Medical Research Section 3
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Genome-wide association meta-analysis yields 20 loci associated with gallstone disease
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Pleiotropic associations of heterozygosityfor the SERPINA1 Z allele
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Increased Prevalence of Alpha-1-Antitrypsin Deficiency in Patients with Biliary Tract Cancer and Its Associated Clinicopathological Features
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Bile duct adenomas in heterozygous (MZ) deficiency of alpha 1-protease inhibitor
Genome-wide association meta-analysis yields
20 loci associated with gallstone
Egil Ferkingstad
Gallstones are responsible for one of the most common diseases in the Western world and are commonly treated with cholecystectomy. We perform a meta-analysis of two genome-wide association studies of gallstone disease in Iceland and the UK, totaling 27,174 cases and 736,838 controls, uncovering 21 novel gallstone-associated variants at 20 loci.
We demonstrate that lower bile acid transport by ASBT is accompanied by greater risk of gallstone disease and highlight the role of the intestinal compartment of the enterohepatic circulation of bile acids in gallstone disease susceptibility. Additionally, two low frequency missense variants in SERPINA1 and HNF4A and 17 common variants represent novel associations with gallstone disease.
We show that the PI Z allele of SERPINA1 associates with increased risk of gallstone disease. Severe AAT deficiency in PI ZZ homozygotes predisposes to emphysema and, less commonly, to liver disease. The precise mechanism of liver disease associated with severe AAT deficiency is not well understood but histopathological findings of liver parenchyma in PI ZZ homozygotes indicate that liver abnormalities result from toxic intracellular accumulation of AAT in hepatocytes. Moderate AAT deficiency in PI MZ heterozygotes has been associated with slightly increased risk of liver disease and intracellular accumulation of AAT in hepatocytes. We speculate that MZ heterozygosity may result in general liver dysfunction as result of toxic accumulation of AAT in hepatocytes over time, thus predisposing to gallstone disease.
Pleiotropic associations of heterozygosity
for the SERPINA1 Z allele
Katherine A. Fawcett
Z allele heterozygosity was strongly associated with increased height (β=1.02 cm, p=3.91×10−68), and with other non respiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function.
Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV1) (β=19.36 mL, p=9.21×10−4) and FEV1/forced vital capacity (β=0.0031, p=1.22×10−5) in nonsmokers, Whereas in smokers, this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function. We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with non respiratory health-related traits
and disease risk.
Increased Prevalence of Alpha-1-Antitrypsin Deficiency in Patients with Biliary Tract Cancer and Its Associated Clinicopathological Features
Martin Cornillet (Feb 2023)
Alpha-1 antitrypsin deficiency (A1ATD) is underdiagnosed and associated with liver diseases. Here, we genotyped 130 patients with biliary tract cancer (BTC) scheduled for liver resection and found A1ATD in 10.8% of the patients. A1ATD was found in all BTC subtypes, and patients had similar clinical features as non-A1ATD BTC, not permitting their identification using clinical routine liver tests. In intrahepatic cholangiocarcinoma (iCCA), the abundance of A1AT protein was increased in the tumor and appeared to be influenced by the genomic alterations. On the one hand, BTC with A1ATD had lower perineural invasion at histopathology and displayed a longer survival, suggesting that a deficiency in this protein is associated with a less aggressive phenotype. On the other hand, iCCA with high A1AT expression had more advanced tumor staging and enriched pathways for complement system and extracellular matrix interactions, indicating that A1AT protein might contribute to a more aggressive phenotype. With increased awareness, screening, and basic studies, A1ATD could represent one more layer of stratification for future targeted therapies in BTC.
Bile duct adenomas in heterozygous (MZ) deficiency of alpha 1-protease inhibitor
P M Scheele 1988
Abstract
A case of bile duct adenomas in association with heterozygous (MZ) deficiency of alpha 1-proteinase inhibitor (API) is presented. The salient features were the presence of large API-containing globules in the adenomatous tissue and only minimally, in granular form, in hepatocytes. alpha 1-Proteinase inhibitor was not demonstrated in portal bile ducts entrapped in the adenomatous tissue or in bile ducts present in the liver parenchyma. Bile duct markers such as cytokeratin and carcinoembryonic antigens were present in the adenomatous tissue and also in the normal bile ducts, but not in the hepatocytes, suggesting that the adenomatous structures are ductular in origin, and probably not from ductular metaplasia of liver cells. Accumulation of API is postulated to be a triggering factor in neoplastic transformation.