Vitamin D and Type 1 Diabetes Risk: A Systematic Review and Meta-Analysis of Genetic Evidence
Abstract
:1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Inclusion and Exclusion Criteria
- 1.
- Population: human of any gender and age, race and geographical distribution.
- 2.
- Exposure: a biological approach to the selection of genetic variants was used, including variants having a biological link to the exposure. Seven vitamin D related SNPs were selected: CYP2R1 (common variant) rs10741657, CYP2R1 (rare variant/low frequency) rs117913124, DHCR7/NADSYN1 rs12785878, GC rs3755967, CYP24A1 rs17216707, AMDHD1 rs10745742, SEC23A rs8018720. Of these selected SNPs, six are common variants identified based on the results of a recent GWAS for 25(OH)D concentration [21] and one is a low-frequency synonymous coding variant seen with a much larger effect on 25(OH)D concentration [22]. Strong genome-wide associations with 25(OH)D were found in genes located upstream (DHCR7/NADSY1 and both CYP2R1 variants), and two downstream (CYP24A1 and GC) of the 25(OH)D metabolite biochemical pathway. Two genes outside the vitamin D metabolism pathway (AMDHD1 and SEC23A) were also found to be significant variants and hence were included. 25(OH)D related proxies not directly present in the recent GWAS were also included if found in high linkage disequilibrium (r2 > 0.8) using the Ldproxy function in LD link (https://ldlink.nci.nih.gov, accessed on 12 April 2021).
- 3.
- Outcome: the primary outcome measure, T1D, was defined by the World Health Organization criteria: diabetes symptoms (polyuria, polydipsia and insulin deficiency), accompanied by exogenous insulin usage once T1D had been diagnosed [27]. T1D could be self-reported or doctor-diagnosed when confirming cases.
- 4.
- Study design: peer-reviewed genetic association, cohort, cross-section, or case-control observational studies and Mendelian randomization (MR) studies, as well as clinical trials and unpublished cohort studies.
- 5.
- A sample size of at least 50 cases and 50 controls were mandatory for sufficient data extraction. Where there were multiple publications from the same study population, the most recent highest quality results with the largest sample size were used.
- 6.
- The publication reported genotype distribution in both cases and controls in order to estimate an odds ratio (OR) with a 95% confidence interval (CI).
- 1.
- Conference papers.
- 2.
- Other types of diabetes.
2.3. Study Selection and Data Extraction
2.4. Statistical Analysis
2.5. Risk of Bias and Credibility of the Evidence Assessment
3. Results
3.1. Study Selection
3.2. Characteristics of Included Studies
3.3. Findings from the Meta-Analysis
4. Discussion
4.1. Main Findings
4.2. Considerations of Alternative Explanation for Observed Results
4.3. Strengths and Limitations
4.4. Guidelines for Future Research
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Study Details | Participant Characteristics | Polymorphism Details | Findings | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Author; Year | Country | Study Design | Ethnicity | n Cases/n Controls | Mean Age of Cases/Controls (Year) | Mean Age of Onset in Cases (Years) | T1D Diagnostic Criteria | Genotyping | Adjusted Factors | Gene | Variant | EA a | Relevant Key Findings |
Manousaki et al., 2021 [45] | Canada, United Kingdom, United States | Cohort | European | 9358/15,705 | NI | NI | Multiple criteria | PCR-RFLP | Age, sex, season of 25OHD measurement, genotype batch, genotype array, assessment centre (proxy for latitude) | CYP2R1 CYP2R1 (low frequency) DHCR7/NADSYN1 GC CYP24A1 AMDHDI SEC23A | rs10741657 rs117913124 rs12785878 rs3755967 b rs17216707 rs10745742 rs8018720 | A G T C c T T G | No association of individual SNPs with T1D. |
Almeida et al., 2020 [25] | Portugal | Case-control | Caucasian Portuguese | 350/490 | 29.0/32.2 | 17.2 | Classic clinical presentation d | PCR-RFLP | Age at bleed, sex, BMI, month of bleed, geographical region | CYP2R1 DHCR7/NADSYN1 GC | rs10741657 rs12785878 rs3755967 b | A T C c | No association of individual SNP with T1D. |
Nam et al., 2019 [44] | Korea | Case-control | Korean | 96/156 | 14.7/14.0 | NI | Classic clinical presentation d | PCR | 25OHD and 1α,25(OH)2D levels. (25OHD measurement obtained in same season) | CYP2R1 | rs10741657 | A | No association of individual SNP with T1D. |
Hussein et al., 2012 [41] | Egypt | Matched case-control | Egyptian | 120/120 | 11.7/11.1 | NI | WHO and ADA | PCR-RFLP | Nil | CYP2R1 | rs10741657 | A | An association of GG genotype of CYP2R1 polymorphism (coded by 25(OH)D decreasing alleles) with risk of T1D in Egyptian children [OR = 2.6, 95% CI = 1.1–6.1, p = 0.03]. A synergistic effect of multiple risk alleles between GG genotype of CYP2R1 and CC genotype of CYP27B1 and T1D risk found. |
Mahmoud et al., 2011 [42] | Egypt | Matched case-control | Egyptian | 59/65 | 13/>24 | 7.5 | WHO | PCR-RFLP | Nil | GC | rs3755967 b | C c | No association between VDBP polymorphisms with T1D. |
Blanton et al., 2011 [48] | United States | Case-control | American | 1705/2033 | NI | 12.9 | Classic clinical presentation d | TaqMan PCR Assays | Sex, onset of T1D, HLA risk | GC | rs3755967 b | C c | No association between VDBP polymorphisms with T1D detected. An association of the phenotype of lower VDBP levels with T1D. |
Ramos-Lopez et al., 2007 [40] | Germany | Case-control | German | 284/294 | NI | 11.5 | WHO | PCR-RFLP | 25(OH)D3 levels | CYP2R1 | rs10741657 | A | An association of the ‘G’ allele of CYP2R1 common variant polymorphisms (coded by 25(OH)D decreasing alleles) with T1D risk. |
Klupa et al., 1999 [43] | United States | Case-control | European | 181/163 | 36.2/52.55 | 10.9 | WHO | PCR | Nil; sensitivity confirmed via stratification by obesity and age at examination | GC | rs3755967 b | C c | No association of individual SNP with T1D. |
FinnGen [46] | Finland | Cohort | Finnish | 1143–1267/82,381–82,655 | NI | NI | Strict definition (Minimal/absent insulin production by pancreas) | Illumina and Affymetrix Chip Arrays | Sex, age, 10 PCs, genotyping batch | CYP2R1 CYP2R1 (low frequency) DHCR7/NADSYN1 GC CYP24A1 AMDHDI SEC23A | rs10741657 rs117913124 b rs12785878 rs3755967 rs17216707 rs10745742 rs8018720 | A G c T C T T G | NI |
UK Biobank [47] | United Kingdom | Cohort | Caucasian British | 3074–3221/370,277–387,397 | NI | NI | WHO | UK Biobank Axiom Array | Age, sex, birth location, assessment centre, SNP array, pc1-pc40, account for relatedness | CYP2R1 CYP2R1 (low frequency) DHCR7/NADSYN1 GC CYP24A1 AMDHDI SEC23A | rs10741657 rs117913124 rs12785878 rs3755967 rs17216707 rs10745742 rs8018720 | A G T C T T G | NI |
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Najjar, L.; Sutherland, J.; Zhou, A.; Hyppönen, E. Vitamin D and Type 1 Diabetes Risk: A Systematic Review and Meta-Analysis of Genetic Evidence. Nutrients 2021, 13, 4260. https://doi.org/10.3390/nu13124260
Najjar L, Sutherland J, Zhou A, Hyppönen E. Vitamin D and Type 1 Diabetes Risk: A Systematic Review and Meta-Analysis of Genetic Evidence. Nutrients. 2021; 13(12):4260. https://doi.org/10.3390/nu13124260
Chicago/Turabian StyleNajjar, Liana, Joshua Sutherland, Ang Zhou, and Elina Hyppönen. 2021. "Vitamin D and Type 1 Diabetes Risk: A Systematic Review and Meta-Analysis of Genetic Evidence" Nutrients 13, no. 12: 4260. https://doi.org/10.3390/nu13124260
APA StyleNajjar, L., Sutherland, J., Zhou, A., & Hyppönen, E. (2021). Vitamin D and Type 1 Diabetes Risk: A Systematic Review and Meta-Analysis of Genetic Evidence. Nutrients, 13(12), 4260. https://doi.org/10.3390/nu13124260