Browsing by Author "Mangino, Massimo"

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    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
    (BioMed Central Ltd, 2021-07-27T00:00:00) Bejar, Cynthia A.; Goyal, Shiwali; Afzal, Shoaib; Mangino, Massimo; Zhou, Ang; van der Most, Peter J.; Bao, Yanchun; Gupta, Vipin; Smart, Melissa C.; Walia, Gagandeep K.; Verweij, Niek; Power, Christine; Prabhakaran, Dorairaj; Singh, Jai Rup; Mehra, Narinder K.; Wander, Gurpreet S.; Ralhan, Sarju; Kinra, Sanjay; Kumari, Meena; de Borst, Martin H.; Hypp�nen, Elina; Spector, Tim D.; Nordestgaard, B�rge G.; Blackett, Piers R.; Sanghera, Dharambir K.
    Context: Multiple observational studies have reported aninverse relationship between 25-hydroxyvitaminD concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results ofshort- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have beeninconsistent. Objectives and methods: To evaluate the causal role of reduced blood25(OH)D in T2D, here we have performed a bidirectional Mendelian randomizationstudy using 59,890 individuals (5,862 T2D cases and 54,028 controls) fromEuropean and Asian Indian ancestries. We used six known SNPs, including threeT2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluatethe causality and direction of the association between T2D and circulating25(OH)D concentration. Results: Results of the combined meta-analysis of eightparticipating studies showed that a composite score of three T2D SNPs wouldsignificantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 � 10�32; Z score 11.86, which, however, hadno significant association with 25(OH)D status (Beta -0.02nmol/L � SE0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the geneticallyinstrumented composite score of 25(OH)D lowering alleles significantlydecreased 25(OH)D concentrations (-2.1nmol/L � SE 0.1nmol/L,p = 7.92 � 10�78; Z score -18.68) but was notassociated 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 anindividual 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 (GCrs2282679, CYP2R1 rs12794714) when used as an individual instrument. Conclusion: Our new data on this bidirectional Mendelianrandomization study suggests that genetically instrumented T2D risk does notcause changes in 25(OH)D levels. However, genetically regulated 25(OH)Ddeficiency due to vitamin D synthesis gene (DHCR7) may influence the risk ofT2D. � 2021, The Author(s).