Vitamin D-related genes and cardiometabolic markers in healthy children: a Mendelian randomisation study

Abstract

Observational studies show associations between low serum 25-hydroxyvitamin D (25(OH)D) and cardiometabolic risk markers. This Mendelian randomisation study examined associations between cardiometabolic markers in children and SNP in genes related to vitamin D metabolism (DHCR7; group-specific complement (GC); cytochrome P450 subfamily IIR1 (CYP2R1); and CYP24A1) and action (CYP27B1 and VDR). In 699 healthy 8–11-year-old children, we genotyped eleven SNP. We generated a genetic risk score based on SNP associated with low 25(OH)D and investigated associations between this and blood pressure, plasma lipids and insulin. Furthermore, we examined whether SNP related to vitamin D actions modified associations between 25(OH)D and the cardiometabolic markers. All GC and CYP2R1 SNP influenced serum 25(OH)D. A risk score based on four of the six SNP was associated with 3·4 (95 % CI 2·6, 4·2) mmol/l lower 25(OH)D per risk allele (P < 0·001), but was not associated with the cardiometabolic markers. However, interactions were indicated for the three VDR SNP (Pinteraction < 0·081) on associations between 25(OH)D and TAG, systolic blood pressure and insulin, which all decreased with increasing 25(OH)D only in major allele homozygotes (β –0·02 (95 % CI –0·04, –0·01) mmol/l; β –0·5 (95 % CI –0·9, –0·1) mmHg; and β –0·5 (95 % CI –1·4, 0·3) pmol/l, respectively). In conclusion, genetic variation affected 25(OH)D substantially, but the genetic score was not associated with cardiometabolic markers in children. However, VDR polymorphisms modified associations with vitamin D, which warrants further investigation of VDR's role in the relationship between vitamin D and cardiometabolic risk.

Association of AGTR1 (rs5186), VDR (rs2228570) genes polymorphism with blood pressure elevation in patients with essential arterial hypertension

“…Lopez-Mayorga et al did not confirm the linkage of VDR gene three polymorphisms with cardiometabolic risk. However, the study was performed on children [ 30 ]. Nevertheless, the conclusion about the association of AGTR1 (rs5186) and VDR (rs2228570) with EAH is questionable and differs in populations due to various designs and patterns of research [ 31 ].…”

Vitamin D metabolism pathway polymorphisms are associated with efficacy and safety in patients under anti-PD-1 inhibitor therapy

“…One recent study showed that the rs6068816T allele is associated with higher levels of 25(OH)D concentration and a lower risk of NSCLC, whereas no such association was found for the rs2296241 allele ( 34 ). However, inconsistent results were found in other studies, which found that both the rs6068816 and rs2296241 polymorphisms were not associated with 25(OH)D concentration levels ( 35 , 36 ). Because of a synonymous polymorphism, rs6068816 and rs2296241 cannot alter the amino acid sequence of CYP24A1 .…”

Association of Vitamin D Genetic Risk Score with Noncommunicable Diseases: A Systematic Review

“…After primarily screening titles and abstracts for eligibility, 70 records were excluded, leaving 51 research articles for full-text secondary screening. Finally, only 11 research articles were chosen after satisfying the inclusion and exclusion criteria [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. These included five Mendelian randomization studies [ 42 , 43 , 44 , 46 ], two case–control studies [ 47 , 49 ], two cohort studies [ 48 , 50 ], and three cross-sectional studies [ 40 , 41 , 42 ].…”

“…Finally, only 11 research articles were chosen after satisfying the inclusion and exclusion criteria [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. These included five Mendelian randomization studies [ 42 , 43 , 44 , 46 ], two case–control studies [ 47 , 49 ], two cohort studies [ 48 , 50 ], and three cross-sectional studies [ 40 , 41 , 42 ]. Reasons for exclusion included the following: no calculation of vitamin D GRS, but the calculation of a polygenetic risk score instead ( n = 12); GRS not based on vitamin D-related SNPs ( n = 9); only serum vitamin D concentration studied as an outcome ( n = 14); genetic predisposition of individual SNPs studied only ( n = 3); and the use of SNPs associated with high 25(OH)D levels ( n = 2).…”

“…On the other hand, all four Mendelian randomization studies [ 42 , 43 , 44 , 46 ] assessed for bias by the Q-Genie tool, Table 1 section D, were evaluated as “Good” since they had quality scores of more than 40 points. However, sources of bias were not fully discussed by most of the studies, especially when considering the gene–environment interaction our research question was asking, as it may be interpreted as an exclusion restriction violation for a Mendelian randomization study.…”