Context Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation. Objective Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease. Design Genetics of Obesity-associated Liver Disease Consortium Setting Population-based Main Outcome: Computed tomography measured liver attenuation. Results Carriers of rs4841132-A (frequency 2-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105bp deletion including rs4841132-A in human hepatocarcinoma cells which increases PPP1R3B, decreases LOC157273 and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on EHR data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides and decreased acetoacetate and beta-hydroxybutyrate. Conclusions These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.

Background: Recent studies have suggested increased rates of lower extremity (LE) musculoskeletal injury after a diagnosed concussion, although significant heterogeneity exists. Purpose: To examine the current body of research and determine whether there is an increased risk for LE musculoskeletal injury after a concussion and to identify populations at an increased risk. Study Design: Systematic review; Level of evidence, 3. Methods: A systematic review of current literature using MEDLINE and PubMed databases was performed. Keywords included concussion, athlete, lower extremity injury, and return to sport. Inclusion criteria required original research articles written in the English language examining the rate of LE injuries after a diagnosed concussion. Results: A total of 13 studies involving 4349 athletes (88.1% male and 11.9% female; mean age, 19.8 years) met inclusion criteria. Athletes were classified as high school (46.1%), collegiate (17.0%), or professional (36.9%). Of the 13 studies, 4 demonstrated an increased risk of LE injury within 90 days of a diagnosed concussion (odds ratio [OR], 3.44; 95% CI, 2.99-4.42), and 6 revealed an elevated risk of injury within 1 year of concussion (OR, 1.85; 95% CI, 1.73-2.84). Increased risk was seen in professional (OR, 2.49; 95% CI, 2.40-2.72) and collegiate (OR, 2.00; 95% CI, 1.96-2.16) athletes compared with high school athletes (OR, 0.97; 95% CI, 0.89-1.05). A stepwise increase in risk of sustaining an LE injury was observed with multiple concussions, with increasing risk observed from ≥2 (OR, 2.29; 95% CI, 1.85-2.83) to ≥3 (OR, 2.86; 95% CI, 2.36-3.48) career concussions. Conclusion: An increased incidence of LE injuries was observed at 90 days and 1 year after the diagnosis of a concussion. Higher levels of competition, such as at the collegiate and professional levels, resulted in an increased risk of sustaining a subsequent LE injury after a diagnosed concussion. These results suggest an at-risk population who may benefit from injury prevention methods after a concussion. Future studies should focus on identifying which injuries are most common, during what time period athletes are most vulnerable, and methods to prevent injury after return to sports.

Human genome-wide association studies found single nucleotide polymorphisms (SNPs) near LYPLAL1 (Lysophospholipase 1) that have sex-specific effects on fat distribution and metabolic traits. To determine whether altering LYPLAL1 affects obesity and metabolic disease we created and characterized a mouse knockout of Lyplal1. We fed the experimental group of mice high fat, high sucrose (HFHS) diet for 23 weeks, and the controls were fed regular chow diet. Here we show that CRISPR-Cas9 whole-body Lyplal1 knockout (KO) mice fed a HFHS diet showed sex-specific differences in weight gain and fat accumulation as compared to chow diet. Female, not male, KO mice weighed less than WT mice, had reduced body fat percentage, white fat mass, and adipocyte diameter not accounted for by changes in metabolic rate. Female, but not male, KO mice had increased serum triglycerides, decreased aspartate, and alanine aminotransferase. Lyplal1 KO mice of both sexes have reduced liver triglycerides and steatosis. These diet-specific effects resemble the effects of SNPs near LYPLAL1 in humans, suggesting that LYPLAL1 has an evolutionary conserved sex-specific effect on adiposity. This murine model can be used to study this novel gene-by-sex-by-diet interaction to elucidate the metabolic effects of LYPLAL1 on human obesity.

Human genome-wide association studies found SNPs near LYPLAL1 that have sex-specific effects on fat distribution and metabolic traits. To determine whether altering LYPLAL1 affects obesity and metabolic disease we created and characterized a mouse knockout of Lyplal1. Here we show that CRISPR-Cas9 whole-body Lyplal1 knockout (KO) mice fed a high fat, high sucrose (HFHS) diet showed sex-specific differences in weight gain and fat accumulation. Female, not male, KO mice weighed less than WT mice, had reduced body fat percentage, white fat mass, and adipocyte diameter not accounted for by changes in metabolic rate. Female, but not male, KO mice had increased serum triglycerides, decreased aspartate, and alanine aminotransferase. Lyplal1 KO mice of both sexes have reduced liver triglycerides and steatosis. These diet-specific effects resemble the effects of SNPs near LYPLAL1 in humans, suggesting that LYPLAL1 has an evolutionary conserved sex-specific effect on adiposity. This murine model can be used to study this novel gene-by-sex-by-diet interaction to elucidate the metabolic effects of LYPLAL1 on human obesity.