Background Abdominal aortic aneurysm （AAA） is a multifactorial disease with strong genetic components. Various genetic loci have been associated with clinical AAA, but few studies have investigated pathological AAA,...Background Abdominal aortic aneurysm （AAA） is a multifactorial disease with strong genetic components. Various genetic loci have been associated with clinical AAA, but few studies have investigated pathological AAA, an intermediate phenotype of the disease. Methods We examined 2263 consecutive autopsies of older Japanese subjects from a study on geriatric diseases in Japanese individuals （The JG-SNP study）. The presence of AAA was determined with a pathological diagnosis during autopsy. Single nucleotide variants （SNVs） associated with AAA were determined with an Illumina HumanExome Beadchip array. Logistic regression analyses were performed to determine ge- netic associations. Age, gender, and other risk factors of AAA were analyzed as covariates. Results 118 subjects with AAA and 2145 sub- jects without AAA were analyzed in a case-control setting. No variants reached significance after applying the Bonferroni correction （P 〈 2.05×10^-6）. The strongest associations were found with rs3750092 （p.E321G, OR： 0.36, 95% CI： 0.24-0.56, P = 6.09 ×10^-6）, a variant in the WAS/WASL interacting protein family 3 （WIPF3）, and with rs1051338 （p.T16P, OR： 2.50, 95% CI： 1.70-3.66, P = 2.79 ×10^-6） and rs2246942 （intronic, OR： 2.32, 95% CI： 1.58-3.41, P = 1.61 ×10^-5）, variants in the lysosomal acid lipase A （LIPA）. LIPA is essential for macrophage cholesterol metabolism. Immunohistological analyses of WIPF3 protein in AAA samples from three subjects revealed that WIPF3 was expressed in macrophages ofatheromatous plaques. Conclusions This study suggests that WIPF3 and LIPA, both of which are expressed in the macrophages are involved in pathological AAA. These results should be regarded as hypothesis-generating; thus, replication study is warranted.展开更多
BACKGROUND Cholesteryl ester storage disease(CESD)is a rare genetic disease.Its symptoms and severity are highly variable.CESD is a systemic disease that can lead to the accumulation of fat and inflammation in the liv...BACKGROUND Cholesteryl ester storage disease(CESD)is a rare genetic disease.Its symptoms and severity are highly variable.CESD is a systemic disease that can lead to the accumulation of fat and inflammation in the liver,as well as gastrointestinal and cardiovascular disease.The majority of patients require liver transplantation due to decompensated cirrhosis.Enzyme replacement therapy has been approved based on a randomized trial.Our study aims to clinically and genetically evaluate two siblings with CESD who underwent liver transplantation,as well as their first-degree family members.CASE SUMMARY The siblings were compound heterozygous for the missense variant in LIPA exon 8,c.894G>A,(p.Gln298Gln)and a single base pair deletion,c.482del(p.Asn161Ilefs*19).Analyses of single nucleotide polymorphisms showed variants with an increased risk of fatty liver disease and fibrosis for both patients.Clinically,both patients show signs of recurrence of CESD in the liver after transplantation and additional gastrointestinal and cardiovascular signs of CESD.Three family members who were LIPA heterozygous had a lysosomal acid lipase activity below the reference value.One of these carriers,a seven-year-old boy,was found to have severe dyslipidemia and was subsequently treated with statins.CONCLUSION Our study underlines that CESD is a multi-organ disease,the progression of which may occur post-liver transplantation.Our findings underline the need for monitoring of complications and assessment of possible further treatment.展开更多
Non-alcoholic fatty liver disease(NAFLD),characterized by the accumulation of excessive intrahepatic fat,is a leading metabolic disorder also considered as the hepatic manifestation of metabolic syndrome(MS).Though mo...Non-alcoholic fatty liver disease(NAFLD),characterized by the accumulation of excessive intrahepatic fat,is a leading metabolic disorder also considered as the hepatic manifestation of metabolic syndrome(MS).Though more commonly observed in obese individuals and those with metabolic risk factors,it also develops in a considerable number of non-obese individuals as well as participants without having any component of MS.The basic mechanism involved in the development of fatty liver is the imbalance between lipid uptake,synthesis,and metabolism in the liver,normally controlled by several mechanisms to maintain lipid homeostasis.As a complex progressive liver disorder,the NAFLD pathogenesis is multifactorial,and several new pathogenic phenomena were discovered over time.The available literature suggests the role of both genetic and environmental factors and associated metabolic factors;however,the mechanism of progression is not completely understood.In this review,we discuss different pathogenic mechanisms and their interplay to provide an elaborate idea regarding NAFLD development and progression.Better understanding of pathogenic mechanisms will be useful in finding new treatment for patients with NAFLD.展开更多
文摘Background Abdominal aortic aneurysm （AAA） is a multifactorial disease with strong genetic components. Various genetic loci have been associated with clinical AAA, but few studies have investigated pathological AAA, an intermediate phenotype of the disease. Methods We examined 2263 consecutive autopsies of older Japanese subjects from a study on geriatric diseases in Japanese individuals （The JG-SNP study）. The presence of AAA was determined with a pathological diagnosis during autopsy. Single nucleotide variants （SNVs） associated with AAA were determined with an Illumina HumanExome Beadchip array. Logistic regression analyses were performed to determine ge- netic associations. Age, gender, and other risk factors of AAA were analyzed as covariates. Results 118 subjects with AAA and 2145 sub- jects without AAA were analyzed in a case-control setting. No variants reached significance after applying the Bonferroni correction （P 〈 2.05×10^-6）. The strongest associations were found with rs3750092 （p.E321G, OR： 0.36, 95% CI： 0.24-0.56, P = 6.09 ×10^-6）, a variant in the WAS/WASL interacting protein family 3 （WIPF3）, and with rs1051338 （p.T16P, OR： 2.50, 95% CI： 1.70-3.66, P = 2.79 ×10^-6） and rs2246942 （intronic, OR： 2.32, 95% CI： 1.58-3.41, P = 1.61 ×10^-5）, variants in the lysosomal acid lipase A （LIPA）. LIPA is essential for macrophage cholesterol metabolism. Immunohistological analyses of WIPF3 protein in AAA samples from three subjects revealed that WIPF3 was expressed in macrophages ofatheromatous plaques. Conclusions This study suggests that WIPF3 and LIPA, both of which are expressed in the macrophages are involved in pathological AAA. These results should be regarded as hypothesis-generating; thus, replication study is warranted.
文摘BACKGROUND Cholesteryl ester storage disease(CESD)is a rare genetic disease.Its symptoms and severity are highly variable.CESD is a systemic disease that can lead to the accumulation of fat and inflammation in the liver,as well as gastrointestinal and cardiovascular disease.The majority of patients require liver transplantation due to decompensated cirrhosis.Enzyme replacement therapy has been approved based on a randomized trial.Our study aims to clinically and genetically evaluate two siblings with CESD who underwent liver transplantation,as well as their first-degree family members.CASE SUMMARY The siblings were compound heterozygous for the missense variant in LIPA exon 8,c.894G>A,(p.Gln298Gln)and a single base pair deletion,c.482del(p.Asn161Ilefs*19).Analyses of single nucleotide polymorphisms showed variants with an increased risk of fatty liver disease and fibrosis for both patients.Clinically,both patients show signs of recurrence of CESD in the liver after transplantation and additional gastrointestinal and cardiovascular signs of CESD.Three family members who were LIPA heterozygous had a lysosomal acid lipase activity below the reference value.One of these carriers,a seven-year-old boy,was found to have severe dyslipidemia and was subsequently treated with statins.CONCLUSION Our study underlines that CESD is a multi-organ disease,the progression of which may occur post-liver transplantation.Our findings underline the need for monitoring of complications and assessment of possible further treatment.
文摘Non-alcoholic fatty liver disease(NAFLD),characterized by the accumulation of excessive intrahepatic fat,is a leading metabolic disorder also considered as the hepatic manifestation of metabolic syndrome(MS).Though more commonly observed in obese individuals and those with metabolic risk factors,it also develops in a considerable number of non-obese individuals as well as participants without having any component of MS.The basic mechanism involved in the development of fatty liver is the imbalance between lipid uptake,synthesis,and metabolism in the liver,normally controlled by several mechanisms to maintain lipid homeostasis.As a complex progressive liver disorder,the NAFLD pathogenesis is multifactorial,and several new pathogenic phenomena were discovered over time.The available literature suggests the role of both genetic and environmental factors and associated metabolic factors;however,the mechanism of progression is not completely understood.In this review,we discuss different pathogenic mechanisms and their interplay to provide an elaborate idea regarding NAFLD development and progression.Better understanding of pathogenic mechanisms will be useful in finding new treatment for patients with NAFLD.
