@article {131, title = {A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.}, journal = {PLoS Genet}, volume = {16}, year = {2020}, month = {2020 04}, pages = {e1008629}, abstract = {

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.

}, keywords = {Alleles, Cholesterol, LDL, Coronary Artery Disease, Datasets as Topic, Fatty Liver, Female, Genetic Predisposition to Disease, Homozygote, Humans, Liver, Liver Cirrhosis, Liver Cirrhosis, Alcoholic, Loss of Function Mutation, Male, Middle Aged, Mitochondrial Proteins, Mutation, Missense, Oxidoreductases}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1008629}, author = {Emdin, Connor A and Haas, Mary E and Khera, Amit V and Aragam, Krishna and Chaffin, Mark and Klarin, Derek and Hindy, George and Jiang, Lan and Wei, Wei-Qi and Feng, Qiping and Karjalainen, Juha and Havulinna, Aki and Kiiskinen, Tuomo and Bick, Alexander and Ardissino, Diego and Wilson, James G and Schunkert, Heribert and McPherson, Ruth and Watkins, Hugh and Elosua, Roberto and Bown, Matthew J and Samani, Nilesh J and Baber, Usman and Erdmann, Jeanette and Gupta, Namrata and Danesh, John and Saleheen, Danish and Chang, Kyong-Mi and Vujkovic, Marijana and Voight, Ben and Damrauer, Scott and Lynch, Julie and Kaplan, David and Serper, Marina and Tsao, Philip and Mercader, Josep and Hanis, Craig and Daly, Mark and Denny, Joshua and Gabriel, Stacey and Kathiresan, Sekar} } @article {38, title = {Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Apr 24}, pages = {1613}, abstract = {

Less than 3\% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5\%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

}, keywords = {Databases, Genetic, Diabetes Mellitus, Type 2, Disease, Gene Frequency, Genetic Testing, Genetic Variation, Humans, Obesity, Phenotype, Proteins, Respiratory Hypersensitivity, United Kingdom}, issn = {2041-1723}, doi = {10.1038/s41467-018-03911-8}, author = {Emdin, Connor A and Khera, Amit V and Chaffin, Mark and Klarin, Derek and Natarajan, Pradeep and Aragam, Krishna and Haas, Mary and Bick, Alexander and Zekavat, Seyedeh M and Nomura, Akihiro and Ardissino, Diego and Wilson, James G and Schunkert, Heribert and McPherson, Ruth and Watkins, Hugh and Elosua, Roberto and Bown, Matthew J and Samani, Nilesh J and Baber, Usman and Erdmann, Jeanette and Gupta, Namrata and Danesh, John and Chasman, Daniel and Ridker, Paul and Denny, Joshua and Bastarache, Lisa and Lichtman, Judith H and D{\textquoteright}Onofrio, Gail and Mattera, Jennifer and Spertus, John A and Sheu, Wayne H-H and Taylor, Kent D and Psaty, Bruce M and Rich, Stephen S and Post, Wendy and Rotter, Jerome I and Chen, Yii-Der Ida and Krumholz, Harlan and Saleheen, Danish and Gabriel, Stacey and Kathiresan, Sekar} } @article {12, title = {ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.}, journal = {J Am Coll Cardiol}, volume = {69}, year = {2017}, month = {2017 Apr 25}, pages = {2054-2063}, abstract = {

BACKGROUND: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3~major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.

OBJECTIVES: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.

METHODS: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3~wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were~defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in~<25\% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.

RESULTS: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17\% reduction in circulating triglycerides and a 12\% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34\% reduction in odds of CAD (odds ratio: 0.66; 95\% confidence interval: 0.44 to 0.98; p~= 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95\% confidence interval: 0.55 to 0.77; p~< 0.001).

CONCLUSIONS: ANGPTL3 deficiency is associated with protection from CAD.

}, keywords = {Adult, Angiopoietin-Like Protein 3, Angiopoietin-like Proteins, Angiopoietins, Animals, Atherosclerosis, Case-Control Studies, Coronary Artery Disease, Female, Humans, Lipids, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Mutation, Missense, Myocardial Infarction, Risk Factors}, issn = {1558-3597}, doi = {10.1016/j.jacc.2017.02.030}, author = {Stitziel, Nathan O and Khera, Amit V and Wang, Xiao and Bierhals, Andrew J and Vourakis, A Christina and Sperry, Alexandra E and Natarajan, Pradeep and Klarin, Derek and Emdin, Connor A and Zekavat, Seyedeh M and Nomura, Akihiro and Erdmann, Jeanette and Schunkert, Heribert and Samani, Nilesh J and Kraus, William E and Shah, Svati H and Yu, Bing and Boerwinkle, Eric and Rader, Daniel J and Gupta, Namrata and Frossard, Philippe M and Rasheed, Asif and Danesh, John and Lander, Eric S and Gabriel, Stacey and Saleheen, Danish and Musunuru, Kiran and Kathiresan, Sekar} }