Association of Vitamin D Serum Levels and Its Common Genetic Determinants, With Severity of Liver Fibrosis in Genotype 1 Chronic Hepatitis C Patients

S. Petta, S. Grimaudo, V. D. Marco, C. Scazzone, F. S. Macaluso, C. Cammà, D. Cabibi, R. Pipitone, A. Craxì

J Viral Hepat. 2013;20(7):486-493.

Abstract and Introduction

Abstract

Lower 25-hydroxyvitamin D [25(OH)D] serum levels have been associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients (G1CHC). In addition, a recent genome-wide study identified genetic variants (rs12785878, near dehydrocholesterol reductase, DHCR7; rs10741657, near CYP2R1; and rs7041, near vitamin D-binding protein, GC) affecting 25(OH)D serum levels in healthy populations. We aimed to assess the association between vitamin D serum levels and its genetic determinants, with the severity of liver fibrosis. Two hundred and sixty patients with biopsy-proven G1CHC were consecutively evaluated. The 25(OH)D serum levels were measured by high-pressure liquid chromatography. All patients were genotyped for DHCR7 rs12785878, CYP2R1 rs10741657 and GC rs7041 single nucleotide polymorphisms. DHCR7 GG genotype (P = 0.003) and the severity of fibrosis (P = 0.03) were independent factors associated with lower 25(OH)D serum levels in multiple linear regression analysis. Interestingly, 53.8% (7/13) of patients with DHCR7 GG genotype had severe liver fibrosis, compared to 27.1% (67/247) of those with DHCR7 TT/TG genotype (P = 0.03). By multivariate logistic regression analysis, severe fibrosis was independently associated with older age (OR, 1.056; 95% CI, 1.023–1.089, P = 0.001), low cholesterol (OR, 0.984; 95% CI, 0.974–0.994, P = 0.002), high triglycerides (OR, 1.008; 95% CI, 1.002–1.015, P = 0.01), low 25(OH)D (OR, 0.958; 95% CI, 0.919–0.999, P = 0.04), DHCR7 GG genotype (OR, 4.222; 95% CI, 1.106–16.120; P = 0.03), moderate–severe steatosis (OR, 2.588; 95% CI, 1.355–4.943; P = 0.004) and moderate–severe necroinflammatory activity (grading) (OR, 2.437; 95% CI, 1.307–4.763; P = 0.001). No associations were found between liver fibrosis and both CYP2R1 and GC genotypes. In patients with G1CHC, GG homozygosis for DHCR7 gene and lower 25(OH)D levels are independently associated with the severity of liver fibrosis.

Introduction

The key issue in patients with chronic hepatitis C (CHC) is the progression of liver fibrosis as a consequence of various mechanisms of tissue damage caused by viral infection,^[1] with the ultimate development of cirrhosis and its complications.

Other than well known risk factors for fibrosis severity, like liver necroinflammation, older age, consumption of alcohol, duration of infection and viral coinfections,^[2] metabolic alterations, namely steatosis,^[3] insulin resistance (IR)^[4] and menopause (in females)^[5] can affect the degree of liver fibrosis.

In this complex and interesting interplay between liver and metabolic factors, growing evidence also suggest a role of vitamin D status on liver disease severity in patients with chronic hepatitis C. In particular, we firstly reported that fully compensated genotype 1 (G1) CHC patients are characterized by a higher prevalence of 25-hydroxyvitamin D [25(OH)D] deficiency compared to a control population, also showing in this clinical setting an independent inverse relationship between 25(OH)D serum levels and liver fibrosis severity.^[6] These clinical data not only were further confirmed by other groups,^[7,8] but also their strength was supported by experimental studies showing that vitamin D, acting via its nuclear vitamin D receptor, exerts its protective effect by inhibiting stellate cell proliferation and their profibrogenic activation.^[9]

Vitamin D has therefore a relevant role in patients with CHC, and its metabolism is regulated by several environmental factors, in particular sunlight and diet. In addition, a recent genome-wide association study (GWAS), in a large screening population of about 30 000 European descent individuals divided in a training and a validation set demonstrated that serum concentrations of 25(OH)-vitamin D are influenced by variants near genes involved in cholesterol synthesis (7-dehydrocholesterol reductase -DHCR7), vitamin D hydroxylation (CYP2R1) and vitamin D transport (vitamin D-binding protein–GC).^[10]

With this in mind, in a cohort of biopsy-proven G1 CHC patients, we aimed to assess the association between vitamin serum levels and its genetic determinants, with the severity of liver fibrosis.

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