Atypical antipsychotics have become a common therapeutic option in both schizophrenia and bipolar disorder. However, these medications come with a high risk of metabolic side effects, particularly dyslipidemia and insulin resistance. Therefore, identification of patients who are at increased risk for metabolic side effects is of great importance. The genetics of fatty acid metabolism is one area of research that may help identify such patients. Therefore, in this present study, we aimed to determine the effect of one commonly studied genetic polymorphism from both fatty acid desaturase 1 (FADS1) and FADS2 gene on a surrogate measure of insulin resistance and lipid levels in a metabolically high-risk population of patients largely exposed to atypical antipsychotics. This study used a cross-sectional design, fasting blood draws, and genetic analysis to investigate associations between polymorphisms, haplotypes, and metabolic measures. A total of 320 subjects with schizophrenia ( ) or bipolar disorder ( ) were included in this study. The mean age of the population was 42.5 years and 45% were male. A significant association between FADS1 and FADS2 haplotypes was found with insulin resistance while controlling for confounders. Further investigation is required to replicate this finding. 1. Background The use of antipsychotics, particularly the atypical antipsychotics (AAPs), is considered the standard of care in schizophrenia symptom management and is becoming a common therapeutic choice in the management of bipolar disorder [1–3]. The fact that AAPs are commonly used in both of these populations may be due to the overlapping symptomatology that is seen as well as the genetic overlap that has been identified in several disease linkage studies [4–7]. Although many studies support the use of AAPs in the severely mentally ill, these medications come with a high risk of metabolic side effects. This risk requires careful monitoring and management as the cardiometabolic side effects have been shown to increase the cost of care, decrease adherence, and, most severely, have negative consequences on length and quality of life [8–11]. Therefore, investigation into lifestyle, diet, and genetic factors that may increase or attenuate the risk of metabolic side effects in patients taking AAPs is important and of high interest. One current line of research within the area of AAP metabolic side effects concentrates on fatty acid metabolism and its influence on metabolic measures. Fatty acids (FAs) serve many important physiological functions including energy reserves,
References
[1]
S. M. Stahl, D. A. Morrissette, L. Citrome, et al., “‘Meta-guidelines’ for the management of patients with schizophrenia,” CNS Spectrums, vol. 18, no. 3, pp. 150–162, 2013.
[2]
J. R. Geddes and D. J. Miklowitz, “Treatment of bipolar disorder,” The Lancet, vol. 381, no. 9878, pp. 1672–1682, 2013.
[3]
K. R. Connolly and M. E. Thase, “The clinical management of bipolar disorder: a review of evidence-based guidelines,” Primary Care Companion to the Journal of Clinical Psychiatry, vol. 13, no. 4, 2011.
[4]
S. H. Lee, S. Ripke, B. M. Neale, et al., “Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs,” Nature Genetics, vol. 45, no. 9, pp. 984–994, 2013.
[5]
J. W. Smoller, N. Craddock, K. Kendler, et al., “Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis,” The Lancet, vol. 381, no. 9875, pp. 1371–1379, 2013.
[6]
E. K. Green, D. Grozeva, I. Jones et al., “The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia,” Molecular Psychiatry, vol. 15, no. 10, pp. 1016–1022, 2010.
[7]
O. L. J. Peerbooms, J. van Os, M. Drukker et al., “Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability?” Brain, Behavior, and Immunity, vol. 25, no. 8, pp. 1530–1543, 2011.
[8]
C. W. Colton and R. W. Manderscheid, “Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states,” Preventing Chronic Disease, vol. 3, no. 2, article A42, 2006.
[9]
A. Fagiolini, K. N. R. Chengappa, I. Soreca, and J. Chang, “Bipolar disorder and the metabolic syndrome: causal factors, psychiatric outcomes and economic burden,” CNS Drugs, vol. 22, no. 8, pp. 655–669, 2008.
[10]
T. M. Laursen, T. Munk-Olsen, and M. Vestergaard, “Life expectancy and cardiovascular mortality in persons with schizophrenia,” Current Opinion in Psychiatry, vol. 25, no. 2, pp. 83–88, 2012.
[11]
A. Ward, P. Quon, S. Abouzaid, N. Haber, S. Ahmed, and E. Kim, “Cardiometabolic consequences of therapy for chronic schizophrenia using second-generation antipsychotic agents in a medicaid population: clinical and economic evaluation,” P and T, vol. 38, no. 2, pp. 109–115, 2013.
[12]
G. Boden and G. I. Shulman, “Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and β-cell dysfunction,” European Journal of Clinical Investigation, vol. 32, supplement 3, pp. 14–23, 2002.
[13]
G. Boden, “Effects of free fatty acids (FFA) on glucose metabolism: significance for insulin resistance and type 2 diabetes,” Experimental and Clinical Endocrinology and Diabetes, vol. 111, no. 3, pp. 121–124, 2003.
[14]
G. Boden, “Obesity, insulin resistance and free fatty acids,” Current Opinion in Endocrinology, Diabetes and Obesity, vol. 18, no. 2, pp. 139–143, 2011.
[15]
D. M. Merino and D. W. Ma, “Genetic variation in lipid desaturases and its impact on the development of human disease,” Lipids in Health and Disease, vol. 9, article 63, 2010.
[16]
C. Glaser, E. Lattka, P. Rzehak, C. Steer, and B. Koletzko, “Genetic variation in polyunsaturated fatty acid metabolism and its potential relevance for human development and health,” Maternal and Child Nutrition, vol. 7, supplement 2, pp. 27–40, 2011.
[17]
E. Lattka, T. Illig, J. Heinrich, and B. Koletzko, “Do FADS genotypes enhance our knowledge about fatty acid related phenotypes?” Clinical Nutrition, vol. 29, no. 3, pp. 277–287, 2010.
[18]
R. K. McNamara, R. Jandacek, T. Rider et al., “Abnormalities in the fatty acid composition of the postmortem orbitofrontal cortex of schizophrenic patients: gender differences and partial normalization with antipsychotic medications,” Schizophrenia Research, vol. 91, no. 1–3, pp. 37–50, 2007.
[19]
A. O. Vik-Mo, A. B. Birkenaes, J. Fern？, H. Jonsdottir, O. A. Andreassen, and V. M. Steen, “Increased expression of lipid biosynthesis genes in peripheral blood cells of olanzapine-treated patients,” International Journal of Neuropsychopharmacology, vol. 11, no. 5, pp. 679–684, 2008.
[20]
Y. Liu, R. Jandacek, T. Rider, P. Tso, and R. K. McNamara, “Elevated delta-6 desaturase (FADS2) expression in the postmortem prefrontal cortex of schizophrenic patients: relationship with fatty acid composition,” Schizophrenia Research, vol. 109, no. 1–3, pp. 113–120, 2009.
[21]
R. K. McNamara, R. Jandacek, T. Rider, P. Tso, A. Cole-Strauss, and J. W. Lipton, “Differential effects of antipsychotic medications on polyunsaturated fatty acid biosynthesis in rats: relationship with liver delta6-desaturase expression,” Schizophrenia Research, vol. 129, no. 1, pp. 57–65, 2011.
[22]
R. K. McNamara, R. Jandacek, T. Rider, P. Tso, A. Cole-Strauss, and J. W. Lipton, “Atypical antipsychotic medications increase postprandial triglyceride and glucose levels in male rats: relationship with stearoyl-CoA desaturase activity,” Schizophrenia Research, vol. 129, no. 1, pp. 66–73, 2011.
[23]
Y. Liu and R. K. McNamara, “Elevated Delta-6 desaturase (FADS2) gene expression in the prefrontal cortex of patients with bipolar disorder,” Journal of Psychiatric Research, vol. 45, no. 2, pp. 269–272, 2011.
[24]
D. R. Matthews, J. P. Hosker, and A. S. Rudenski, “Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man,” Diabetologia, vol. 28, no. 7, pp. 412–419, 1985.
[25]
R. Muniyappa, S. Lee, H. Chen, and M. J. Quon, “Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage,” The American Journal of Physiology, vol. 294, no. 1, pp. E15–E26, 2008.
[26]
S. M. R？ssner, M. Neovius, A. Mattsson, C. Marcus, and S. Norgren, “HOMA-IR and QUICKI: decide on a general standard instead of making further comparisons,” Acta Paediatrica, International Journal of Paediatrics, vol. 99, no. 11, pp. 1735–1740, 2010.
[27]
J. F. Ascaso, S. Pardo, J. T. Real, R. I. Lorente, A. Priego, and R. Carmena, “Diagnosing insulin resistance by simple quantitative methods in subjects with normal glucose metabolism,” Diabetes Care, vol. 26, no. 12, pp. 3320–3325, 2003.
[28]
A. Borai, C. Livingstone, I. Kaddam, and G. Ferns, “Selection of the appropriate method for the assessment of insulin resistance,” BMC Medical Research Methodology, vol. 11, article 158, 2011.
[29]
C. Sabatti, S. K. Service, A.-L. Hartikainen et al., “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population,” Nature Genetics, vol. 41, no. 1, pp. 35–46, 2009.
[30]
T. Tanaka, J. Shen, G. R. Abecasis et al., “Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI study,” PLoS Genetics, vol. 5, no. 1, Article ID e1000338, 2009.
[31]
Y. S. Aulchenko, S. Ripatti, I. Lindqvist, et al., “Loci influencing lipid levels and coronary heart disease risk in 16 european population cohorts,” Nature Genetics, vol. 41, no. 1, pp. 47–55, 2009.
[32]
L. Schaeffer, H. Gohlke, M. Müller et al., “Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids,” Human Molecular Genetics, vol. 15, no. 11, pp. 1745–1756, 2006.
[33]
G. Malerba, L. Schaeffer, L. Xumerle et al., “SNPs of the FADS gene cluster are associated with polyunsaturated fatty acids in a cohort of patients with cardiovascular disease,” Lipids, vol. 43, no. 4, pp. 289–299, 2008.
[34]
S. Kathiresan, C. J. Willer, G. M. Peloso, et al., “Common variants at 30 loci contribute to polygenic dyslipidemia,” Nature Genetics, vol. 41, no. 1, pp. 56–65, 2009.
[35]
S. Marsh, C. R. King, A. A. Garsa, and H. L. McLeod, “Pyrosequencing of clinically relevant polymorphisms,” Methods in Molecular Biology, vol. 311, pp. 97–114, 2005.
[36]
J. C. Barrett, B. Fry, J. Maller, and M. J. Daly, “Haploview: analysis and visualization of LD and haplotype maps,” Bioinformatics, vol. 21, no. 2, pp. 263–265, 2005.
[37]
M. Stephens, N. J. Smith, and P. Donnelly, “A new statistical method for haplotype reconstruction from population data,” The American Journal of Human Genetics, vol. 68, no. 4, pp. 978–989, 2001.
[38]
M. Stephens and P. Donnelly, “A comparison of bayesian methods for haplotype reconstruction from population genotype data,” The American Journal of Human Genetics, vol. 73, no. 5, pp. 1162–1169, 2003.
[39]
J. Dupuis, C. Langenberg, I. Prokopenko, et al., “New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk,” Nature Genetics, vol. 42, no. 2, pp. 105–116, 2010.
[40]
E. Ingelsson, C. Langenberg, M.-F. Hivert et al., “Detailed physiologic characterization reveals diverse mechanisms for novel genetic loci regulating glucose and insulin metabolism in humans,” Diabetes, vol. 59, no. 5, pp. 1266–1275, 2010.
[41]
O. Y. Kim, H. H. Lim, L. I. Yang, J. S. Chae, and J. H. Lee, “Fatty acid desaturase (FADS) gene polymorphisms and insulin resistance in association with serum phospholipid polyunsaturated fatty acid composition in healthy Korean men: cross-sectional study,” Nutrition and Metabolism, vol. 8, article 24, 2011.
[42]
S. Bokor, J. Dumont, A. Spinneker et al., “Single nucleotide polymorphisms in the FADS gene cluster are associated with delta-5 and delta-6 desaturase activities estimated by serum fatty acid ratios,” Journal of Lipid Research, vol. 51, no. 8, pp. 2325–2333, 2010.
[43]
H. E. Bays, P. P. Toth, P. M. Kris-Etherton, et al., “Obesity, adiposity, and dyslipidemia: a consensus statement from the national lipid association,” Journal of Clinical Lipidology, vol. 7, no. 4, pp. 304–383, 2013.
