Evidence for the role of EP HX2 gene variants in anorexia nervosa

Abstract

Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor-ß (ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (p=0.0004). The association of EPHX2 variants was further delineated in: 1. a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set p=0.00000016); 2. Single locus studies in a cohort of 386 previously genotyped broadly-defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus p<0.01). Since EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS females and males (N = 229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (p<0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN, and provide a foundation for future study of this important yet poorly understood condition.

A genome-wide association study of anorexia nervosa

“…Additionally, one of our prioritized SNPs (rs6558000) (Table S5) is located in close vicinity (9kb upstream) of the EPHX2 gene that was recently identified as a susceptibility locus to AN through candidate gene sequencing study of early-onset severe AN cases and controls. 43 …”

“…42 Recently, a sequencing and genotyping study of 152 candidate genes in 1205 AN cases and 1948 controls suggested a novel association of a cholesterol metabolism influencing EPHX2 gene with susceptibility to AN. 43 …”

Effect of soluble epoxide hydrolase polymorphism on substrate and inhibitor selectivity and dimer formation

“…Several human genetic studies have associated the polymorphs of sEH with a range of diseases (11)(12)(13)(14). Previous work demonstrated there are signifi cant differences in the specifi c activity of the SNPs using surrogate substrates ( 10,15,17 ).…”

“…Lower plasma FA epoxide-to-diol ratios were observed in K55R Caucasians but not African Americans ( 38 ), suggesting that other factors besides sEH catalytic activity play a role in the pathologies associated with this SNP. There is no indication in the literature that the pathologies associated with the other SNPs resulted from altered EpFA metabolism (11)(12)(13)(14). Separately, the observation that in some tissues the concentration of sEH ( Table 3 ) is higher than its natural substrates ( 1,18,19 ) suggests that >90% inhibition of the enzyme is needed to signifi cantly alter EpFA metabolism is some tissues, such as the liver and kidneys.…”

The role of leptin, melanocortin, and neurotrophin system genes on body weight in anorexia nervosa and bulimia nervosa

“…For example, AGRP is the inverse agonist of melanocortins, and data suggest that melanocortin signaling may play a role in the regulation of circulating cholesterol: in rodents, inhibition of melanocortin system in the central nervous system leads to an increase in high-density lipoprotein cholesterol in a manner independent of food intake or body weight (Perez-Tilve et al, 2010). Interestingly, the top hit in the recent Price Foundation AN high-throughput sequencing study was in the EPHX2 gene, known to influence cholesterol function (Scott-Van Zeeland et al, 2013). Considering that patients with AN often present with elevated cholesterol levels (Ohwada et al, 2006; Matzkin et al, 2006; Rigaud et al, 2009; Jauregui-Garrido et al, 2012), this clinical abnormality could be at least partially a sign of a disruption in the melanocortin system.…”