabolic syndrome and CVD [73]. But it could only explain 4.6% of total slope representing the elevation in S-25(OH)D concentration post VitD therapy.
The renin–angiotensin system (RAS) contributed in the regulation of BP, volume and electrolyte homeostasis. Dys-activation of the RAS may cause to hypertension. VitD is an effective endocrine suppressor of renin production and a negative regulator of the RAS. In animal model, lacking the VitD receptor (VDR) has elevated production of renin and angiotensin II, leading to hypertension. Low VitD status has been connected with an higher risk of cardiovascular disease and [74, 75] hypertension[76]. Vimaleswaran and co-researchers reported that elevated 25(OH)D values were related with lower SBP (β per 10% alteration= –0.12 mm Hg, 95% CI:–0.20 to –0.04; p=0.003) and decreased risk of hypertension (OR=0.98, 95% CI:0.97–0.99; p=0.0003); but, they did not found an relationship between 25(OH)D level and DBP (β =–0.02 mm Hg, 95% CI:–0.08 to 0.03; p=0·37)[77]. VitD can suppress renin biosynthesis with influencing the juxtaglomerular apparatus [78] and actually endothelial cells contain VDR, so offering a favorite vascular substrate for VitD to perform actions [79]. Moreover, VitD can repress parathyroid hormone production, itself related with CVD, and can inhibit generation of pro-inflammatory cytokine [80], which has been contributed in the enhancement of arterial stiffness. In a meta-analysis including 46 trials with 4541 subjects, no effect of VitD supplementation was found on SBP and/or DBP [81]. However, we could demonstrate that SBP and DBP is a modifier of 12.2% of incremental 25(OH)D in individuals on VitD supplements.
Moreover, responsiveness to VitD treatment is a multifactorial condition in which various parameters interact in non-linear biological pathways, which likely require a particular mathematical method, i.e. ANNs, to be understood. It has been suggested that ANN analysis offers a promising alternative to traditional statistical techniques for the statistical analysis of multivariate data in order to finding patterns in data encompassing many variables [82]. In current study, the feed-forward ANN with back-propagation as the training algorithm has been used to computing the magnitude of response to supplementation concerning to cardiometabolic risk factors in large population. But this research was limited solely to the adolescent girls population.