Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis

Manousaki, Despoina; Dudding, Tom; Haworth, Simon; Hsu, Yi Hsiang; Liu, Ching‐Ti; Medina-Gómez, Carolina; Voortman, Trudy; Velde, Nathalie van der; Melhus, Håkan; Robinson‐Cohen, Cassianne; Cousminer, Diana L.; Nethander, Maria; Vandenput, Liesbeth; Noordam, Raymond; Forgetta, Vincenzo; Greenwood, Celia; Biggs, Mary L.; Psaty, Bruce M.; Rotter, Jerome I.; Zemel, Babette S.; Mitchell, Jonathan A.; Taylor, Bruce; Lorentzon, Mattias; Karlsson, Magnus; Jaddoe, Vincent; Tiemeier, Henning; Campos‐Obando, Natalia; Franco, Oscar H.; Utterlinden, Andre G.; Broer, Linda; Schoor, Natasja M. van; Ham, Annelies C.; Ikram, M. Arfan; Karasik, David; Mutsert, Renée de; Rosendaal, Frits R.; Heijer, Martin den; Wang, Thomas J.; Lind, Lars; Orwoll, Eric S.; Mook‐Kanamori, Dennis O.; Michaëlsson, Karl; Kestenbaum, Bryan; Ohlsson, Claes; Mellström, Dan; Groot, Lisette C. P. G. M. de; Grant, Struan F.A.; Kiel, Douglas P.; Zillikens, M. Carola; Rivadeneira, Fernando; Sawcer, Stephen; Timpson, Nicholas J.; Richards, J. Brent

doi:10.1016/j.ajhg.2018.11.010

Cited by 37 publications

(56 citation statements)

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“…Of these, 15 loci were low-frequency variants (MAF < 0.05), and 106 regions had no previously identified associations. All six loci reported in previous vitamin D GWAS 8,19,20 were replicated in our study. While recognising that the COJO method cannot distinguish between SNPs in perfect LD, we note that within the 143 COJO independent variants: (a) 14 were nonsynonymous variants that alter protein coding (NRIP1, DSG1, TM6SF2, PLA2G3, GCKR, APOE, PCSK9, SEC23A, FLG, NPHS1, SDR42E1, CPS1, ADH1B, UGT1A5), and (b) 9 were annotated to include small insertion/deletions.…”

Section: Resultssupporting

confidence: 77%

“…rs116970203 is a low-frequency variant (MAF = 0.03 (A)) located in intron 11 of the PDE3B gene. It is also a perfect proxy for rs117913124 (LD r 2 = 1), a low-frequency synonymous coding variant in CYP2R1, which was previously reported to associate with 25OHD 19 . Another CYP2R1 synonymous variant was also identified (rs12794714; MAF = 0.42 (A)).…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration

et al. 2020

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Vitamin D deficiency is a candidate risk factor for a range of adverse health outcomes. In a genome-wide association study of 25 hydroxyvitamin D (25OHD) concentration in 417,580 Europeans we identify 143 independent loci in 112 1-Mb regions, providing insights into the physiology of vitamin D and implicating genes involved in lipid and lipoprotein metabolism, dermal tissue properties, and the sulphonation and glucuronidation of 25OHD. Mendelian randomization models find no robust evidence that 25OHD concentration has causal effects on candidate phenotypes (e.g. BMI, psychiatric disorders), but many phenotypes have (direct or indirect) causal effects on 25OHD concentration, clarifying the epidemiological relationship between 25OHD status and the health outcomes examined in this study.

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Section: Resultssupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration

et al. 2020

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“…Many of these single nucleotide polymorphisms lie close to genes associated with immune function, typically in regulatory rather than coding regions. Functional variants identified include those within IL7R , IL2RA , TNFR1 , BAFF and CYP2R1 . Mendelian randomization studies have provided evidence for a role of vitamin D and obesity as independent risk factors causing disease.…”

Section: Epidemiology and Aetiologymentioning

confidence: 99%

Multiple sclerosis – a review

Dobson

Giovannoni

2018

Euro J of Neurology

1,439

877

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Multiple sclerosis (MS) is the commonest non-traumatic disabling disease to affect young adults. The incidence of MS is increasing worldwide, together with the socioeconomic impact of the disease. The underlying cause of MS and mechanisms behind this increase remain opaque, although complex geneenvironment interactions almost certainly play a significant role. The epidemiology of MS indicates that low serum levels of vitamin D, smoking, childhood obesity and infection with the Epstein-Barr virus are likely to play a role in disease development. Changes in diagnostic methods and criteria mean that people with MS can be diagnosed increasingly early in their disease trajectory. Alongside this, treatments for MS have increased exponentially in number, efficacy and risk. There is now the possibility of a diagnosis of 'pre-symptomatic MS' being made; as a result potentially preventive strategies could be studied. In this comprehensive review, MS epidemiology, potential aetiological factors and pathology are discussed, before moving on to clinical aspects of MS diagnosis and management.

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“…In humans, deficient/insufficient 25(OH)D concentrations have also been linked to multiple autoimmune conditions, including multiple sclerosis, rheumatoid arthritis, Crohn’s disease, celiac disease, systemic lupus erythematosus, and asthma . In diabetes‐prone non‐obese diabetic (NOD) mice, lifelong vitamin D supplementation significantly reduced diabetes development in both male and female mice .…”

Section: Introductionmentioning

confidence: 99%

Vitamin D status, enterovirus infection, and type 1 diabetes in Italian children/adolescents

et al. 2018

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At the time of the clinical onset of type 1 diabetes (T1D), we investigated 82 pediatric cases in parallel with 117 non-diabetic controls matched by age, geographic area, and time of collection. The occurrence of an enteroviral infection was evaluated in peripheral blood using a sensitive method capable of detecting virtually all human enterovirus (EV) types. While non-diabetic controls were consistently EV-negative, 65% of T1D cases carried EVs in blood. The vitamin D status was assessed by measuring the concentration of 25-hydroxyvitamin D [25(OH)D] in serum. Levels of 25(OH)D were interpreted as deficiency (≤50 nmol/L), insufficiency (52.5-72.5 nmol/L), and sufficiency (75-250 nmol/L). In T1D cases, the median serum concentration of 25(OH)D was 54.4 ± 27.3 nmol/L vs 74.1 ± 28.5 nmol/L in controls (P = .0001). Diabetic children/adolescents showed deficient levels of vitamin D 25(OH)D (ie, 72.5 nmol/L) in 48.8% cases vs 17.9% in non-diabetic controls (P = .0001). Unexpectedly, the median vitamin D concentration was significantly reduced in virus-positive vs virus-negative diabetics (48.2 ± 22.5 vs 61.8 ± 31.2 nmol/L; P = .015), with deficient levels in 58.5% vs 31.0%, respectively. Thus, at the time of clinical onset, EV-positive cases had reduced vitamin D levels compared with EV-negative cases. This could indicate either that the virus-negative children/adolescents had been hit by a non-infectious T1D-triggering event, or that children/adolescents with proper levels of vitamin D had been able to rapidly clear the virus. Thus, it would be important to assess whether adequate vitamin D supplementation before or during the prediabetic phase of T1D may counteract the diabetogenic potential of infectious pathogens.

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Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis

Cited by 37 publications

References 0 publications

Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration

Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration

Multiple sclerosis – a review

Vitamin D status, enterovirus infection, and type 1 diabetes in Italian children/adolescents

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