Association between liver-specific gene polymorphisms and their expression levels with nonalcoholic fatty liver disease.

UNLABELLED: Genetic factors account for a significant proportion of the phenotypic variance of nonalcoholic fatty liver disease (NAFLD); however, very few predisposing genes have been identified. We aimed to (1) identify novel genetic associations with NAFLD by performing a genome-wide association study (GWAS), and (2) examine the biological expression of the strongest genetic associations in a separate cohort. We performed GWAS of a population-based cohort (Raine Study) of 928 adolescents assessed for NAFLD by ultrasound at age 17. Expression of genes with single nucleotide polymorphisms (SNPs) that were associated with NAFLD at a significance level of P < 10(-5) was examined in adults with NAFLD and controls by quantifying hepatic messenger RNA (mRNA) expression and serum levels of protein. After adjustment for sex and degree of adiposity, SNPs in two genes expressed in liver were associated with NAFLD adolescents: group-specific component (GC) (odds ratio [OR], 2.54; P = 1.20 × 10(-6)) and lymphocyte cytosolic protein-1 (LCP1) (OR, 3.29; P = 2.96 × 10(-6)). SNPs in two genes expressed in neurons were also associated with NAFLD: lipid phosphate phosphatase-related protein type 4 (LPPR4) (OR, 2.30; P = 4.82 × 10(-6)) and solute carrier family 38 member 8 (SLC38A8) (OR, 3.14; P = 1.86 × 10(-6) ). Hepatic GC mRNA was significantly reduced (by 83%) and LCP1 mRNA was increased (by 300%) in liver biopsy samples from patients with NAFLD compared to controls (P < 0.05). Mean serum levels of GC protein were significantly lower in patients with NAFLD than controls (250 ± 90 versus 298 ± 90, respectively; P = 0.004); GC protein levels decreased with increasing severity of hepatic steatosis (P < 0.01). CONCLUSION: The association between GC and LCP1 SNPs and NAFLD as well as altered biological expression implicate these genes in the pathogenesis of NAFLD.

Adverse pregnancy outcomes are associated with shorter telomere length in the 17-year-old child.

This study examined associations between pregnancy and infant birth outcomes with child telomere length at age 17 years; and investigated if there are sex differences between pregnancy complications and telomere length. We utilised the population-based prospective Raine cohort study in Western Australia, Australia. 2900 pregnant women were recruited at 16-20 weeks' gestation (Gen 1), and their children (Gen 2) were followed up over several years. Generalised linear models were used to examine relationships between pregnancy or birth outcomes (gestational diabetes, pre-eclampsia, preterm birth, low birth weight, macrosomia), and as a composite, with telomere length, measured via a DNA sample from blood at 17 years of age. Analyses were adjusted for a range of confounders. Among the 1202 included children, there were no differences in child telomere length for any of the individual maternal or birth weight pregnancy outcomes nor were there any significant interactions between each of the complications (individual or composite) and the sex of the child. However, females born from any of the 5 adverse outcomes had shorter telomeres (estimated mean (SE) = -0.159 (0.061), p = 0.010) than females born in the absence of these complications. Specifically, females born from a pre-eclamptic pregnancy had shorter telomeres than females not born from a pre-eclamptic pregnancy (estimated mean (SE) = -0.166 (0.072), p = 0.022). No relationships were observed in males. Further longitudinal studies are needed to understand mediating factors that are important in predicting offspring telomere length and the necessity to investigate females and males independently.

Secreted Frizzled related protein-4 (sFRP4) promotes epidermal differentiation and apoptosis.

The skin provides vital protection from infection and dehydration. Maintenance of the skin is through a constant program of proliferation, differentiation and apoptosis of epidermal cells, whereby proliferating cells in the basal layer differentiating to form the keratinized, anucleated stratum corneum. The WNT signalling pathway is known to be important in the skin. WNT signalling has been shown to be important both in epidermal development and in the maintenance and cycling of hair follicles and epidermal stem cells. However, the precise role for this pathway in epidermal differentiation remains unknown. We investigated the role of the WNT signalling inhibitor sFRP4 in epidermal differentiation. sFRP4 is expressed in both normal skin and keratinocytes in culture. Expression of sFRP4 mRNA and protein increases with keratinocyte differentiation and apoptosis, whilst exposure of keratinocytes to exogenous sFRP4 promotes apoptosis and expression of the terminal differentiation marker Involucrin. These data suggest sFRP4 promotes epidermal differentiation.