Objective-Mutations of the ANGPTL3 gene have been associated with a novel form of primary hypobetalipoproteinemia, the combined hypolipidemia (cHLP), characterized by low total cholesterol and low HDL-cholesterol levels. The aim of this work is to define the role of ANGPTL3 gene as determinant of the combined hypolipidemia phenotype in 2 large cohorts of 913 among American and Italian subjects with primary hypobetalipoproteinemia (total cholesterol Ͻ5th percentile). Methods and Results-The combined hypolipidemia cut-offs were chosen according to total cholesterol and HDL-cholesterol levels reported in the ANGPTL3 kindred described to date: total cholesterol levels, Ͻ2nd percentile and HDL-cholesterol, levels Ͻ2nd decile. Seventy-eight subjects with combined hypolipidemia were analyzed for ANGPTL3 and APOB genes. We identified nonsense and/or missense mutations in ANGPTL3 gene in 8 subjects; no mutations of the APOB gene were found. Mutated ANGPTL3 homozygous/compound heterozygous subjects showed a more severe biochemical phenotype compared to heterozygous or ANGPTL3 negative subjects, although ANGPTL3 heterozygotes did not differ from ANGPTL3 negative subjects. Conclusion-These results demonstrated that in a cohort of subjects with severe primary hypobetalipoproteinemia the prevalence of ANGPTL3 gene mutations responsible for a combined hypolipidemia phenotype is about 10%, whereas mutations of APOB gene are absent. Key Words: epidemiology Ⅲ lipoproteins Ⅲ genetics Ⅲ hypobetalipoproteinemia P rimary hypobetalipoproteinemia (pHBL) is a monogenic condition inherited as a dominant or recessive trait 1 characterized by total cholesterol (TC) and/or LDL cholesterol (LDL-C) and/or apolipoprotein B (APOB) levels below the 5th percentile of the reference population. Heterozygous APOB gene mutations are responsible for the majority of the dominant pHBL, 1,2 causing the familial hypobetalipoproteinemia (FHBL). The clinical phenotype of heterozygous FHBL is usually mild, being frequently characterized by fatty liver and levels of APOB and LDL-C reduced by 60%. 1,2 The homozygous or compound heterozygous APOB mutations are in some cases responsible for a more severe biochemical and clinical phenotype, similar to the abetalipoproteinemia (ABL) due to homozygous mutations in the MTP gene, characterized 3,4 by intestinal malabsorption, pigmentary retinal degeneration, ataxic neuropathy, and almost undetectable levels of LDL-C and APOB.Recently mutations in the PCSK9 gene have been identified as cause of FHBL in kindred of African American 5 and Caucasian 6 descent. These mutations are associated with a pHBL phenotype that is not complicated by fatty liver as shown in FHBL due to APOB gene mutations.Mutations in the ANGPTL3 gene have been recently identified in a kindred affected by "familial combined hypolipidemia." 7 The affected members of the kindred were found to be compound heterozygous for 2 ANGPTL3 nonsense mutations and their lipid profile was characterized by low levels of TC, triglycerides (TG), LDL-C, and high-densi...

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OBJECTIVES:Non-celiac wheat sensitivity (NCWS) is defined as a reaction to ingested wheat after exclusion of celiac disease and wheat allergy. As its pathogenesis is incompletely understood, we evaluated the inflammatory response in the rectal mucosa of patients with well-defined NCWS.METHODS:The prospective study included 22 patients with irritable bowel syndrome (IBS)-like clinical presentation, diagnosed with NCWS by double-blind placebo-controlled challenge. Eight IBS patients not improving on wheat-free diet were used as controls. Two weeks after oral challenge was performed with 80 grams of wheat daily, cells were isolated from rectal biopsies and thoroughly characterized by fluorescence-activated cell sorting analysis for intracellular cytokines and surface markers.RESULTS:Rectal biopsies from wheat-challenged NCWS patients showed that a significant mucosal CD45+ infiltrate consisted of CD3+ and CD3− lymphocytes, with the latter spontaneously producing more interferon (IFN)-γ than IBS controls. About 30% of IFN-γ-producing CD45+ cells were T-bet+, CD56−, NKP44−, and CD117−, defining them as a type-1 innate lymphoid cells (ILC1). IFN-γ-producing ILC1 cells significantly decreased in 10 patients analyzed 2 weeks after they resumed a wheat-free diet.CONCLUSIONS:These data indicate that, in patients with active NCWS, IFN-γ-producing ILC1 cells infiltrate rectal mucosa and support a role for this innate lymphoid cell population in the pathogenesis of NCWS.

Our study shows that TC, TG, HDL, and Apo-AI are reduced in cirrhotics with AI. In particular, because both HDL and Apo-AI play a primary role in providing substrates for steroidogenesis to adrenal cells, this deficiency may contribute to the pathogenesis of AI in these patients.