Original / Otros. Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, DF. - PDF

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Nutr Hosp. 2014;30(3): ISSN CODEN NUHOEQ S.V.R. 318 Original / Otros A genetic variant of the CAPN10 gene in Mexican subjects with dyslipidemia is associated with increased HDL-cholesterol

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Nutr Hosp. 2014;30(3): ISSN CODEN NUHOEQ S.V.R. 318 Original / Otros A genetic variant of the CAPN10 gene in Mexican subjects with dyslipidemia is associated with increased HDL-cholesterol concentrations after the consumption of a soy protein and soluble fiber dietary portfolio Martha Guevara-Cruz 1, Nimbe Torres1, Armando R. Tovar1, M Elizabeth Tejero 2, Ashley Castellanos-Jankiewicz 2,3 and Laura del Bosque-Plata 2* 1 Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, DF. b Laboratorio de Nutrigenética y Nutrigenómica, Instituto Nacional de Medicina Genómica, México, DF. c Escuela de Nutrición, Universidad Anáhuac Mayab, Mérida, México. México. Abstract Dyslipidemia is a major public health problem, and therefore, it is important to develop dietary strategies to diminish the prevalence of this disorder. It was recently reported that diet may play an important role in triggering insulin resistance by interacting with genetic variants at the CAPN10 gene locus in patients with metabolic syndrome. Nonetheless, it remains unknown whether genetic variants of genes involved in the development of type 2 diabetes are associated with variations in high-density lipoprotein cholesterol (HDL-C). The study used a single-center, prospective, cohort design. Here, we assessed the effect of four variants of the CAPN10 gene on HDL-C levels in response to a soy protein and soluble fiber dietary portfolio in subjects with dyslipidemia. In 31 Mexican dyslipidemic individuals, we analyzed four CAPN10 gene variants (rs , rs , rs , and rs ) associated with type 2 diabetes. Subjects with the GG genotype of the rs variant of the CAPN10 gene were better responders to dietary intervention, showing increased HDL-C concentrations from the first month of treatment. HDL-C concentrations in participants with the wild type genotype increased by 17.0%, whereas the HDL-C concentration in subjects with the variant genotypes increased by only 3.22% (p = 0.03); the low-density lipoprotein cholesterol levels of GG carriers tended to decrease (-12.6%). These results indicate that Mexican dyslipidemic carriers of the rs gg genotype are better responders to this dietary intervention. (Nutr Hosp. 2014;30: ) DOI: /nh Key words: Calpain-10, polymorphism, dietary portfolio, hypercholesterolemic, dyslipidemia. Correspondence/Correspondencia: Laura del Bosque-Plata. Mailing address: Periferico Sur 4809, Arenal Tepepan, Tlalpan, Ciudad de Mexico, Distrito Federal. addres: Recibido: 20-V Aceptado: 28-VI UNA VARIANTE GENÉTICA DEL GEN CAPN10 EN SUJETOS MEXICANOS CON DISLIPIDEMIA SE ASOCIA CON UN AUMENTO DE LAS CONCENTRACIONES DE COLESTEROL HDL DESPUÉS DEL CONSUMO DE UN PORTAFOLIO DIETARIO DE DE SOYA Y FIBRA SOLUBLE Resumen Dyslipidemia is a major public health problem, and therefore, it is important to develop dietary strategies to diminish the prevalence of this disorder. It was recently reported that diet may play an important role in triggering insulin resistance by interacting with genetic variants at the CAPN10 gene locus in patients with metabolic syndrome. Nonetheless, it remains unknown whether genetic variants of genes involved in the development of type 2 diabetes are associated with variations in high-density lipoprotein cholesterol (HDL-C). The study used a single-center, prospective, cohort design. Here, we assessed the effect of four variants of the CAPN10 gene on HDL-C levels in response to a soy protein and soluble fiber dietary portfolio in subjects with dyslipidemia. In 31 Mexican dyslipidemic individuals, we analyzed four CAPN10 gene variants (rs , rs , rs , and rs ) associated with type 2 diabetes. Subjects with the GG genotype of the rs variant of the CAPN10 gene were better responders to dietary intervention, showing increased HDL-C concentrations from the first month of treatment. HDL-C concentrations in participants with the wild type genotype increased by 17.0%, whereas the HDL-C concentration in subjects with the variant genotypes increased by only 3.22% (p = 0.03); the low-density lipoprotein cholesterol levels of GG carriers tended to decrease (-12.6%). These results indicate that Mexican dyslipidemic carriers of the rs gg genotype are better responders to this dietary intervention. (Nutr Hosp. 2014;30: ) DOI: /nh Palabras clave: Calpain-10, polymorphism, dietary portfolio, hypercholesterolemic, dyslipidemia. 671 Introduction Dyslipidemia in Mexican adults is most commonly associated with low plasma levels of high-density lipoprotein cholesterol (HDL-C), which is often related to the development of diseases classified as metabolic syndrome (MetS) 1. The levels of plasma lipids are controlled by multiple pathways and influenced by complex interactions between many different genes and environmental factors such as diet composition 2. A low saturated fat diet (LSF) in combination with soy protein and soluble fiber can improve the lipid profile of Mexican subjects with hyperlipidemia 3 independent of genetic variants involved in lipid metabolism. Low-density lipoprotein cholesterol (LDL-C) is reported to be positively associated with the risk of myocardial infarction, whereas HDL-C has an inverse association 4. LDL-C and HDL-C are among the most commonly measured biomarkers of cardiovascular disease risk in clinical medicine 5, and lower levels of HDL-C have been consistently associated with an increased risk of coronary heart disease (CHD) 6. Recent studies have shown that LSF, in combination with soy protein and soluble fiber, can increase HDL-C levels in the Mexican population with the ABCA1 (ATP-binding cassette cholesterol transporter A1) R230C variant 7, which appears to be exclusive to Native Americans 8. Approximately 74% of the Mexican population with MetS has low a HDL-C concentration and a higher predisposition to develop type 2 diabetes mellitus 9. Nonetheless, it is not known whether genetic variants of genes involved in the development of diabetes are associated with low HDL-C. The Calpain-10 (CAPN10) gene is located on chromosome 2q37 and encodes for a cytoplasmic cysteine protease that requires calcium ions for its activity. In mice, CAPN10 plays an important role in regulating obesity and type 2 diabetes 10. This gene has attracted considerable attention because of the association between calpain genetic variation and type 2 diabetes in humans CAPN10 has been associated with various risk factors of MetS, such as elevated body mass index (BMI) 14, plasma cholesterol concentration 15, hypertension 16, 17 and hypertriglyceridemia 18, and plays an important role in insulin resistance 19. It has been suggested that CAPN10 facilitates the translocation of insulin-regulated glucose transporter type 4 (GLUT4) by the reorganization of the cytoskeleton 20. Variations in the CAPN10 gene are associated with elevated triglyceride levels and reduced expression of CAPN10 in the adipose tissue of obese subjects 18. Variations in CAPN10 confer a risk for type 2 diabetes in several populations, including those of Mexican origin 14-17, However, it is not known whether subjects with variants of the CAPN10 gene would respond to dietary treatments to improve HDL-C levels. Thus, the aim of this study was to analyze the effects of variations in CAPN10 on HDL-C levels in Mexican adults in response to a dyslipidemia dietary treatment based on a soy protein and soluble fiber dietary portfolio. Materials and Methods Study design The studied population was selected from a previous study 3. The study used a single-center, prospective, cohort design. Medical examination was performed each month on all subjects. One nutritionist was assigned for the follow-up of every 10 patients. Body weight and height were measured according to standardize methods to calculate the total energy intake for each patient. Patients were given an LSF diet in accordance with the National Cholesterol Education Program Adult Treatment Panel III (ATPIII) for four weeks (Period 1) 5. For the next two months, patients were instructed to consume an LSF and dietary portfolio consisting of 25 g of soy protein and 15 g of soluble fiber (LSF-SSF diet) (Period 2). Body weight was monitored during the study, and blood samples were collected after a 12-h overnight fasting period once every month for three months. Nutritionists maintained contact with the subjects twice per week and assessed their dietary consumption using the 24-h recall method and a standard scale. Study population Thirty-one hyperlipidemic participants (15 males and 16 females) who completed the three-month dietary protocol were included in the study. The participants had no history of cardiovascular, renal, or liver disease, no history of type 2 diabetes or hypertension, had no smoking or alcohol consumption history, and were not taking hypolipidemic agents. Subjects were asked to maintain their habitual level of physical activity throughout the study. All subjects were fully informed of the protocol, and written informed consent was obtained. This study was approved by the Committee of Studies in Humans at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Biochemical assays A 5-ml blood sample was obtained after a 12-h fasting period each month. Blood was centrifuged at 400 x g, and serum was separated and kept at 20 C until analysis. Serum was analyzed for total cholesterol (TC), triglyceride (TG), and HDL-C. TC and TG were determined using an enzymatic assay (SERA-PAK Plus, Bayer de México, Mexico City). Serum HDL-C was determined using an immunoassay method 24 (DiaSys Diagnostics Systems GmbH, Holzheim, Germany), and LDL-C was calculated using the method 672 Nutr Hosp. 2014;30(3): Martha Guevara-Cruz et al. of Friedewald et al. 25. [LDL- C = TC (TG / HDL-C)]. Genotyping During the initial visit, an additional 5-ml blood sample was drawn, and DNA was extracted from leukocytes as described by Miller et al. 26. The four single-nucleotide polymorphisms (SNPs) of the gene CAPN10 previously associated with type 2 diabetes (rs , rs , rs , and rs ) were determined using polymerase chain reaction (PCR)-based TaqMan allele discrimination assays (ABI Prism 7900HT Sequence Detection System; Applied Biosystems, Foster City, CA) 27. The rs , rs , and rs genotypes were distributed according to Hardy-Weinberg equilibrium (http://ihg2.helmholtz-muenchen.de/cgi-bin/hw/ hwa1.pl), whereas the rs genotype was not. Statistical analyses Descriptive statistical analyses were conducted for all analyzed variables. Continuous variables were expressed as the means ± SEM. Dichotomous variables were expressed as frequencies and percentages. Variable distribution was assessed using the Kolmogorov-Smirnov Z test; variables with a non-normal distribution were log-transformed prior to analysis. Differences between the basal and final parameters were evaluated using one-way analysis of variance (ANOVA), and differences between genotypes and the percentage change after treatment were tested using an independent sample Student s T-test. Allele frequencies were analyzed using a χ² goodness-of-fit test to determine whether the observed values differed from Hardy Weinberg equilibrium. Differences with p 0.05 were considered significant for biochemical parameters. Data were analyzed using SPSS for Windows (version 10.00; SPSS Inc., Chicago, IL). The effect-size correlation was determined using the Cohen s d calculation; values 0.67 were considered large effects. Results At recruitment, participants had a mean (±SEM) age of 41.8 (1.46) years with a BMI of 27.9 (0.89) kg/m 2. The mean serum TC, LDL-C, HDL-C, and TG concentrations were 276 (8.6), 176 (9.62), 39.8 (1.3), and (15.7) mg/dl, respectively. The genotype distributions (wild-type allele homozygote, variant heterozygote, variant homozygote) for each polymorphism were as follows: rs (18, 10, 3), rs (8, 18, 5), rs (19, 11, 1), and rs (31, 0, 0). The allele frequencies (wild type, variant) were as follows: rs (74%, 26%), rs (65%, 45%), rs (79%, 21%), and rs (100%, 0%). The variant rs was monomorphic in our study population; therefore, it was excluded from the analysis. These four variants have been reported to occur in linkage disequilibrium in various ethnic groups among American Hispanics 28. CAPN10 variant rs The percentage change between the basal and final HDL-C levels after the consumption of the dietary treatment was significantly higher in hyperlipidemic subjects with the GG genotype in the rs variant (p = 0.03) than in subjects with the GA and AA genotypes (table I). The subjects with the wild-type genotype were better responders to the LSF diet (1.3% increase in HDL-C) than were the subjects with the polymorphism (0.4% decrease in HDL-C). An effect of the dietary portfolio was observed from the first month of the dietary treatment. The percentage change in HDL-C concentrations in the wild type genotype after the dietary treatment was ± 9.02, whereas in subjects with the variant genotypes, the change was ± 2.13 (p = 0.03) (fig. 1). The analysis of the effect size, a measure of the strength of a phenomenon, showed that GG genotype had a large effect on the dietary treatment, with increased HDL-C levels (Cohen s (d) = 2.10, effect size (r) = 0.72) 29. Although there was no significant interaction between the GG Percent change in HDL-C CC CT/TT GG GA/AA GG 0 rs rs rs Fig. 1. The percentage change in HDL-C concentrations in hyperlipidemic subjects after one month of the low saturated fat diet (LSF) and two months of the LSF diet in addition to 25 g of soy protein and 15 g of soluble fiber (LSF+SSF) divided according to the CAPN10 genotypes. The wild type genotype show the black bars, whereas in subjects with the variant genotypes show the white bars. Values are the means ± SEM. Differences between genotypes and the percentage change after treatment was tested using an independent sample Student s t-test. *Differences with p * GA/AA A genetic variant of the CAPN10 gene in Mexican subjects with dyslipidemia is associated with increased HDL-cholesterol Nutr Hosp. 2014;30(3): Tabla I Serum lipid levels in hyperlipidemic subjects after one month of the LSF diet and after one and two months of the LSF diet in addition to 25 g of soy protein and 15 g of soluble fiber (LSF+SSF). Data are listed according to the CAPN10 genotypes Genotypes (n) Basal 1-mo. LSFD 2-mo LSFD + SSF 3-mo LSF + SSF Percent change after 3 mo. of treatment Total cholesterol (mg/dl) rs CC (18) 275 ± 12.7 a 255 ± 13.5 a,b 229 ± 13.3 a,b 219 ± 12.7 b ± CT and TT (13) 278 ± 10.9 a 251 ± 13.6 a,b 227 ± 7.52 b 227 ± 5.90 b ± 2.05 rs GG (8) 251 ± 18.3 a 212 ± 15.9 a,b 205 ± 13.8 a,b 194 ± 14.1 b ± GA and AA (23) 285 ± 9.25 a 267 ± 10.2 a,b 237 ± 9.6 a,b 232 ± 8.3 b ± 2.01 rs GG (19) 284 ± 10.8 a 260 ± 12.5 a,b 234 ± 10.5 b 229 ± 9.52 b ± GA and AA (12) 264 ± 13.9 a 242 ± 14.8 a,b 219 ± 13.5 a,b 212 ± 12.9 b ± 2.66 Triglycerides (mg/dl) rs CC (18) 313 ± 21.4 a 312 ± 25.5 a 176 ± 13.8 b 193 ± 10.5 b ± CT and TT (13) 279 ±22.0 a 249 ± 35.8 a,b 150 ± 19.0 b 169 ± 26.4 b ± 7.61 rs GG (8) 288 ± ± ± ± ± GA and AA (23) 302 ± 17.8 a 288 ± 23.8 a 163 ± 12.5 b 184 ± 14.8 b ± 5.45 rs GG (19) 284 ±18.9 a 270 ± 25.8 a 162 ± 13.4 b 173 ± 15.6 b ± GA and AA (12) 321 ± 26.6 a 310 ± 37.9 a 168 ± 21.1 b 198 ± 21.3 b ± 5.76 HDL-cholesterol (mg/dl) rs CC (18) 38.6 ± ± ± ± ± CT and TT (13) 41.6 ± ± ± ± ± 5.35 rs GG (8) 37.5 ± ± ± ± ± GA and AA (23) 40.6 ± ± ± ± ±2.13 rs GG (19) 41.8 ± ± ± ± ± GA and AA (12) 36.7 ± ± ± ± ± 6.12 P 674 Nutr Hosp. 2014;30(3): Martha Guevara-Cruz et al. Tabla I (cont.) Serum lipid levels in hyperlipidemic subjects after one month of the LSF diet and after one and two months of the LSF diet in addition to 25 g of soy protein and 15 g of soluble fiber (LSF+SSF). Data are listed according to the CAPN10 genotypes P Percent change after 3 mo. of treatment 3-mo LSF + SSF 2-mo LSFD + SSF Genotypes (n) Basal 1-mo. LSFD LDL-cholesterol (mg/dl) rs CC (18) 174 ± ± ± ± ± CT and TT (13) 180 ± ± ± ± ± 4.61 rs GG (8) 156 ± ± ± ± ± GA and AA (23) 184 ± ± ± ± ± 3.74 rs GG (19) 185 ± ± ± ± ± GA and AA (12) 163 ± ± ± ± ± 3.94 Values are the means ± SEM. Differences between the basal and final parameters were evaluated using a one-way ANOVA, and the differences between genotypes and the percentage change after treatment were tested using an independent sample Student s t-test. Values within a row bearing different superscript letters were significantly different (p 0.05; a b c). genotype and dietary treatment affecting the levels of LDL, there was a 12.6% decrease after three months of treatment, and the effect size of the GG genotype was considered to be large (Cohen s (d) = 2.79, effect size (r) = 0.81) 29. CAPN10 variants rs and rs In the rs and rs variants, the dietary treatment with soy protein and soluble fiber had no effect on the percentage change in HDL-C concentrations after (HDL P = 0.985, P = and LDL P = 0.985, P = 0.464). Despite the lack of a statistically significant difference (P = 0.080), the HDL-C concentrations in subjects with the GA and AA genotypes in rs increased by 10.48%; the effect size of the GA and AA genotypes on the dietary treatment with respect to HDL-C levels was large (Cohen s (d) = 2.234, effect size (r) = 0.74) 29, 30. Discussion Dyslipidemia is a serious public health problem 30, and it is important to develop dietary strategies to diminish its prevalence. This study presents the first report that patients with dyslipidemia and the GG genotype in the rs gene variant of the CAPN10 gene were better responders to a dietary intervention consisting of soy protein and soluble fiber, showing increased HDL-C concentrations (17%). In addition, GG carriers showed 12.6% lower levels of LDL-C; the effect size was large despite the lack of a statistically significant interaction. The genotype GG had a beneficial effect on the lipid profile; i.e., the levels of HDL increased significantly, and the levels of LDL tended to decrease. This effect may have been associated with an improved reverse cholesterol transport efficiency and a reduced risk of CHD. However, despite not showing a statistically significant interaction (P = 0.080), subjects with the GA and AA genotypes in rs showed an HDL-C level increase of 10.48%. It is well known that HDL-C plasma concentrations can be affected by genetic and environmental factors 31. For example, it was demonstrated that Mexican hyperlipidemic patients who consumed a dietary portfolio that included a beverage with soy protein (25 g) and soluble fiber (15 g) and presented the R230C genotype in the ABCA1 gene are better responders to the dietary treatment, showing HDL-C increases of 14.6% and 22% in men and women, respectively 7. It is important to note that changes in lipids were not related to weight loss because the patients body weight was not significantly reduced during the present study. There is evidence that CAPN10 is a regulator of exocytosis in pancreatic β-cells, and it is believed that an isoform of CAPN10 senses Ca 2+ and triggers exocytosis in these cells; furthermore, CAPN10 protein A genetic variant of the CAPN10 gene in Mexican subjects with dyslipidemia is associated with increased HDL-cholesterol Nutr Hosp. 2014;30(3): concentrations are correlated with the amount of insulin secreted from β-cells 32. However, physiologically relevant concentrations of apoa-i and apoa-ii (either lipid-free or as a constituent of discoidal reconstituted HDL) significantly increase β-cell insulin secretion, indicating that interventions that increase HDL-C levels may be beneficial in type 2 diabetes treatment 27. One of the limitations of this study was the small sample size, it is necessary to conduct properly powered prospective studies to determin
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