GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians

Nongmaithem, Suraj S.; Joglekar, Charudatta; Krishnaveni, Ghattu V.; Sahariah, Sirazul A.; Ahmad, Meraj; Ramachandran, S; Gandhi, Meera; Chopra, Harsha; Pandit, Anand; Potdar, Ramesh; Fall, Caroline; Yajnik, Chittaranjan S; Chandak, Giriraj Ratan

doi:10.1093/hmg/ddx156

Cited by 23 publications

(14 citation statements)

References 56 publications

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“…The mechanisms behind high vitB12 levels are unknown, but there are some indications of potential explanations from the literature. First, in clinical settings, high levels of vitB12 associate with high TCN1 , 22 the major transport molecule for vitB12 in serum 27,42 . Genetic variants in TCN1 influence vitB12 levels 24 and high gene expression of TCN1 was recently found to associate with poor verbal memory, 43 a cognitive impairment which may be relevant for patients with ND.…”

Section: Discussionmentioning

confidence: 99%

Higher vitamin B12 levels in neurodevelopmental disorders than in healthy controls and schizophrenia

et al. 2020

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Recent studies suggest that both high and low levels of vitamin B12 (vitB12) may have negative health impacts. We measured VitB12 in patients with the Neurodevelopmental disorders (ND) (n = 222), comprised of Autism Spectrum Disorders, specific Developmental disorders, and Intellectual Disability (aged 2‐53 years), schizophrenia (n = 401), and healthy controls (HC) (n = 483). Age‐and gender‐adjusted vitB12 z‐scores were calculated by comparisons with a reference population (n = 76 148). We found higher vitB12 in ND (median 420 pmol/L, mean z‐score: 0.30) than in HC (316 pmol/L, z‐score: 0.06, P < .01) and schizophrenia (306 pmol/L, z‐score: −0.02, P < .001), which was significant after adjusting for age, gender, vitB12 supplement, folate, hemoglobin, leukocytes, liver, and kidney function (P < .02). In ND, 20% (n = 44) had vitB12 above 650 pmol/L, and 1% (n = 3) had below 150 pmol/L (common reference limits). In 6.3% (n = 14) of ND, vitB12 was above 2SD of mean in the age‐and gender‐adjusted reference population, which was more frequent than in HC (n = 8, 1.6%), OR: 4.0, P = .001. Low vitB12 was equally frequent as in HC, and vitB12 z‐scores were equal across the age groups. To conclude, vitB12 was higher in ND than in HC and schizophrenia, suggesting a specific feature of ND, which warrants further studies to investigate the underlying mechanisms.

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Section: Discussionmentioning

confidence: 99%

Higher vitamin B12 levels in neurodevelopmental disorders than in healthy controls and schizophrenia

et al. 2020

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“…First, it is important to state that certain aspects of the data from Table 1 stand in direct contrast to findings from GWAS of common traits/ diseases where often a very large number of loci explain a small fraction of the inter-individual variation or trait heritabilities. Second, we found a dearth of (discovery) studies undertaken in other ethnic groupings, although a small number of replication studies were undertaken in East Asian and African-American cohorts (50)(51)(52)(53)(54) . Third, there seems to be a general lack of utility provided by the identified genetic variants for prediction of individual and/or group-level status although GWAS have provided some novel insight into mechanisms that underpin interindividual variability in micronutrient status.…”

Section: Mnmentioning

confidence: 97%

“…To date, all micronutrient biomarker status heritability studies have been done on Caucasian population groups, and very few GWAS have investigated genetic association to micronutrient status in other ethnicities. In fact, merely two association studies have been done on vitamin B 12 status in Asian populations (52,53) , and one on Fe status in African Americans (54) . Consequently, there is a major gap and skew in knowledge with regard to understanding the genetic basis of micronutrient status variability in different ethnicities, potentially tempering the portability of GWAS findings within and across populations of different ancestry and the translatability of the latter into relevant public health application.…”

Section: Identifying Trans-ethnic and Ethnic-specific Genetic Effectsmentioning

confidence: 99%

A critical evaluation of results from genome-wide association studies of micronutrient status and their utility in the practice of precision nutrition

2019

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Rapid advances in ‘omics’ technologies have paved the way forward to an era where more ‘precise’ approaches – ‘precision’ nutrition – which leverage data on genetic variability alongside the traditional indices, have been put forth as the state-of-the-art solution to redress the effects of malnutrition across the life course. We purport that this inference is premature and that it is imperative to first review and critique the existing evidence from large-scale epidemiological findings. We set out to provide a critical evaluation of findings from genome-wide association studies (GWAS) in the roadmap to precision nutrition, focusing on GWAS of micronutrient disposition. We found that a large number of loci associated with biomarkers of micronutrient status have been identified. Mean estimates of heritability of micronutrient status ranged between 20 and 35 % for minerals, 56–59 % for water-soluble and 30–70 % for fat-soluble vitamins. With some exceptions, the majority of the identified genetic variants explained little of the overall variance in status for each micronutrient, ranging between 1·3 and 8 % (minerals), <0·1–12 % (water-soluble) and 1·7–2·3 % for (fat-soluble) vitamins. However, GWAS have provided some novel insight into mechanisms that underpin variability in micronutrient status. Our findings highlight obvious gaps that need to be addressed if the full scope of precision nutrition is ever to be realised, including research aimed at (i) dissecting the genetic basis of micronutrient deficiencies or ‘response’ to intake/supplementation (ii) identifying trans-ethnic and ethnic-specific effects (iii) identifying gene–nutrient interactions for the purpose of unravelling molecular ‘behaviour’ in a range of environmental contexts.

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“…The SNP FUT2 rs602662 and calpain 10 (CAP10) rs3792267 deviated from the HWE; however, these SNPs were not excluded from analysis. The FUT2 SNP rs602662 previously departed from HWE in a GWA study conducted in India; the authors ruled out that the deviation was not due to a genotyping error and still used this SNP for analysis in their study [30]. In addition, the KASP™ genotyping technology used in our study has been independently assessed to be over 99.8% accurate.…”

Section: Snp Selection and Genotypingmentioning

confidence: 99%

A genetic approach to examine the relationship between vitamin B12 status and metabolic traits in a South Asian population

Surendran

Alsulami

Lankeshwara

et al. 2019

Int J Diabetes Dev Ctries

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Background Observational studies in South Asian populations have suggested an association between vitamin B 12 status and metabolic traits; however, the findings have been inconclusive. Hence, the aim of the present study was to use a genetic approach to explore the relationship between metabolic traits and vitamin B 12 status in a Sri Lankan population and to investigate whether these relationships were modified by dietary intake. Methods A total of 109 Sinhalese adults (61 men and 48 women aged 25-50 years) from Colombo City underwent anthropometric and biochemical measurements, dietary intake analysis, and genetic tests. Genetic risk scores (GRS) based on 10 metabolic single nucleotide polymorphisms (SNPs) (metabolic-GRS) and 10 vitamin B 12 SNPs (B12-GRS) were constructed. Results The B12-GRS was significantly associated with serum vitamin B 12 (p = 0.008) but not with metabolic traits (p > 0.05), whereas the metabolic-GRS had no effect on metabolic traits (p > 0.05) and vitamin B 12 concentrations (p > 0.05). An interaction was observed between B12-GRS and protein energy intake (%) on waist circumference (p = 0.002). Interactions were also seen between the metabolic-GRS and carbohydrate energy intake (%) on waist-to-hip ratio (p = 0.015). Conclusion Our findings suggest that a genetically lowered vitamin B 12 concentration may have an impact on central obesity in the presence of a dietary influence; however, our study failed to provide evidence for an impact of metabolic-GRS on lowering B 12 concentrations. Given that our study has a small sample size, further large studies are required to confirm our findings. Keywords SNP. Body mass index. Obesity. Metabolic traits. Vitamin B 12 pathway. Sinhalese. Sri Lanka. Nutrigenetics Abbreviations SNPs Single nucleotide polymorphisms MTHFR Methylenetetrahydrofolate reductase CPS1 Carbamoyl-phosphate synthase 1 CUBN Cubulin CD320 CD320 molecule Electronic supplementary material The online version of this article (

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GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians

Cited by 23 publications

References 56 publications

Higher vitamin B12 levels in neurodevelopmental disorders than in healthy controls and schizophrenia

Higher vitamin B12 levels in neurodevelopmental disorders than in healthy controls and schizophrenia

A critical evaluation of results from genome-wide association studies of micronutrient status and their utility in the practice of precision nutrition

A genetic approach to examine the relationship between vitamin B12 status and metabolic traits in a South Asian population

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