Schizophrenia (SZ) is a severe brain disorder afflicting approximately 1% of the world's population and often leads to a lifetime of disability and emotional distress . Family, twin, and adoption studies strongly indicate that genetics contribute to the etiology of SZ, probably by transmission of multiple susceptibility genes each exerting weak-to-moderate effects on predisposition [2, 3]. Many candidate susceptibility genes have been identified, including the dopamine receptor D2, neuregulin1, and disrupted in schizophrenia 1 (DISC-1) [4–6].
Epidemiological studies have also revealed that people with SZ are at greater risk for obesity, type 2 diabetes, dyslipidemia, and hypertension than the general population . Recently, it was suggested that SZ patients are at increased risk of metabolic problems and that the associated symptoms are a serious threat to patient health . Metabolic problems are often triggered by antipsychotic medication. Indeed, significant weight gain is common in AAP-treated SZ patients, especially patients administered clozapine, olanzapine, quetiapine, or risperidone .
The peptide ghrelin (product of the GHRL gene) is an important metabolic regulator produced by the stomach and pancreas. Specific SNPs of GHRL have been associated with variations in BMI, blood pressure, high-density lipoproteins, low-density lipoproteins, serum cholesterol, blood glucose, and metabolic syndrome [10–14]. Ghrelin, originally isolated from the rat stomach, stimulates food intake and controls energy balance [15, 16]. Studies on animal models revealed that GHRL increased food intake and adiposity [17, 18]. However, circulating GHRL levels were decreased in obese individuals, and serum GHRL levels were inversely correlated with BMI, suggesting that GHRL is not directly involved in most cases of obesity [19, 20]. Studies on the relationship between WG, circulating GHRL, and AAP have yielded inconsistent findings. Patients taking clozapine or olanzapine showed greater WG than patients on other antipsychotics . In one study, plasma total GHRL and active GHRL were increased significantly immediately after olanzapine treatment, but the changes in BMI and body weight were not significant after 6 months of treatment . In contrast, another study found that serum bioactive GHRL levels decreased significantly from baseline after 4 weeks of olanzapine monotherapy . In humans, GHRL plays an important role in the long-term regulation of body weight (BW) as well as in the short-term regulation of appetite [19, 21]. Ghrelin stimulated preadipocyte differentiation, increased the BMI, and inhibited the anorexigenic effect of leptin . Drug altering GHRL function may have distinct short- and long-term effects on BMI.
The human GHRL gene is located on chromosome 3 (3p25-p26), and consists of 4 exons and 3 introns [25, 26]. Several SNPs in the coding region of prepro-ghrelin have been described, but there is no known specific association between genetic variations in the human GHRL gene and SZ risk. However, region 3p25.1-26.1 is strongly associated with schizophrenia. In addition to GHRL, this region contains SYN2, HRH1, and GRM7, all candidate genes for schizophrenia. The positive symptoms of schizophrenia are associated with dysfunction in dopaminergic signaling, which is closely associated with a GHRL mutation [27–29]. Previous studies demonstrated that SNPs in GHRL were associated with high BMI; the Leu72Met allele was significantly associated with BMI and coronary artery disease [18, 19, 30], but this was not confirmed in other studies [26, 31, 32].
In light of the increase metabolic syndrome symptoms observed in SZ patients on AAPs, as well as the important role of GHRL as a metabolic regulator and the association between GHRL SNPs and metabolic indices, we hypothesized that (1) GHRL might be a candidate gene for SZ and that (2) allelic variants of GHRL might be associated with the propensity for BMI changes induced by AAP treatment. In addition, we tested (3) whether a putative relationship between GHRL SNPs and metabolic effects was specific to individual AAP types. Finally, (4) we examined if GHRL alleles influenced the clinical efficacy of AAPs. To these ends, we genotyped four SNPs and investigated whether they were associated with SZ and the therapeutic and metabolic effects of AAPs in the Han Chinese population.