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Yukio Horikawa - One of the best experts on this subject based on the ideXlab platform.
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Calpain-10 (NIDDM1) as a Susceptibility Gene for Common Type 2 Diabetes.
Endocrine journal, 2006Co-Authors: Yukio HorikawaAbstract:IT is assumed that susceptibility genes associated with lifestyle-related diseases including type 2 or non-insulin-dependent diabetes mellitus (NIDDM) were positively selected for energy conservation but act adversely in modern conditions. These "thrifty genes" can be identified on the "common disease common variant" hypothesis, but detailed analysis of the genetic polymorphisms in many ethnic groups is required to clarify the molecular evolution of these susceptibility alleles. At present, single nucleotide polymorphisms (SNPs) represent the most useful data for genetic analyses of non-Mendelian polygenic lifestyle-related diseases, the common diseases including diabetes, hypertension, and obesity. Although many association studies have been conducted using single SNPs, they are problematical for several reasons, including ethnic differences within the study population, unknown environmental factors, misdiagnosed disease, and genetic mistyping. Haplotype analysis whereby several tag SNPs can be monitored simultaneously improves and complements the search. NIDDM1 (Calpain-10) is the first susceptibility gene for type 2 diabetes to be identified by this method.
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genetic variants in the Calpain 10 gene and the development of type 2 diabetes in the japanese population
Journal of Human Genetics, 2005Co-Authors: Naoko Iwasaki, Takafumi Tsuchiya, Yukio Horikawa, Yutaka Kitamura, T Nakamura, Yukio Tanizawa, Yoshitomo Oka, Kazuo Hara, Takashi Kadowaki, Takuya AwataAbstract:Variation in the gene encoding the cysteine protease Calpain-10 has been linked and associated with risk of type 2 diabetes. We have examined the effect of three polymorphisms in the Calpain-10 gene (SNP-43, Indel-19, and SNP-63) on the development of type 2 diabetes in the Japanese population in a pooled analysis of 927 patients and 929 controls. We observed that SNP-43, Indel-19, and SNP-63 either individually or as a haplotype were not associated with altered risk of type 2 diabetes with the exception of the rare 111/221 haplogenotype (odds ratio (OR) =3.53, P=0.02). However, stratification based on the median age-at-diagnosis in the pooled study population (<50 and ≥50 years) revealed that allele 2 of Indel-19 and the 121 haplotype were associated with reduced risk in patients with later age-at-diagnosis (age-at-diagnosis ≥50 years OR=0.82 and 0.80, respectively; P=0.04 and 0.02). Thus, variation in the Calpain-10 gene may affect risk of type 2 diabetes in Japanese, especially in older individuals.
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Genetic variants in the Calpain-10 gene and the development of type 2 diabetes in the Japanese population
Journal of Human Genetics, 2005Co-Authors: Naoko Iwasaki, Takafumi Tsuchiya, Yukio Horikawa, Yutaka Kitamura, T Nakamura, Yukio Tanizawa, Kazuo Hara, Takashi Kadowaki, Takuya Awata, Masashi HondaAbstract:Variation in the gene encoding the cysteine protease Calpain-10 has been linked and associated with risk of type 2 diabetes. We have examined the effect of three polymorphisms in the Calpain-10 gene (SNP-43, Indel-19, and SNP-63) on the development of type 2 diabetes in the Japanese population in a pooled analysis of 927 patients and 929 controls. We observed that SNP-43, Indel-19, and SNP-63 either individually or as a haplotype were not associated with altered risk of type 2 diabetes with the exception of the rare 111/221 haplogenotype (odds ratio (OR) =3.53, P =0.02). However, stratification based on the median age-at-diagnosis in the pooled study population (
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RyR2 and Calpain-10 Delineate a Novel Apoptosis Pathway in Pancreatic Islets
The Journal of biological chemistry, 2004Co-Authors: James D. Johnson, Yukio Horikawa, Graeme I Bell, Zhiqiang Han, Kenichi Otani, Yan Zhang, Stanley Misler, Kenneth S PolonskyAbstract:Abstract Cells are programmed to die when critical signaling and metabolic pathways are disrupted. Inhibiting the type 2 ryanodine receptor (RyR2) in human and mouse pancreatic β-cells markedly increased apoptosis. This mode of programmed cell death was not associated with robust caspase-3 activation prompting a search for an alternative mechanism. Increased Calpain activity and Calpain gene expression suggested a role for a Calpain-dependent death pathway. Using a combination of pharmacological and genetic approaches, we demonstrated that the Calpain-10 isoform mediated ryanodine-induced apoptosis. Apoptosis induced by the fatty acid palmitate and by low glucose also required Calpain-10. Ryanodine-induced Calpain activation and apoptosis were reversed by glucagon-like peptide or short-term exposure to high glucose. Thus RyR2 activity seems to play an essential role in β-cell survival in vitro by suppressing a death pathway mediated by Calpain-10, a type 2 diabetes susceptibility gene with previously unknown function.
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Genetic Variations in Calpain-10 Gene Are Not a Major Factor in the Occurrence of Type 2 Diabetes in Japanese
The Journal of clinical endocrinology and metabolism, 2003Co-Authors: Yukio Horikawa, Naohisa Oda, Shigeo Imamura, Kentaro Fujiwara, Masaki Makino, Yutaka Seino, Mitsuyasu Itoh, Jun TakedaAbstract:The 112/121 haplotype combination defined by the UCSNP-43, -19, and -63 alleles in the Calpain-10 gene is associated with type 2 diabetes in Mexican Americans. To determine whether this genetic variation constitutes risk of type 2 diabetes in Japanese, we investigated its frequency in 177 patients with type 2 diabetes and 172 controls. Though this variation occurs in Japanese more frequently than in Mexican Americans, there is no significant difference in frequency between diabetic (29.9%) and control (31.9%) subjects. We also screened all exons and the putative promoter of the Calpain-10 gene for mutations in 96 of the genotyped patients, resulting in the identification of 7 coding variants, including 3 missense mutations and 5 nucleotide alterations in the promoter. However, their frequencies all are similar in patients and controls, suggesting that these genetic variations are not a major factor in the occurrence of type 2 diabetes in Japanese, although they could yet be associated with various phenotypes of the disease.
Graeme I Bell - One of the best experts on this subject based on the ideXlab platform.
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Calpain-10 is a component of the obesity-related quantitative trait locus Adip1.
Journal of Lipid Research, 2010Co-Authors: James M. Cheverud, Joseph P. Jarvis, Elizabeth A. Norgard, Mihaela Pavlicev, L. Susan Pletscher, Honggang Ye, Kenneth S Polonsky, Gloria L Fawcett, Graeme I Bell, Clay F SemenkovichAbstract:We recently mapped Adip1, an obesity quantitative trait locus (QTL), to the middle portion of mouse chromosome 1, between microsatellite markers D1Mit10 (92,584,545 bp) and D1Mit139 (128,413,910 bp) in a set of LGXSM recombinant inbred (RI) strains (1, 2). This same region was found to affect body size at necropsy and body size growth between 3 and 10 weeks of age in replicate F2 intercrosses of LG/J with SM/J mice (3, 4), the parent strains of the LGXSM RI strain set. In the RI line mapping study, this region was found to have significant effects on all four measured fat depots (reproductive, renal, mesenteric, and inguinal), body weight at necropsy, and serum leptin and cholesterol levels. These effects were observed in both sexes and on both high and low fat diets. The Calpain-10 locus (Capn10, Chromosome 1 begins at 94,830,953 bp) is one of 134 genes identified in this QTL region (1). The Calpains are a family of cytoplasmic cysteine proteases (5, 6). Their physiological functions are poorly understood, but they have been implicated in the regulation of a variety of cellular processes including adipocyte differentiation (7, 8). One isoform, Calpain-10, may also affect the risk of type 2 diabetes (9, 10). Calpain-10, which is ubiquitously expressed, may affect apoptosis in pancreatic islet cells (11), mitochondrial function (12), insulin secretion (13, 14), and oxidative utilization of glucose in muscles (15). Genetic variation in CAPN10 has been associated with insulin resistance, dyslipidemia, and high fatty acid levels in a Japanese population (16); obesity in a Scandinavian population (17); and free fatty acid levels in a Finnish population (18). It has also been suggested that some CAPN10 alleles confer higher risk for cardiovascular disease in those with diabetes (19). Human studies suggest that CAPN10 variants may affect a large array of disease-related phenotypes, although replication of results across populations has proven difficult. The Calpain-10 gene is also a very good candidate for being the locus responsible for Adip1, the obesity-related QTL. Here, we test the hypothesis that Capn10 is responsible for the observed QTL effects in populations derived from the LG/J–by–SM/J cross using a quantitative hybrid complementation test (QHCT) (20). This test has been successfully applied in QTL studies in Drosophila (21, 22), Arabidopsis (23), and mice (24, 25). This is not the same as an ordinary complementation test, but it has a similar interpretation. In a QHCT, two experimental strains (LG/J and SM/J) are each crossed with two tester strains, a mutant strain (Capn10−/−) and its wild-type control (C57BL/6J). If the mutant–wild-type contrast is significantly different for crosses involving the two experimental strains, then there is a quantitative failure of the mutant to complement the experimental strain alleles. Quantitative failure to complement is indicated by a significant experimental-by-tester strain interaction among the four classes of hybrids (Fig. 1). A quantitative failure to complement signifies either that the QTL alleles at the locus of interest are responsible for the observed phenotypic variation or that other loci differing between the experimental strains interact with the mutant allele. In either case, the locus of interest is confirmed as being involved in trait variation. Here we cross experimental mouse strains LG/J and SM/J with a Capn10 knock-out strain (Capn10−/−) (H. Ye and G. I. Bell, unpublished observations) and its C57BL/6J wild-type control strain to test whether the Capn10 gene may be responsible for the observed LG/J–by–SM/J intercross QTL effects. Fig. 1. Quantitative hybrid complementation test (QHCT)(20). Two experimental strains (LG/J and SM/J) are crossed to two tester strains (Capn10 knockout and C57BL/6J wild-type) producing four sets of F1 hybrids. When the difference between the mutant and wild-type ...
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Calpain-10 gene and protein expression in human skeletal muscle: effect of acute lipid-induced insulin resistance and type 2 diabetes.
The Journal of clinical endocrinology and metabolism, 2007Co-Authors: Luke Norton, Graeme I Bell, Tim Parr, K. Chokkalingam, Ronald G. Bardsley, Maurice M. A. L. Pelsers, L.j.c. Van Loon, Kostas TsintzasAbstract:Objective: Our objective was to investigate the effect of lipid-induced insulin resistance and type 2 diabetes on skeletal muscle Calpain-10 mRNA and protein levels. Research Design and Methods: In the first part of this study, 10 healthy subjects underwent hyperinsulinemic euglycemic (4.5 mmol/liter) clamps for 6 h with iv infusion of either saline or a 20% Intralipid emulsion (Fresenius Kabi AG, Bad Homburg, Germany). Skeletal muscle biopsies were taken before and after 3- and 6-h insulin infusion and analyzed for Calpain-10 mRNA and protein expression. In the second part of the study, muscle samples obtained after an overnight fast in 10 long-standing, sedentary type 2 diabetes patients, 10 sedentary, weight-matched, normoglycemic controls, and 10 age-matched, endurance-trained cyclists were analyzed for Calpain-10 mRNA and protein content. Results: Intralipid infusion in healthy subjects reduced whole body glucose disposal by approximately 50% (P < 0.001). Calpain-10 mRNA (P = 0.01) but not protein content was reduced after 6-h insulin infusion in both the saline and Intralipid emulsion trials. Skeletal muscle Calpain-10 mRNA and protein content did not differ between the type 2 diabetes patients and normoglycemic controls, but there was a strong trend for total Calpain-10 protein to be greater in the endurance-trained athletes (P = 0.06). Conclusions: These data indicate that skeletal muscle Calpain-10 expression is not modified by insulin resistance per se and suggest that hyperinsulinemia and exercise training may modulate human skeletal muscle Calpain-10 expression.
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Common polymorphisms of Calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes
Diabetologia, 2006Co-Authors: Jussi Pihlajamaki, Urpu Salmenniemi, Markku Vänttinen, Eija Ruotsalainen, I. Vauhkonen, Maggie C.y. Ng, Johanna Kuusisto, Sakari Kainulainen, Graeme I BellAbstract:Aims/hypothesis The mechanisms by which the Calpain-10 gene (CAPN10) affects the risk of type 2 diabetes are unclear. Therefore, we investigated the effects of four polymorphisms in CAPN10 (single nucleotide polymorphism [SNP]-43, SNP-44, Insertion/Deletion [Indel]-19 and SNP-63) on insulin secretion, insulin action and abdominal fat distribution in offspring of patients with type 2 diabetes.
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RyR2 and Calpain-10 Delineate a Novel Apoptosis Pathway in Pancreatic Islets
The Journal of biological chemistry, 2004Co-Authors: James D. Johnson, Yukio Horikawa, Graeme I Bell, Zhiqiang Han, Kenichi Otani, Yan Zhang, Stanley Misler, Kenneth S PolonskyAbstract:Abstract Cells are programmed to die when critical signaling and metabolic pathways are disrupted. Inhibiting the type 2 ryanodine receptor (RyR2) in human and mouse pancreatic β-cells markedly increased apoptosis. This mode of programmed cell death was not associated with robust caspase-3 activation prompting a search for an alternative mechanism. Increased Calpain activity and Calpain gene expression suggested a role for a Calpain-dependent death pathway. Using a combination of pharmacological and genetic approaches, we demonstrated that the Calpain-10 isoform mediated ryanodine-induced apoptosis. Apoptosis induced by the fatty acid palmitate and by low glucose also required Calpain-10. Ryanodine-induced Calpain activation and apoptosis were reversed by glucagon-like peptide or short-term exposure to high glucose. Thus RyR2 activity seems to play an essential role in β-cell survival in vitro by suppressing a death pathway mediated by Calpain-10, a type 2 diabetes susceptibility gene with previously unknown function.
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Linkage of Calpain 10 to Type 2 Diabetes: The Biological Rationale
Diabetes, 2004Co-Authors: M. Geoffrey Hayes, Takafumi Tsuchiya, Graeme I BellAbstract:The follow-up studies to the original report of association of variation at Calpain 10 (CAPN10) with type 2 diabetes in the Mexican-American population of Starr County, Texas, encompass a broad range of science. There are association studies on genetic variation at CAPN10 in different human populations over a range of phenotypes related to type 2 diabetes, physiological studies on the biological functions of Calpain proteases, and evolutionary studies on CAPN10 and the NIDDM1 region. We review here the studies published to date on CAPN10, as well as the latest findings from positional cloning studies on a number of other complex disorders. Collectively, these studies provide perspective on the challenges of moving from the linkage mapping and positional cloning studies on which we have been focused to an understanding of the biology shaping the relationship of genotype to phenotype at loci influencing susceptibility to complex disorders like type 2 diabetes.
Cuizhi Geng - One of the best experts on this subject based on the ideXlab platform.
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clinical significance of sher2 ecd and Calpain 10 expression in tumor tissues of patients with breast cancer
Oncology Reports, 2020Co-Authors: Yawen Ding, Shejun Gao, Junying Liu, Cuizhi GengAbstract:Human epidermal growth factor receptor 2 (HER2) is composed of an extracellular domain (ECD), a lipophilic transmembrane region and an intracellular domain (ICD). The most commonly used method to determine the status of HER2 is immunohistochemistry. However, false‑negative results are sometimes given, which causes some patients to lose the opportunity for anti‑HER2 therapy. We found that Calpain‑10 may prohibit HER2‑ECD into peripheral blood resulting in a HER2‑negative result by the immunohistochemical method. We enrolled 289 patients into our experiment to assess the relationship between sHER2‑ECD and Calpain‑10. The results showed that there was a positive correlation between sHER2‑ECD and Calpain‑10. Moreover, we also investigated the prognostic values of sHER2‑ECD and Calpain‑10 in breast cancer patients. According to the follow‑up results, positive sHER2‑ECD and tissue Calpain‑10 were indicative of a poor prognosis in breast cancer patients. Subsequently, we further validated the relationship between the two molecules in in vitro experiments. In the in vitro experiments, the level of HER2‑ECD in the culture medium was increased or decreased with a decrease or increase in Calpain‑10 by transfection technology, showing an inverse association. The results indicated that sHER2‑ECD and tissue Calpain‑10 levels were powerful factors to assess the status of HER2. In combination with tissue HER2 detection, the occurrence of false‑negative HER2 was reduced, providing patients with additional treatment opportunities. In conclusion, sHER2‑ECD and tissue Calpain‑10 may be used as new prognostic indices for breast cancer.
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Clinical significance of sHER2‑ECD and Calpain‑10 expression in tumor tissues of patients with breast cancer
Oncology reports, 2020Co-Authors: Yawen Ding, Shejun Gao, Junying Liu, Cuizhi GengAbstract:Human epidermal growth factor receptor 2 (HER2) is composed of an extracellular domain (ECD), a lipophilic transmembrane region and an intracellular domain (ICD). The most commonly used method to determine the status of HER2 is immunohistochemistry. However, false‑negative results are sometimes given, which causes some patients to lose the opportunity for anti‑HER2 therapy. We found that Calpain‑10 may prohibit HER2‑ECD into peripheral blood resulting in a HER2‑negative result by the immunohistochemical method. We enrolled 289 patients into our experiment to assess the relationship between sHER2‑ECD and Calpain‑10. The results showed that there was a positive correlation between sHER2‑ECD and Calpain‑10. Moreover, we also investigated the prognostic values of sHER2‑ECD and Calpain‑10 in breast cancer patients. According to the follow‑up results, positive sHER2‑ECD and tissue Calpain‑10 were indicative of a poor prognosis in breast cancer patients. Subsequently, we further validated the relationship between the two molecules in in vitro experiments. In the in vitro experiments, the level of HER2‑ECD in the culture medium was increased or decreased with a decrease or increase in Calpain‑10 by transfection technology, showing an inverse association. The results indicated that sHER2‑ECD and tissue Calpain‑10 levels were powerful factors to assess the status of HER2. In combination with tissue HER2 detection, the occurrence of false‑negative HER2 was reduced, providing patients with additional treatment opportunities. In conclusion, sHER2‑ECD and tissue Calpain‑10 may be used as new prognostic indices for breast cancer.
Julie Evans - One of the best experts on this subject based on the ideXlab platform.
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Variation within the Type 2 Diabetes Susceptibility Gene Calpain-10 and Polycystic Ovary Syndrome
The Journal of Clinical Endocrinology and Metabolism, 2002Co-Authors: Lema Haddad, Julie Evans, Neda Gharani, Carole Robertson, Karen Rush, Steven Wiltshire, Andrew Demaine, Timothy J. Wilkin, Timothy M Frayling, Ann MillwardAbstract:Variation within the Calpain-10 gene (CAPN10) has been proposed to account for linkage to type 2 diabetes on chromosome 2q in Mexican-Americans, and associations with diabetes have been reported in several other populations. Given the epidemiological, physiological, and genetic overlap between type 2 diabetes and polycystic ovary syndrome (PCOS), CAPN10 represents a strong candidate gene for a role in PCOS susceptibility. Using both family based and case-control association resources (146 parent-offspring trios; 185 additional PCOS cases; 525 control subjects, all of European ancestry), we sought association between CAPN10 variation and PCOS, focusing on four single nucleotide polymorphism (SNP) variants (SNP-44, SNP-43; SNP-19; SNP-63). On single-locus transmission disequilibrium analysis in the 146 trios, there was nominal evidence (P 0.03) of excess transmission of the more common allele at SNP-63. This association was not, however, replicated in the case-control analysis. No other significant associations were observed at the single-locus or haplotype level in either the transmission-disequilibrium or case-control analyses. The relative risk for the high-risk diabetes susceptibility 112/121 genotype (SNPs 43–19-63) was 0.84 (95% confidence intervals, 0.40 –1.71). No associations were seen with intermediate traits of relevance to diabetes and PCOS pathogenesis. We have found no evidence from these analyses that CAPN10 gene variation influences susceptibility to PCOS. (J Clin Endocrinol Metab 87: 2606 –2610, 2002)
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Association of the Calpain-10 gene with microvascular function
Diabetologia, 2002Co-Authors: Angela C. Shore, Julie Evans, Timothy M Frayling, Andrew T Hattersley, Yukio Horikawa, Pm Clark, Bc Lee, John E. TookeAbstract:Aims/hypothesis. Genotype could influence vascular function. In some populations, Calpain 10 gene polymorphisms increase susceptibility to diabetes or insulin resistance. Alterations in microvascular function could contribute to insulin resistance. This study investigated whether polymorphisms in the Calpain-10 gene influence microvascular function.
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Haplotype Combinations of Calpain 10 Gene Polymorphisms Associate With Increased Risk of Impaired Glucose Tolerance and Type 2 Diabetes in South Indians
Diabetes, 2002Co-Authors: Paul G Cassell, Julie Evans, Alan E. Jackson, Bernard V. North, Denise Syndercombe-court, Christopher Phillips, Ambady Ramachandran, Chamukuttan Snehalatha, Susan V. Gelding, Shanti VijayaravaghanAbstract:Haplotype combination 112/121 and its intrinsic variants (UCSNP43, -19, and -63) identified within the Calpain 10 gene are associated with increased risk of type 2 diabetes in Mexican-Americans. We evaluated whether this haplotype combination and its constituent haplotypes and variants contribute to increased susceptibility to impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) and type 2 diabetes in a South Indian population. Two study groups were used: 95 families ascertained through a proband with type 2 diabetes and 468 subjects recruited as part of an urban survey (69.1% with normal glucose tolerance, 12.8% with IFG/IGT, and 18.2% with type 2 diabetes). The four-locus haplotype combination 1112/1121 (UCSNP44, -43, -19, and -63) in South Indians conferred both a 10.7-fold increased risk for IFG/IGT (P 0.001) and a 5.78- to 6.52-fold increased risk for type 2 diabetes in the two study groups (families P 0.025, urban survey P 0.015). A combination of the 1112 haplotype with the 1221 haplotype also appeared to increase risk for both IFG/IGT and type 2 diabetes. Contrary to what might be expected, quantitative trait analysis in the families found that transmission of the disease-related 1121 and 1112 haplotypes was associated with a reduced hip size and lower waist-to-hip ratio, respectively. This study supports the paradigm that specific haplotype combinations of Calpain 10 variants increase risk of both IFG/IGT and type 2 diabetes. However, the relative infrequency of the “at-risk” combinations in the South Indian population suggests that Calpain 10 is not a common determinant of susceptibility to type 2 diabetes. Diabetes 51:1622‐1628, 2002
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Variation in the Calpain-10 Gene Affects Blood Glucose Levels in the British Population
Diabetes, 2002Co-Authors: Stephen Lynn, Julie Evans, Timothy M Frayling, Andrew T Hattersley, Christopher J. White, Doug M Turnbull, Yukio Horikawa, Graeme I Bell, Mark WalkerAbstract:Variation in the Calpain-10 gene (CAPN10) has been shown to be associated with type 2 diabetes in Mexican-Americans and in at least three Northern European populations. Studies in nondiabetic Pima Indians showed that one of the at-risk DNA polymorphisms, single-nucleotide polymorphism (SNP)-43, in CAPN10 was associated with insulin resistance, and individuals with the G/G-genotype had significantly higher fasting plasma glucose and 2-h insulin concentrations after a 75-g oral glucose tolerance test (OGTT). We have examined the effect of variation in CAPN10 on plasma glucose and insulin levels in a group of 285 nondiabetic British subjects after a 75-g OGTT. The results showed that subjects with G/G genotype at SNP-43 had higher 2-h plasma glucose levels than the combined G/A + A/A group (P = 0.05). We also examined the SNP-43, -19, and -63 haplotype combination 112/121, which is associated with an approximately threefold increased risk of diabetes. Subjects with the 112/121 haplotype combination (n = 29) had increased fasting (P = 0.004) and 2-h plasma glucose levels (P = 0.003) compared with the rest of the study population after correction for age, sex, and BMI. The 112/121 haplotype combination was also associated with a marked decrease in the insulin secretory response, adjusted for the level of insulin resistance (P = 0.002). We conclude that genetic variation in the CAPN10 gene influences blood glucose levels in nondiabetic British subjects and that this is due, at least in part, to the effects of Calpain-10 on the early insulin secretory response.
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Studies of Association between the Gene for Calpain-10 and Type 2 Diabetes Mellitus in the United Kingdom
American Journal of Human Genetics, 2001Co-Authors: Julie Evans, Graham A. Hitman, P. J. Saker, Timothy M Frayling, Stephen O'rahilly, Paul G Cassell, Jonathan C. Levy, Mark Walker, Amanda J BennettAbstract:Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease Calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, λS, of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of Calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P=.033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P=.015) and in combination with a Mexican American study (P=.004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms—L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific Calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.
Qiu-fang Lian - One of the best experts on this subject based on the ideXlab platform.
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correlation between Calpain 10 single nucleotide polymorphisms and obstructive sleep apnea hypopnoea syndrome with ischemic stroke in a chinese population a population based study
Medicine, 2017Co-Authors: Wei Zhang, Zhi-ru Zhao, Chang-fei Dai, Rong Zhang, Jie Chen, Hui-juan Tian, Yun-long Wang, Ji-hong Sun, Qiu-fang LianAbstract:BACKGROUND Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a common chronic disorder which is followed by various complications. Calpain-10 belongs to a commonly expressed member of the Calpain-like cysteine protease family, which acts as risk marker for some diseases. The purpose of this study is to elucidate correlation between Calpain-10 single-nucleotide polymorphisms (SNPs) and the incidence of OSAHS followed by ischemic stroke (IS). METHODS OSAHS patients were divided as OSAHS + IS, OSAHS, and control groups, respectively. Immunohistochemistry was performed for Calpain-10 protein expression, polymerase chain reaction (PCR)-restriction fragment length polymorphism for detection of gene polymorphisms of SNP 43 and SNP 19, and PCR-allele specific amplification for SNP 44. Polysomnography was conducted to check the nocturnal polysomnography indicators, and also Montreal Cognitive Assessment (MoCA), Scientific Data System scores cognition and anxiety of patients, respectively. Logistic analysis was used for the risky factors for OSAHS. RESULTS Calpain-10 protein expression was significantly increased in the OSAHS + IS and OSAHS groups compared with the control group. Significant differences in SNP 43 and SNP 44 genotype, and also allele frequency were observed in 3 groups, among which the OSAHS + IS group had higher SNP 43 and SNP 44 allele frequency than the control and OSAHS groups. There were differences regarding apnea-hypopnea index, minimum fingertip blood oxygen saturation (LSaO2 [%]), oxygen reduction index (ODI) between patients with different genotypes of SNP 43 and SNP 44 in OSAHS patients, and also GC and AT frequency in the OSAHS + IS and OSAHS groups. As compared with the OSAHS group, the MoCA scores and MoCA subitems in the OSAHS + IS group were declined, whereas the Scientific Data System scores were elevated. Additionally, GG 43 genotype, high apnea-hypopnea index, and body mass index were detected as the risk factors of OSAHS. CONCLUSION These findings indicate that the Calpain-10 SNP 43 may be related to OSAHS with IS, with SNP 43 GG genotype as a risk factor for OSAHS with IS.
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Correlation between Calpain-10 single-nucleotide polymorphisms and obstructive sleep apnea/hypopnoea syndrome with ischemic stroke in a Chinese population: A population-based study.
Medicine, 2017Co-Authors: Wei Zhang, Zhi-ru Zhao, Chang-fei Dai, Rong Zhang, Jie Chen, Hui-juan Tian, Yun-long Wang, Ji-hong Sun, Qiu-fang LianAbstract:BACKGROUND Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a common chronic disorder which is followed by various complications. Calpain-10 belongs to a commonly expressed member of the Calpain-like cysteine protease family, which acts as risk marker for some diseases. The purpose of this study is to elucidate correlation between Calpain-10 single-nucleotide polymorphisms (SNPs) and the incidence of OSAHS followed by ischemic stroke (IS). METHODS OSAHS patients were divided as OSAHS + IS, OSAHS, and control groups, respectively. Immunohistochemistry was performed for Calpain-10 protein expression, polymerase chain reaction (PCR)-restriction fragment length polymorphism for detection of gene polymorphisms of SNP 43 and SNP 19, and PCR-allele specific amplification for SNP 44. Polysomnography was conducted to check the nocturnal polysomnography indicators, and also Montreal Cognitive Assessment (MoCA), Scientific Data System scores cognition and anxiety of patients, respectively. Logistic analysis was used for the risky factors for OSAHS. RESULTS Calpain-10 protein expression was significantly increased in the OSAHS + IS and OSAHS groups compared with the control group. Significant differences in SNP 43 and SNP 44 genotype, and also allele frequency were observed in 3 groups, among which the OSAHS + IS group had higher SNP 43 and SNP 44 allele frequency than the control and OSAHS groups. There were differences regarding apnea-hypopnea index, minimum fingertip blood oxygen saturation (LSaO2 [%]), oxygen reduction index (ODI) between patients with different genotypes of SNP 43 and SNP 44 in OSAHS patients, and also GC and AT frequency in the OSAHS + IS and OSAHS groups. As compared with the OSAHS group, the MoCA scores and MoCA subitems in the OSAHS + IS group were declined, whereas the Scientific Data System scores were elevated. Additionally, GG 43 genotype, high apnea-hypopnea index, and body mass index were detected as the risk factors of OSAHS. CONCLUSION These findings indicate that the Calpain-10 SNP 43 may be related to OSAHS with IS, with SNP 43 GG genotype as a risk factor for OSAHS with IS.
