Browsing by Author "Krawczyk, Marcin"

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    Genetics of biliary lithiasis from an ethnic perspective
    (2013) Krawczyk, Marcin; Miquel Poblete, Juan Francisco; Stokes, Caroline S.; Zuniga, Silvia; Hampe, Jochen; Mittal, Balraj; Lammert, Frank
    Gallstone disease represents one of the most common gastroenterological disorders worldwide. Gallstones affect over 15% of adults in Europe and 25-30% of Hispanic populations in Central and South America. The heritability of gallstones varies considerably according to ethnicity, with Native Americans and Hispanics with Amerindian admixture being the most susceptible populations. Genetic factors have been shown to account for 25-30% of total gallstone risk in Europe, however, in Hispanic populations, this risk percentage may increase to 45-65%. Recent genome-wide association and candidate gene studies have identified common polymorphisms in enterohepatic transporters (ABCG5/8, SLC10A2) and the Gilbert syndrome UGT1A1 variant as genetic determinants of gallstone formation. Together, these polymorphisms cover a significant proportion of the previously predicted genetic background of gallstones in European populations. New lithogenic genes need to be discovered in future studies in high-risk populations. In this review, we address the latest developments in the genetic analysis of gallstones and discuss the ethnic background of this condition in European, Central and South American and Asian populations. (C) 2012 Elsevier Masson SAS. All rights reserved.
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    Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles
    (2022) Martinez-Arranz, Ibon; Bruzzone, Chiara; Noureddin, Mazen; Gil-Redondo, Ruben; Minchole, Itziar; Bizkarguenaga, Maider; Arretxe, Enara; Iruarrizaga-Lejarreta, Marta; Fernandez-Ramos, David; Lopitz-Otsoa, Fernando; Mayo, Rebeca; Embade, Nieves; Newberry, Elizabeth; Mittendorf, Bettina; Izquierdo-Sanchez, Laura; Smid, Vaclav; Arnold, Jorge; Iruzubieta, Paula; Perez Castano, Ylenia; Krawczyk, Marcin; Marigorta, Urko M.; Morrison, Martine C.; Kleemann, Robert; Martin-Duce, Antonio; Hayardeny, Liat; Vitek, Libor; Bruha, Radan; Aller de la Fuente, Rocio; Crespo, Javier; Romero-Gomez, Manuel; Banales, Jesus M.; Arrese, Marco; Cusi, Kenneth; Bugianesi, Elisabetta; Klein, Samuel; Lu, Shelly C.; Anstee, Quentin M.; Millet, Oscar; Davidson, Nicholas O.; Alonso, Cristina; Mato, Jose M.
    Background and Aims We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. Approach and Results We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL-apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL5,6, and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A. Conclusions Metabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratification.
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    Phytosterol and cholesterol precursor levels indicate increased cholesterol excretion and biosynthesis in gallstone disease
    (WILEY-BLACKWELL, 2012) Krawczyk, Marcin; Luetjohann, Dieter; Schirin Sokhan, Ramin; Villarroel, Luis; Nervi, Flavio; Pimentel, Fernando; Lammert, Frank; Francisco Miquel, Juan
    In hepatocytes and enterocytes sterol uptake and secretion is mediated by Niemann-Pick C1-like 1 (NPC1L1) and ATP-binding cassette (ABC)G5/8 proteins, respectively. Whereas serum levels of phytosterols represent surrogate markers for intestinal cholesterol absorption, cholesterol precursors reflect cholesterol biosynthesis. Here we compare serum and biliary sterol levels in ethnically different populations of patients with gallstone disease (GSD) and stone-free controls to identify differences in cholesterol transport and synthesis between these groups. In this case-control study four cohorts were analyzed: 112 German patients with GSD and 152 controls; two distinct Chilean ethnic groups: Hispanics (100 GSD, 100 controls), and Amerindians (20 GSD, 20 controls); additionally an 8-year follow-up of 70 Hispanics was performed. Serum sterols were measured by gas chromatography / mass spectrometry. Gallbladder bile sterol levels were analyzed in cholesterol GSD and controls. Common ABCG5/8 variants were genotyped. Comparison of serum sterols showed lower levels of phytosterols and higher levels of cholesterol precursors in GSD patients than in controls. The ratios of phytosterols to cholesterol precursors were lower in GSD patients, whereas biliary phytosterol and cholesterol concentrations were elevated as compared with controls. In the follow-up study, serum phytosterol levels were significantly lower even before GSD was detectable by ultrasound. An ethnic gradient in the ratios of phytosterols to cholesterol precursors was apparent (Germans > Hispanics > Amerindians). ABCG5/8 variants did not fully explain the sterol metabolic trait of GSD in any of the cohorts. Conclusion: Individuals predisposed to GSD display increased biliary output of cholesterol in the setting of relatively low intestinal cholesterol absorption, indicating enhanced whole-body sterol clearance. This metabolic trait precedes gallstone formation and is a feature of ethnic groups at higher risk of cholesterol GSD. (HEPATOLOGY 2012)