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Association of an INSIG2 obesity allele with cardiovascular phenotypes is gender and age dependent
Kimberly A Skelding, Glenn S Gerhard, Helen Vlachos, Faith Selzer, Sheryl F Kelsey, Xin Chu, Robert Erdman, David O Williams, Kevin E Kip
BMC Cardiovascular Disorders , 2010, DOI: 10.1186/1471-2261-10-46
Abstract: Nine hundred forty six patients undergoing percutaneous coronary intervention (PCI) in wave 5 of the multicenter NHLBI Dynamic Registry were genotyped using RT-PCR/TaqMan/allelic discrimination for the rs7566605 SNP near the INSIG2 gene. Clinical variables analyzed include demographics, medical history, and procedural details. The prevalence of peripheral vascular disease (PVD) was significantly higher in older men (≥65 years) who were either homozygous or carriers of the obesity/lipid risk allele ("C") compared to non-carriers (odds ratio 3.4, p = 0.013) using a logistic regression model incorporating history of hypercholesterolemia, history of hypertension, cerebrovascular disease, history of diabetes, and BMI. A similar relationship with cerebrovascular disease was found in older (>65) women (odds ratio 3.4, p = 0.013). The INSIG2 SNP was not associated with BMI, nor with other clinical variables.Age and gender may influence the association of the INSIG2 obesity SNP with PVD and cerebrovascular disease in patients with pre-existing CVD.Risk factors for atherosclerosis related disorders include dyslipidemia and obesity. The insulin signaling protein type 2 gene (INSIG2) has been shown to be involved in lipid and cholesterol metabolism in vitro and in animal studies [1-3], and has been linked to obesity in humans through genetic studies. For example, INSIG2 interacts with transcription factors that activate the synthesis of cholesterol and fatty acids in the liver and other organs [4]. In addition, a common single nucleotide polymorphism (SNP rs7566605) near the INSIG2 gene was found to be associated with BMI in a genome-wide association study from the Framingham Heart Study offspring cohort [5]. Playing both a key role in cholesterol homeostasis and as a genetic susceptibility factor for obesity makes it an attractive candidate locus for lipid-related phenotypes such as cardiovascular disease, as well as for BMI.The initial association of BMI with homozygosity for
The INSIG2 rs7566605 polymorphism is not associated with body mass index and breast cancer risk
Daniele Campa, Anika Hüsing, James D McKay, Olga Sinilnikova, Ulla Vogel, Anne Tj?nneland, Kim Overvad, Jakob Stegger, Fran?oise Clavel-Chapelon, Nathalie Chabbert-Buffet, Guy Fagherazzi, Antonia Trichopoulou, Dimosthenis Zylis, Erifili Oustoglou, Sabine Rohrmann, Birgit Teucher, Eva Fisher, Heiner Boeing, Giovanna Masala, Vittorio Krogh, Carlotta Sacerdote, Salvatore Panico, Rosario Tumino, N Charlotte Onland-Moret, Carla H van Gils, H Bueno-de-Mesquita, Eiliv Lund, María Chirlaque, Núria Sala, José Quirós
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-563
Abstract: we tested in a large-scale association study (3,973 women, including 1,269 invasive BC cases and 2,194 controls), nested within the EPIC cohort, the involvement of rs7566605 as predictor of BMI and BC risk.In this study we were not able to find any statistically significant association between this SNP and BMI, nor did we find any significant association between the SNP and an increased risk of breast cancer overall and by subgroups of age, or menopausal status.Herbert and coworkers [1] conducted a genome-wide association study (GWAS) on 694 subjects of the Framingham Heart Study with a family-based design to identify genetic loci (single nucleotide polymorphisms, SNPs) contributing to obesity using body mass index (BMI) as the primary phenotype. The authors reported strong statistical evidence that the SNP rs7566605 located near the 5' end of INSIG2 (Chr2:118,552,255) was associated with increased BMI [1]. In this initial study, association of rs7566605 with BMI was replicated in ethnically distinct populations, including European and African Americans. INSIG2 has been functionally linked to lipid metabolism, due to its role in endogenous cholesterol and fatty acid synthesis feedback inhibition [2]. It is an endoplasmic reticulum membrane bound protein that inhibits the proteolytic activation of Sterol Response Element Binding Proteins (SREPs) in response to cholesterol or insulin [2]. Thus, the biological function of the INSIG2 gene product is consistent with the initially observed association.A series of follow-up studies sought to validate the association of INSIG2 rs7566605 with markers of obesity in humans, with several publications reporting inconsistent findings [3-13].There is ample evidence that excessive body weight is a risk factor for a number of diseases. In particular, the evidence that body fatness is a cause of postmenopausal breast cancer (BC) is convincing [14]. On the other hand, body fatness is inversely associated with BC risk in premenopausal
INSIG2 gene polymorphism is associated with increased subcutaneous fat in women and poor response to resistance training in men
Funda E Orkunoglu-Suer, Heather Gordish-Dressman, Priscilla M Clarkson, Paul D Thompson, Theodore J Angelopoulos, Paul M Gordon, Niall M Moyna, Linda S Pescatello, Paul S Visich, Robert F Zoeller, Brennan Harmon, Richard L Seip, Eric P Hoffman, Joseph M Devaney
BMC Medical Genetics , 2008, DOI: 10.1186/1471-2350-9-117
Abstract: We genotyped the INSIG2 SNP rs7566605 in college-aged population enrolled in a controlled resistance-training program, (the Functional Polymorphism Associated with Human Muscle Size and Strength, FAMuSS cohort, n = 752 volunteers 18–40 yrs). In this longitudinal study, we examined the effect of the INSIG2 polymorphism on subcutaneous fat and muscle volumes of the upper arm measured by magnetic resonance imaging (MRI) before and after 12 wks of resistance training. Gene/phenotype associations were tested using an analysis of covariance model with age and weight as covariates. Further, the % variation in each phenotype attributable to genotype was determined using hierarchical models and tested with a likelihood ratio test.Women with a copy of the C allele had higher levels of baseline subcutaneous fat (GG: n = 139; 243473 ± 5713 mm3 vs. GC/CC: n = 181; 268521 ± 5003 mm3; p = 0.0011); but men did not show any such association. Men homozygous for the G ancestral allele showed a loss of subcutaneous fat, while those with one or two copies of the C allele gained a greater percentage of subcutaneous fat with resistance training (GG: n = 103; 1.02% ± 1.74% vs. GC/CC: n = 93; 6.39% ± 1.82%; p = 0.035).Our results show that the INSIG2 rs7566605 polymorphism underlies variation in subcutaneous adiposity in young adult women and suppresses the positive effects of resistance training on men. This supports and extends the original finding that there is an association between measures of obesity and INSIG2 rs7566605 and further implicates this polymorphism in fat regulation.Obesity is increasing in prevalence and is an important public health problem. In the United States, 17.1% of children 2 to 19 years are overweight and 32.2% of adults aged > 20 years are obese. The prevalence of being overweight among children and adolescents and obesity among men increased significantly between 1999 and 2004 [1]. Obesity is a major risk factor for the development of hypertension, diabetes, c
Association between the -455T>C promoter polymorphism of the APOC3 gene and the metabolic syndrome in a multi-ethnic sample
Rebecca L Pollex, Matthew R Ban, T Kue Young, Peter Bjerregaard, Sonia S Anand, Salim Yusuf, Bernard Zinman, Stewart B Harris, Anthony JG Hanley, Philip W Connelly, Murray W Huff, Robert A Hegele
BMC Medical Genetics , 2007, DOI: 10.1186/1471-2350-8-80
Abstract: Subjects were genotyped for both the APOC3 -455T>C and INSIG2 rs7566605 polymorphisms, and classified for the presence or absence of MetS (NCEP ATP III and IDF definitions). The total study population included 2675 subjects (≥18 years of age) from six different geographical ancestries.For the overall study population, the prevalence of MetS was 22.6% (NCEP ATP III definition). Carriers of ≥1 copy of APOC3 -455C were more likely to have MetS (NCEP ATP III definition) than noncarriers (carrier odds ratio 1.73, 95% CI 1.40 to 2.14, adjusting for age and study group). The basis of the association was related not only to a higher proportion of -455C carriers meeting the triglyceride and high-density lipoprotein cholesterol criteria, but also the blood pressure criteria compared with wild-type homozygotes. Plasma apo C-III concentrations were not associated with APOC3 -455T>C genotype. The INSIG2 rs7566605 polymorphism was not associated with MetS or measures of obesity.Meta-analysis of the sample of multiple geographic ancestries indicated that the functional -455T>C promoter polymorphism in APOC3 was associated with an approximately 2-fold increased risk of MetS, whereas the INSIG2 rs7566605 polymorphism was not associated with MetS.The metabolic syndrome (MetS) is a clinical entity characterized by abdominal obesity, hypertension, hypertriglyceridemia, low plasma high-density lipoprotein (HDL) cholesterol and elevated glucose [1,2]. MetS is common, and will likely become even more pervasive, considering the poor lifestyle habits prevalent in many societies today. While the increased prevalence in MetS is primarily related to an imbalance between caloric intake and expenditure, genetic factors are also likely to be important. Each defining component has been previously associated with genetic factors, suggesting that genetic factors might underlie the overall MetS both independently and through more complex interactions [3]. While the precise definition of MetS is contr
The INSIG2 rs7566605 genetic variant does not play a major role in obesity in a sample of 24,722 individuals from four cohorts
Jan Bressler, Myriam Fornage, Craig L Hanis, Wen Kao, Cora E Lewis, Ruth McPherson, Robert Dent, Thomas H Mosley, Len A Pennacchio, Eric Boerwinkle
BMC Medical Genetics , 2009, DOI: 10.1186/1471-2350-10-56
Abstract: Differences in mean body mass index (BMI) and other anthropometric measures including weight, waist circumference, and waist-to-hip ratio were assessed by a general linear model in individuals categorized by INSIG2 rs7566605 genotype. Multivariable logistic regression was used to predict the risk of obesity (BMI ≥ 30 kg/m2).There was no discernable variation in the frequencies of the three INSIG2 SNP genotypes observed between white, Hispanic, and African-American obese individuals and non-obese study subjects. When the relationship between rs7566605 and BMI considered either as a categorical variable or a continuous variable was examined, no significant association with obesity was found for participants in any of the four study populations or in a combined analysis (p = 0.38) under a recessive genetic model. There was also no association between the INSIG2 polymorphism and the obesity-related quantitative traits except for a reduced waist-to-hip ratio in white ARIC study participants homozygous for the C allele, and an increased waist-to-hip ratio in African-Americans in the ARIC cohort with the same genotype (p = 0.04 and p = 0.01, respectively). An association with waist-to-hip ratio was not seen when the combined study sample was analyzed (p = 0.74).These results suggest that the INSIG2 rs7566605 variant does not play a major role in determining obesity risk in a racially and ethnically diverse sample of 24,722 individuals from four cohorts.Obesity results from an imbalance between food intake and energy expenditure, and is a major risk factor for many of the chronic diseases of adulthood including hypertension, type 2 diabetes, coronary heart disease and stroke [1,2]. Although the results of twin and adoption studies provide strong support for a genetic influence on body weight [3-5], mutations causing monogenic forms of obesity are rare in the population [6], and major genes contributing to common obesity have not been described. In addition, interaction betw
INSIG2 is Associated with Lower Gain in Weight-for-Length Between Birth and Age 6 Months
Ann Chen Wu, Matthew W. Gillman, Elsie M. Taveras and Augusto A. Litonjua
Clinical Medicine Insights: Pediatrics , 2012,
Abstract: Researchers have described the association of a common DNA polymorphism, rs7566605, near INSIG2 (insulin-induced gene 2) with obesity in multiple independent populations that include subjects ages 11–60 years.1 To our knowledge, no studies have examined the association of this polymorphism with weight status during early childhood. We explored the association of the rs7566605 polymorphism with weight-for-length among 319 children at 6 months and 3 years participating in Project Viva, a pre-birth cohort study. In contrast to studies of older individuals, CC homozygosity was associated with lower gain in weight-for-length z-score between birth and age 6 months than GG homozygosity or GC heterozygosity. At age 3, we did not find an association. The association of INSIG2 gene with obesity may change direction with age.
INSIG2 is Associated with Lower Gain in Weight-for-Length Between Birth and Age 6 Months
Ann Chen Wu,Matthew W. Gillman,Elsie M. Taveras,Augusto A. Litonjua
Clinical Medicine : Pediatrics , 2009,
Abstract: Researchers have described the association of a common DNA polymorphism, rs7566605, near INSIG2 (insulin-induced gene 2) with obesity in multiple independent populations that include subjects ages 11–60 years.1 To our knowledge, no studies have examined the association of this polymorphism with weight status during early childhood. We explored the association of the rs7566605 polymorphism with weight-for-length among 319 children at 6 months and 3 years participating in Project Viva, a pre-birth cohort study. In contrast to studies of older individuals, CC homozygosity was associated with lower gain in weight-for-length z-score between birth and age 6 months than GG homozygosity or GC heterozygosity. At age 3, we did not find an association. The association of INSIG2 gene with obesity may change direction with age.
Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design?  [PDF]
Iris M. Heid equal contributor ,Cornelia Huth equal contributor,Ruth J. F. Loos,Florian Kronenberg,Vera Adamkova,Sonia S. Anand,Kristin Ardlie,Heike Biebermann,Peter Bjerregaard,Heiner Boeing,Claude Bouchard,Marina Ciullo,Jackie A. Cooper,Dolores Corella,Christian Dina,James C. Engert,Eva Fisher,Francesc Francès,Philippe Froguel,Johannes Hebebrand,Robert A. Hegele,Anke Hinney,Margret R. Hoehe,Frank B. Hu,Jaroslav A. Hubacek,Steve E. Humphries,Steven C. Hunt,Thomas Illig,Marjo-Riita J?rvelin,Marika Kaakinen,Barbara Kollerits,Heiko Krude,Jitender Kumar,Leslie A. Lange,Birgit Langer,Shengxu Li,Andreas Luchner,Helen N. Lyon,David Meyre,Karen L. Mohlke,Vincent Mooser,Almut Nebel,Thuy Trang Nguyen,Bernhard Paulweber,Louis Perusse,Lu Qi,Tuomo Rankinen,Dieter Rosskopf,Stefan Schreiber,Shantanu Sengupta,Rossella Sorice,Anita Suk,Gudmar Thorleifsson,Unnur Thorsteinsdottir,Henry V?lzke,Karani S. Vimaleswaran,Nicholas J. Wareham,Dawn Waterworth,Salim Yusuf,Cecilia Lindgren,Mark I. McCarthy,Christoph Lange,Joel N. Hirschhorn,Nan Laird equal contributor,H.-Erich Wichmann equal contributor
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000694
Abstract: The INSIG2 rs7566605 polymorphism was identified for obesity (BMI≥30 kg/m2) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status (‘healthy population’, HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I2 measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I2 measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI≥32.5, 35.0, 37.5, 40.0 kg/m2 versus BMI<25 kg/m2) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.
A tagging SNP in INSIG2 is associated with obesity-related phenotypes among Samoans
Ranjan Deka, Ling Xu, Prodipto Pal, Palanitina T Toelupe, Tuiasina S Laumoli, Huifeng Xi, Ge Zhang, Daniel E Weeks, Stephen T McGarvey
BMC Medical Genetics , 2009, DOI: 10.1186/1471-2350-10-143
Abstract: We studied 907 adult Samoan participants from a longitudinal study of adiposity and cardiovascular disease risk in two polities, American Samoa and Samoa. Four tagSNPs were identified from the Chinese HapMap database based on pairwise r2 of ≥0.8 and minor allele frequency of ≥0.05. Genotyping was performed using the TaqMan assay. Tests of association with BMI and ABDCIR were performed under the additive model.We did not find association of rs7566605 with either BMI or ABDCIR in any group of the Samoans. However, the most distally located tagSNPs in Intron 3 of the gene, rs9308762, showed significant association with both BMI (p-value 0.024) and ABDCIR (p-value 0.009) in the combined sample and with BMI (p-value 0.038) in the sample from Samoa.Although rs7566605 was not significantly associated with obesity in our study population, we can not rule out the involvement of INSIG2 in obesity related traits as we found significant association of another tagSNP in INSIG2 with both BMI and ABDCIR. This study suggests the importance of comprehensive assessment of sequence variants within a gene in association studies.Using genome-wide association analysis, Herbert et al. [1] reported a common variant, rs7566605, in the 5' region of the INSIG2 gene associated with obesity in the Framingham Heart Study population samples and also replicated this finding in four independent cohorts of European and African American ancestries. However, the association of this variant remains inconclusive with confirmation or lack thereof in several follow-up studies conducted in populations of diverse ethnicities [2-12]. Analysis of a single variant could be perceived as a limitation in assessing genetic association of a putative locus. To guard against this potential limitation we conducted a comprehensive association analysis of common tagging SNPs in the INSIG2 gene among adult Samoans, Polynesians of the Western Pacific, residing in Samoa and American Samoa.Our study sample derives from a lo
Effects of Extracorporeal Shockwave Therapy and Hand Massage on Body Composition and Serum Lipids According to Serum Cholesterol Level in Korean Women  [PDF]
Kyung Jin Lee, Jin Ik Park, Soo Yeon Oh
Journal of Cosmetics, Dermatological Sciences and Applications (JCDSA) , 2019, DOI: 10.4236/jcdsa.2019.92015
Abstract: Obesity, particularly abdominal obesity, increases the risk of cardiovascular disease (CVD). This study investigates the effects of six-week (twice a week, 12 sessions total) extracorporeal shockwave therapy (SWT) and hand massage therapy (HT) on body composition and serum lipids in overweight and obese Korean women aged between 35 and 59, according to their serum cholesterol level (≥200 mg/dL versus <200 mg/dL). After the program, weights decreased significantly in both the HT Group and SWT Group (p < 0.05); weights of those with cholesterol < 200 mg/dL significantly decreased in the HT Group (p = 0.038), while weights of those with cholesterol ≥ 200 mg/dL significantly decreased in the SWT Group (p = 0.001). BMIs decreased significantly in both the HT Group and the SWT Group (p < 0.05); BMIs of those with cholesterol < 200 mg/dL significantly decreased in the HT Group (p = 0.018), while BMIs of those with cholesterol ≥ 200 mg/dL significantly decreased in the SWT Group (p = 0.001). The body fat percentage of subjects significantly decreased only in the SWT Group (p = 0.027); the waist-hip ratio significantly decreased only in HT Group (p = 0.034). Serum cholesterol levels significantly decreased in those with cholesterol < 200 mg/dL in the HT Group (p < 0.05) and those with cholesterol ≥ 200 mg/dL in SWT Group (p = 0.055). Triglyceride significantly decreased in both those with cholesterol < 200 mg/dL and those with cholesterol ≥ 200 mg/dL, but did not significantly decrease in either subgroup of the HT Group. The study results suggest that SWT is effective in improving body measurements and serum lipids in those with cholesterol ≥ 200 mg/dL, while HT therapy is effective in those with cholesterol < 200 mg/dL. In conclusion, SWT and HT improved abdominal obesity by reducing body weight and waist circumference and helped improving serum lip index, suggesting the benefit for managing body measurements and serum lipids of overweight and obese individuals.
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