TY - JOUR
T1 - A Bidirectional Mendelian Randomization Study to evaluate the causal role of reduced blood vitamin D levels with type 2 diabetes risk in South Asians and Europeans
AU - Bejar, Cynthia A
AU - Goyal, Shiwali
AU - Afzal, Shoaib
AU - Mangino, Massimo
AU - Zhou, Ang
AU - van der Most, Peter J
AU - Bao, Yanchun
AU - Gupta, Vipin
AU - Smart, Melissa C
AU - Walia, Gagandeep K
AU - Verweij, Niek
AU - Power, Christine
AU - Prabhakaran, Dorairaj
AU - Singh, Jai Rup
AU - Mehra, Narinder K
AU - Wander, Gurpreet S
AU - Ralhan, Sarju
AU - Kinra, Sanjay
AU - Kumari, Meena
AU - de Borst, Martin H
AU - Hyppönen, Elina
AU - Spector, Tim D
AU - Nordestgaard, Børge G
AU - Blackett, Piers R
AU - Sanghera, Dharambir K
N1 - © 2021. The Author(s).
PY - 2021/7/27
Y1 - 2021/7/27
N2 - CONTEXT: Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent.OBJECTIVES AND METHODS: To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 individuals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration.RESULTS: Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10-32; Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10-78; Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12; Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7; rs12785878) as an individual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004; Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an individual instrument.CONCLUSION: Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D.
AB - CONTEXT: Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent.OBJECTIVES AND METHODS: To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 individuals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration.RESULTS: Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10-32; Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10-78; Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12; Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7; rs12785878) as an individual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004; Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an individual instrument.CONCLUSION: Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D.
KW - Asians/genetics
KW - Diabetes Mellitus, Type 2/genetics
KW - Humans
KW - Mendelian Randomization Analysis
KW - Polymorphism, Single Nucleotide
KW - Vitamin D
KW - Vitamin D Deficiency/genetics
UR - http://www.scopus.com/inward/record.url?scp=85111651500&partnerID=8YFLogxK
U2 - 10.1186/s12937-021-00725-1
DO - 10.1186/s12937-021-00725-1
M3 - Journal article
C2 - 34315477
SN - 1475-2891
VL - 20
SP - 71
JO - Nutrition Journal
JF - Nutrition Journal
IS - 1
M1 - 71
ER -