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Vitamin D Status and Associated Genetic Polymorphisms in a Cohort of UK Children with Non- Alcoholic Fatty Liver Disease

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Vitamin D Status and Associated Genetic Polymorphisms in a Cohort of UK Children with Non- Alcoholic Fatty Liver Disease ORIGINALRESEARCH doi:10.1111/ijpo.12293 Vitamin D status and associated genetic polymorphisms in a cohort of UK children with non- alcoholic fatty liver disease P. S. Gibson1,3, A. Quaglia2, A. Dhawan3,H.Wu1, S. Lanham-New1, K. H. Hart1, RESEARCH E. Fitzpatrick3,† and J. B. Moore1,4,† 1Department of Nutritional Sciences, School of Summary Biosciences and Medicine, Faculty of Health and Background: Vitamin D deficiency has been associated with non-alcoholic fatty Medical Sciences, University of Surrey, Guildford, UK; 2Institute of Liver Studies, King’s College liver disease (NAFLD). However, the role of polymorphisms determining vitamin D ORIGINAL London School of Medicine at King’s College status remains unknown. Hospital, London, UK; 3Pediatric Liver, GI and Objectives: The objectives of this study were to determine in UK children with Nutrition Centre, King’s College London School of Medicine at King’s College Hospital, London, biopsy-proven NAFLD (i) their vitamin D status throughout a 12-month period and UK; 4School of Food Science and Nutrition, (ii) interactions between key vitamin D-related genetic variants (nicotinamide adenine University of Leeds, Leeds, UK dinucleotide synthase-1/dehydrocholesterol reductase-7, vitamin D receptor, group-specific component, CYP2R1) and disease severity. †Joint senior authors. Methods: In 103 paediatric patients with NAFLD, serum 25-hydroxyvitamin D Address for correspondence: (25OHD) levels and genotypes were determined contemporaneously to liver biopsy Dr. J Bernadette Moore, University of and examined in relation to NAFLD activity score and fibrosis stage. Leeds, School of Food Science and Nutrition, West Yorkshire, Leeds Results: Only 19.2% of children had adequate vitamin D status; most had mean fi < À1 fi LS2 9JT, UK. 25OHD levels considered de cient ( 25 nmol·L , 25.5%) or insuf cient À1 E-mail: [email protected] (<50 nmol·L , 55.3%). Patients had significantly lower 25OHD levels in winter – À1 – Dr. E Fitzpatrick, Pediatric Liver, GI and months (95% CI: 22.7 31.2 nmol·L ) when compared with spring (30.5 À1 – À1 < Nutrition Centre, King’s College 42.1 nmol·L ; P = 0.0089), summer (36.3 47.2 nmol·L ; P 0.0001) and au- À1 London School of Medicine, London tumn (34.2–47.5 nmol·L ; P = 0.0003). Polymorphisms in the nicotinamide ade- SE5 9RS, UK. nine dinucleotide synthase-1/dehydrocholesterol reductase-7 (rs3829251, E-mail: emer.fi[email protected] rs12785878) and vitamin D receptor (rs2228570) genes were independently asso- ciated with increased steatosis; while a group-specific component variant (rs4588) Received 31 December 2017; revised 20 March was associated with increased inflammation in liver biopsies. 2018; accepted 4 April 2018 Conclusions: Children with NAFLD in the UK have particularly low winter vitamin D sta- tus, with vitamin D insufficiency prevalent throughout the year. Polymorphisms in the vita- min D metabolic pathway are associated with histological severity of paediatric NAFLD. Keywords: 25OHD, genotype, non-alcoholic fatty liver disease, vitamin D. Abbreviations: NAFLD, non-alcoholic fatty liver disease; 25OHD, 25- hydroxyvitamin D; BMI, body mass index; AST, aspartate transaminase; ALT, alanine transaminase; NAS, NAFLD activity score; SNPs, single nucleotide polymorphisms; NADSYN1, nicotinamide adenine dinucleotide synthase-1; NASH, non-alcoholic steatohepatitis; DHCR7, dehydrocholesterol reductase-7; GC, group-specific component; VDR, vitamin D receptor; PNPLA3, patatin-like phospholipase domain-containing protein 3 Introduction obese children, NAFLD is now the most common chronic liver disease in the paediatric population and A growing body of research suggests a relationship fast becoming the most common indication for liver between vitamin D deficiency and chronic liver dis- transplantation (1). Although transplantation for ease, in particular non-alcoholic fatty liver disease NAFLD in children is exceedingly rare, the histological (NAFLD). With prevalence estimated up to 80% in pattern of paediatric disease (type 2 non-alcoholic © 2018 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd Pediatric Obesity 13, 433–441, July 2018 on behalf of World Obesity Federation This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 434 | P. S. Gibson et al. steatohepatitis, NASH) is associated with more severe comprehensive clinical work up including abdominal disease and possibly with a rapid rate of progression (2). ultrasound, exclusion of viral hepatitis, Wilson disease Despite the high prevalence of NAFLD however, its and inborn errors of metabolism including lysosomal molecular pathogenesis remains only partially under- acid lyase deficiency. Liver biopsy was undertaken in stood and targeting those who are most likely to prog- the case of persistently abnormal liver function tests ress is difficult. The development and progression of (>2 upper limit of normal aspartate transaminase RESEARCH the disease are presumed to be multifactorial in nature [AST] or alanine transaminase [ALT]) with a duration and influenced by both genetic and nutritional factors over 6 months and/or an enlarged spleen (>1cm (3). Lifestyle change is the only proven effective treat- above upper limit of normal for age/height) on ultra- ment for paediatric NAFLD (4) and identifying those sound on two or more occasions suggesting signifi- at increased risk of progression may allow more cant liver injury. Liver biopsies were formalin-fixed targeted individualized therapy. Recent studies have and paraffin-embedded. Sections were stained with demonstrated that low vitamin D status associates haematoxylin and eosin, orcein, Perl’s and reticulin. with paediatric NAFLD independently of body mass Liver copper was also measured. Histological assess- ORIGINAL index (BMI) in Australian (5) and Italian (6) cohorts, ment was performed by a single hepato- raising the question of whether improvement in vita- histopathologist who was blinded to the patient’s clin- min D status through diet or supplementation may ical details and scored according to the Kleiner/Brunt be beneficial in some patients (7). system. Each biopsy was assigned a score for The most commonly used biomarker of vitamin D steatosis (0–3), lobular inflammation (0–3), hepatocyte status is 25-hydroxyvitamin D (25OHD), which is the ballooning (0–2) and fibrosis (0–4), and the NAFLD ac- most stable circulating form of vitamin D and reflects tivity score (NAS) was calculated. BMI was calculated both dietary intake and cutaneous synthesis (8). In by dividing weight, in kilograms by height, measured the UK, 25OHD status is highest in the summer and with a fixed stadiometer, in meters squared. lowest during winter and spring months. Vitamin D status has a strong hereditary component with dis- General biochemistry and measurement tinct sets of common gene variants, explaining some of 25-hydroxyvitamin D of the differences observed in vitamin D status be- tween different ethnic populations (9,10). Given the Liver enzymes and lipids were analysed using stan- possible association between low vitamin D status dard methods on the ADVIA 2400 analyser (Sie- and NAFLD, and the hereditary component of vitamin mens Healthcare Diagnostics, UK). Serum 25OHD D status, the aims of this study were to determine in a levels were measured only once due to low sample multi-ethnic cohort of children from the UK with volumes using a chemiluminescent immunoassay, biopsy-proven NAFLD (i) their 25OHD status and ex- the ADVIA Centaur Vitamin D Total Assay. Samples tent of vitamin D deficiency/insufficiency throughout were coded, and the researcher was blinded to clin- a given 12-month period and (ii) interactions between ical details. The sensitivity of the assay is estimated key polymorphisms related to vitamin D metabolism to range from 10 nmol·LÀ1 to 375 nmol·LÀ1, while and NAFLD disease severity. the inter-assay variation was 4.2–11.9% and the percentage of cross reactivity with vitamin D2 and fi Methods D3 was 1.1%. We used thresholds de ned by the Study design and patients UK Department of Health (11) and the US Institute of Medicine (8) for assessing vitamin D status; This observational study received ethical approval 25OHD concentrations below 25 nmol·LÀ1 were from the UK National Research Ethics Service (09/ considered deficient and below 50 nmol·LÀ1 as in- H0808/15) and was conducted according to the Hel- sufficient, respectively. sinki declaration. Anonymised clinical data were ex- amined from patients who had attended a tertiary Genotyping paediatric liver centre (King’s College Hospital, London, UK) between March 2001 and July 2013; Eight candidate polymorphisms were selected based who had suspected NAFLD confirmed by biopsy on their established influence on vitamin D status and had buffy coat samples available. All patients in- (9,10,12) and/or liver disease (13,14). The variants in- cluded were less than 19 years of age at sample col- cluded two intronic single nucleotide polymorphisms lection. Patients were excluded if taking vitamin D (SNPs) (rs12785878 and rs3829251) in the nicotin- supplementation or if NAFLD was not the primary liver amide adenine dinucleotide (NAD) synthetase-1 diagnosis. Other liver diseases were ruled out through (NADSYN1) gene, responsible for the final step in the Pediatric Obesity 13, 433–441, July 2018 © 2018 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation Vitamin D-related polymorphisms in NAFLD | 435 biosynthesis of NAD. The NADSYN1 gene is located August values were used for all comparisons. We immediately proximal to the dehydrocholesterol have estimated that for this cohort (n = 103), consid- reductase-7 (DHCR7) gene on chromosome 11q12, ering an α error = 0.05 and SD = 19.33 nmol·LÀ1 in which encodes the rate-limiting enzyme responsible serum vitamin D levels, we had a power of >80% to for the reduction of 7-dehydrocholesterol to choles- detect a difference of 5.34 nmol·LÀ1 within this group.
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