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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 7 3601-3605
Copyright © 2004 by The Endocrine Society

Variation in the Calpain-10 Gene Is Associated with Elevated Triglyceride Levels and Reduced Adipose Tissue Messenger Ribonucleic Acid Expression in Obese Swedish Subjects

Emma Carlsson, Jenny Fredriksson, Leif Groop and Martin Ridderstråle

Department of Endocrinology, Malmö University Hospital, Lund University, S-205 02 Malmö, Sweden

Address all correspondence and requests for reprints to: Emma Carlsson, Department of Endocrinology, Lund University, Wallenberg Laboratory, Malmö University Hospital, S-205 02 Malmö, Sweden. E-mail: emma.carlsson{at}endo.mas.lu.se.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Our aim was to investigate the possible role of the type 2 diabetes susceptibility gene CAPN10 in obesity. A case control study consisting of 235 obese Swedish subjects [body mass index, 40 (35–45) kg/m2] and 235 controls matched for age and gender [body mass index, 22 (21–24) kg/m2], and a transmission disequilibrium test consisting of 116 parents-offspring trios, where the offspring was abdominally obese [waist, 100 (95–110) cm], were performed. CAPN10 mRNA expression was studied in adipose tissue biopsies from 33 of the obese subjects participating in the case control study. The CAPN10 single-nucleotide polymorphism (SNP)-43 was genotyped using PCR followed by NdeI digestion or by allelic discrimination. CAPN10 mRNA levels were quantified using real-time RT-PCR with Cyclophilin A as an internal standard. No significant associations between CAPN10 SNP-43 and obesity were seen, neither in the case control study nor in the transmission disequilibrium test, but obese subjects homozygous for the SNP-43 G allele had significantly elevated triglyceride levels compared with subjects carrying the A allele [1.7 (1.1–2.4) vs. 1.4 (1.0–2.0); P = 0.03]. The CAPN10 mRNA expression in sc fat was significantly reduced in subjects with the SNP-43 G/G genotype compared with carriers of SNP-43 G/A (G/G, 0.33 ± 0.02, vs. G/A, 0.51 ± 0.09; P = 0.048), and a similar trend was observed in visceral fat (G/G, 0.52 ± 0.06, vs. G/A, 0.65 ± 0.10; P = 0.22). Our data suggest that reduced CAPN10 expression may be a risk factor for features associated with the metabolic syndrome in obese subjects, although variation in the gene does not seem to contribute to the risk for developing obesity per se.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE GENE ENCODING calpain-10 (CAPN10), located on chromosome 2q37, has been identified as a candidate gene for type 2 diabetes (1). In Pima Indians, the diabetes-associated intronic single-nucleotide polymorphism (SNP)-43 G/G genotype was associated with reduced muscle CAPN10 mRNA expression and impaired insulin-stimulated glucose metabolism, mainly impaired glucose oxidation (2). Calpain-10 is a cysteine protease expressed in many tissues important in glucose metabolism, including skeletal muscle, liver, pancreas, and adipose tissue (3, 4), but the explanation for how calpain-10 increases susceptibility for type 2 diabetes is not yet completely known. Recent results suggest that calpain-10 may be involved in both glucose transporter 4 translocation to the cell membrane in adipocytes (5) as well as pancreatic ß-cell insulin secretion (6).

The relationship between obesity and type 2 diabetes has long been recognized, and although not all obese subjects develop type 2 diabetes, the majority of the latter patients are obese. Free fatty acid (FFA) levels are increased in obese individuals, primarily due to an increase in the rate of lipolysis from the expanded fat cell mass, and have been suggested to play an essential role in the development of skeletal muscle insulin resistance (7, 8, 9, 10). In skeletal muscle, an increased flux of FFAs increase intramyocellular triglyceride stores, and this enhanced intracellular lipid accumulation is significantly and inversely correlated with insulin sensitivity (11, 12). Recently, SNPs or their combinations in CAPN10 have been shown to predispose to insulin resistance and elevated FFA levels (13). Genetic variation in CAPN10 has also been associated with both reduced ß3-adrenoeceptor function in adipocytes from obese subjects (14) and increased plasma cholesterol in Japanese (15). Our aim was to investigate the possible role of CAPN10 in obesity and related features. In the present study, we performed a case control association study for obesity, and a transmission disequilibrium test (TDT) for offspring with abdominal obesity, and studied the expression of CAPN10 in adipose tissue and whether it is influenced by variation in the gene.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

The case control study consisted of 235 obese nondiabetic Swedish subjects [age, 43 ± 12 yr; body mass index (BMI), 40 (35–45) kg/m2] and 235 controls matched for age and gender [age, 43 ± 12 yr; BMI, 22 (21–24) kg/m2; Table 1Go]. One hundred sixteen parents-offspring trios, where the offspring was abdominally obese (waist, >80 and >94 cm for females and males, respectively; Table 1Go), were genotyped to follow transmission of CAPN10 SNP-43 alleles. Abdominal visceral and sc adipose tissues were obtained from 33 of the obese subjects participating in the case control study when they were undergoing bariatric surgery at Landskrona Hospital in Sweden (age, 39 ± 10 yr; BMI, 41 ± 5 kg/m2; Table 1Go). Biopsies were immediately frozen in liquid nitrogen and stored at –80 C until further processing. All subjects gave informed consent, and the study was approved by the local ethics committee.


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  		TABLE 1. Clinical characteristics of subjects included in the three different studies

 
Body weight and height were measured with subjects in light clothing without shoes, and BMI was calculated as weight (kilograms) divided by height (meters) squared. Waist circumference was measured with a soft tape on standing subjects midway between the lowest rib and the iliac crest. Hip circumference was measured over the widest part of the gluteal region, and waist-to-hip ratio (WHR) was accordingly calculated. Plasma glucose was determined using an automated glucose oxidase method (Glucose Analyzer 2; Beckman Instruments, Fullerton, CA). Serum insulin concentrations were measured with RIA (Pharmacia, Uppsala, Sweden). Triglyceride concentrations were measured on a Cobas Mira analyzer (Hoffmann-La Roche, Basel, Switzerland). Total body fat percentage was calculated using bioimpedance analysis.

Genotyping

DNA was extracted from blood using a conventional method (16) or using DNA Mini-Prep (Qiagen, Hilden, Germany) at the DNA/RNA Genotyping Lab, SWEGENE Resource Center for Profiling Polygenic Disease, Lund University, Malmö University Hospital (Malmö, Sweden). In the case control study, the CAPN10 SNP-43 was amplified with primers 5'-GCT GGC TGG TGA CAT CAG TGC-3' and 5'-ACC AAG TCA AGG CTT AGC CTC ACC TTC ATA-3'. PCR was carried out in a 20-µl volume containing 10 µM each dNTP, 3.0 mM MgCl2, 0.5 U Taq polymerase (Amersham Pharmacia Biotech, Piscataway, NJ), 10 pmol each primer, and 25 ng genomic DNA. The cycling conditions were 94 C for 5 min, 32 cycles of 94 C for 30 sec, 60 C for 30 sec, and 72 C for 30 sec, followed by a final extension at 72 C for 10 min. PCR products were digested with 10 U NdeI (New England Biolabs, Beverly, MA) for 16 h at 37 C. The digested products were separated on a 4% agarose gel. Allele G was detected as a 254-bp fragment, and allele A as 223- and 31-bp fragments. In the TDT, CAPN10 SNP-43 was genotyped using allelic discrimination in the ABI PRISM 7900 Sequence Detection System (Applied Biosystems, Foster City, CA) in a 5-µl reaction according to the manufacturer’s instructions. Primers and probes were designed using Assays-by-Design (Applied Biosystems) and were as follows: forward primer, 5'-GCG CTC ACG CTT GCT-3'; reverse primer, 5'-CCT CAC CAA GTC AAG GCT TAG C-3'; probe G, 5'-(VIC)-AAG TAA GGC GTT TGA AG-(nonfluorescent quencher)-3'; and probe A, 5'-(FAM)-AAG TAA GGC ATT TGA AG-(nonfluorescent quencher)-3'.

Measurement of CAPN10 mRNA using real-time RT-PCR

Extraction of total RNA from the fat biopsies was performed with the RNeasy mini-kit (Qiagen), and cDNA was synthesized using Superscript II RNase H– Reverse Transcriptase (Life Technologies, Rockville, MD) and random hexamer primers (Life Technologies). Real-time semiquantitative RT-PCR was performed using the ABI PRISM 7900 Sequence Detection System (Applied Biosystems) according to the manufacturer’s instructions. PCR were run in 25 µl containing 12.5 µl Mastermix, 1.25 µl primers and probe, and 75 ng cDNA. Cyclophilin A was used as an endogenous control to standardize the amount of cDNA added to the reactions using a ready-to-use mix of primers and a VIC-labeled probe. Primers and probe for CAPN10 mRNA were ordered as a ready-to-use mix of primers and a FAM-labeled probe. All reagents were purchased from Applied Biosystems. The CAPN10 primers and probe recognize seven of the eight isoforms of calpain-10, which is important because it was shown that reduced skeletal muscle CAPN10 transcript levels are due to a cumulative decrease in major isoforms (17). All samples were run in duplicate, and data were calculated using the standard curve method and expressed as a ratio to the Cyclophilin A reference.

Statistical analyses

Descriptive data displaying normal distribution are presented as means ± SD, whereas data that were not normally distributed are given as median and interquartile range in parentheses. Expression data are presented as means ± SEM. Values of P < 0.05 were considered statistically significant. Statistical calculations were performed using NCSS 2000 software (NCSS, Kaysville, UT). CAPN10 mRNA levels in visceral and sc adipose tissue were log-transformed to get a normal distribution. Otherwise, nonparametric statistical calculations (Wilcoxon between- and Mann-Whitney within-groups, and Spearman for correlation analysis) were used. The {chi}2 test was used to compare allele and genotype frequencies between groups, and also to identify significant departures from the Hardy-Weinberg equilibrium. The TDT was performed using Genhunter 2.1 (18).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Case control association study

There were no significant differences in genotype (G/G, 51 vs. 52%; G/A, 41 vs. 42%; and A/A, 8 vs. 6%; P = 0.7) or allele frequencies (G, 72 vs. 73%; A, 28 vs. 27%; P = 0.9) between the obese subjects and the controls regarding CAPN10 SNP-43 (Table 2Go). The genotype frequencies were in Hardy-Weinberg equilibrium. No significant differences were found between subjects homozygous for the SNP-43 G allele and carriers of the A allele regarding age, BMI, waist, WHR, fasting plasma glucose, or triglyceride levels in the controls (Table 3Go). On the other hand, obese subjects carrying the SNP-43 G/G genotype had significantly elevated triglyceride levels compared with subjects carrying the SNP-43 G/A or A/A genotype [1.7 (1.1–2.4) vs. 1.4 (1.0–2.0); P = 0.03], but no differences regarding age, BMI, waist, WHR, or fasting plasma glucose were seen (Table 3Go).


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  		TABLE 2. Genotype frequencies of CAPN10 SNP-43 in obese subjects and controls

 

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  		TABLE 3. Clinical characteristics of obese subjects and controls according to CAPN10 SNP-43 genotype

 
TDT

Ninety-six of 232 transmissions were informative. The CAPN10 SNP-43 alleles showed no significant departure from the expected Mendelian 50:50 ratio in the TDT (49 vs. 47 transmissions of the G and A allele, respectively; P = 0.84).

CAPN10 mRNA expression in visceral and sc adipose tissue

The mRNA levels of CAPN10 were increased in visceral compared with sc fat obtained from obese subjects undergoing bariatric surgery (0.58 ± 0.06 vs. 0.41 ± 0.04; P = 0.001; Fig. 1Go). We found an inverse relationship between CAPN10 mRNA expression in sc adipose tissue and total body fat percentage (R = –0.43; P = 0.02; Fig. 2Go) and a trend in the same direction for visceral fat and CAPN10 mRNA expression (R = –0.28; P = 0.14). Visceral and sc CAPN10 mRNA levels were also correlated to each other (R = 0.49; P = 0.004; Fig. 3Go). The CAPN10 mRNA expression in sc fat was significantly reduced in subjects with the SNP-43 G/G genotype compared with carriers of SNP-43 G/A [G/G, 0.33 ± 0.02 (n = 18), vs. G/A, 0.51 ± 0.09 (n = 15); P = 0.048], and a similar trend was observed in visceral fat [G/G, 0.52 ± 0.06 (n = 18), vs. G/A, 0.65 ± 0.10 (n = 15); P = 0.22; Fig. 4Go]. None of these subjects carried the rare A/A genotype.



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  		FIG. 1. Expression of CAPN10 mRNA in adipose tissue. CAPN10 mRNA was increased in visceral compared with sc adipose tissue from 33 obese subjects. CAPN10 mRNA was quantified by real-time PCR and normalized to Cyclophilin A mRNA.

 


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  		FIG. 2. Correlation between CAPN10 mRNA and total body fat percentage. CAPN10 mRNA levels in sc adipose tissue were negatively correlated to total body fat percentage in obese subjects. CAPN10 mRNA was quantified by real-time PCR and normalized to Cyclophilin A mRNA.

 


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  		FIG. 3. Correlation between CAPN10 mRNA in visceral and sc adipose tissue. Visceral and sc CAPN10 mRNA levels were correlated to each other. CAPN10 mRNA was quantified by real-time PCR and normalized to Cyclophilin A mRNA.

 


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  		FIG. 4. CAPN10 mRNA expression in adipose tissue in relation to SNP-43 genotype. The CAPN10 mRNA expression in sc fat was significantly reduced in subjects with the SNP-43 G/G genotype compared with carriers of SNP-43 G/A, and a similar trend was observed in visceral fat. CAPN10 mRNA was quantified by real-time PCR and normalized to Cyclophilin A mRNA.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The main findings of this study were that 1) CAPN10 SNP-43 showed no association to obesity in the case control association study or in the TDT, 2) variation in CAPN10 SNP-43 was associated with triglyceride levels in obese subjects, 3) the expression of CAPN10 mRNA was higher in visceral compared with sc adipose tissue, 4) there was a positive correlation between CAPN10 mRNA levels in the two different fat depots, and 5) variation in CAPN10 SNP-43 was associated with the expression of CAPN10 mRNA at least in sc fat.

Our finding that obese subjects carrying the SNP-43 G/G genotype have significantly higher triglyceride levels than subjects with the A allele are in agreement with earlier findings showing that fasting FFA levels are significantly higher in carriers of the SNP-43 G allele compared with carriers of the A/A genotype (13). Interestingly, this was not the case among our controls, suggesting that the effect of the genotype is manifested only under certain conditions, i.e. obesity. It can also be a reflection of the lack of power.

There was no association between variants in CAPN10 SNP-43 and obesity in the case control association study or in the TDT performed with abdominal obese offspring, suggesting that calpain-10, or at least the CAPN10 SNP-43, is involved in the development of insulin resistance rather than in the development of obesity per se. Many studies investigating the role of CAPN10 in type 2 diabetes, have evaluated its influence on BMI, WHR, and/or total body fat mass. Most of the studies failed to show any significant associations between variation in CAPN10 and obesity-related parameters (2, 13, 19, 20, 21, 22, 23, 24, 25, 26, 27). In addition, an analysis of the relationship between variation in CAPN10 and extreme early-onset obesity revealed no evidence for linkage or association (28). One smaller case control study for CAPN10 and obesity has been performed earlier in a Scandinavian population, and it failed to show association to SNP-19, -43, and -63 (14). However, a TDT performed with obese, type 2 diabetic offspring showed increased transmission of the less common C allele at SNP-44 to affected probands (29). Contrary to what might be expected, a quantitative TDT in South Indians found that transmission of the SNP-43 G allele or the type 2 diabetes-risk haplotype 1121 (SNP-44, -43, -19, and -63) to the diabetic offspring was associated with a decrease in BMI and hip size (30). In a study of healthy nonobese subjects, individuals with the CAPN10 SNP-43 G/G genotype had significantly lower BMI compared with carriers of the A allele (31). Recently published results showed that the CAPN10 SNP-19 and -63 are associated with BMI in Japanese (32).

SNP-43 is located in intron 3 of CAPN10, and this polymorphism has been suggested as a regulator of CAPN10 expression (1). In Pima Indians with normal glucose tolerance, carriers of the CAPN10 SNP-43 G/G genotype showed lower expression levels of CAPN10 mRNA compared with carriers of the A allele in skeletal muscle (2). We observed the same in adipose tissue from obese Swedish subjects, although it reached statistical significance only in sc adipose tissue. This is in accordance with the common variant hypothesis suggesting that variants that increase susceptibility for a complex polygenic disease do so through effects on gene expression (33). In addition, we found that the expression of CAPN10 in sc adipose tissue is inversely correlated to total body fat percentage, suggesting that a larger proportion of body fat in the already-obese subjects, corresponding to a reduced CAPN10 expression, is associated with an increased risk of metabolic perturbation. However, it should be pointed out that the expression levels of CAPN10 were studied in a very obese population. CAPN10 mRNA was more abundant in visceral than in sc fat, which is interesting because visceral fat is more metabolically active than sc (34). On the other hand, CAPN10 mRNA levels in sc and visceral adipose tissue were positively correlated to each other suggesting that the expression of CAPN10 is coregulated in the two different adipose depots.

In conclusion, intronic variation in CAPN10 is associated with elevated triglyceride levels and reduced adipose tissue mRNA expression in morbidly obese Swedish subjects, suggesting that a low CAPN10 expression may be a risk factor for conditions related to the metabolic syndrome.


   Footnotes
 
This work was supported by Crafoord Foundation, Malmö University Hospital Foundation, Albert Påhlsson Foundation, Swedish Medical Research Council, Diabetes Association in Malmö, Juvenile Diabetes-Wallenberg Foundation, Lundberg Foundation, European Community–a Genomics Integrated Force for Type 2 Diabetes, Novo Nordisk Foundation, Region Skåne, ALF, Magnus Bergvall Foundation, Fredrik and Ingrid Thurings Foundation, and Borgströms Foundation.

Abbreviations: BMI, Body mass index; FFA, free fatty acid; SNP, single-nucleotide polymorphism; TDT, transmission disequilibrium test; WHR, waist-to-hip ratio.

Received December 10, 2003.

Accepted March 18, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH, Mashima H, Schwartz PE, del Bosque-Plata L, Horikawa Y, Oda Y, Yoshiuchi I, Colilla S, Polonsky KS, Wei S, Concannon P, Iwasaki N, Schulze J, Baier LJ, Bogardus C, Groop L, Boerwinkle E, Hanis CL, Bell GI 2000 Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26:163–175[CrossRef][Medline]
  2. Baier LJ, Permana PA, Yang X, Pratley RE, Hanson RL, Shen G-Q, Mott D, Knowler WC, Cox NJ, Horikawa Y, Oda N, Bell GI, Bogardus C 2001 A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest 106:R69–R73
  3. Screenan SK, Zhou Y-P, Otani K, Hansen PA, Currie KPM, Pan C-Y, Lee J-P, Ostrega DM, Pugh W, Horikawa Y, Cox NJ, Hanis CL, Burant CF, Fox AP, Bell GI, Polonsky KS 2001 Calpains play a role in insulin secretion and action. Diabetes 50:2013–2020[Abstract/Free Full Text]
  4. Molinari M, Carafoli E 1997 Calpain: a cytosolic proteinase active at the membranes. J Membr Biol 156:1–8[CrossRef][Medline]
  5. Paul DS, Harmon AW, Winston CP, Patel YM 2003 Calpain facilitates GLUT4 vesicle translocation during insulin-stimulated glucose uptake in adipocytes. Biochem J 15:625–632
  6. Zhou Y-P, Sreenan S, Pan C-Y, Currie KPM, Bindokas VP, Horikawa Y, Lee J-P, Osrega D, Ahmed N, Baldwin AC, Cox NJ, Fox AP, Miller RJ, Bell GI, Polonsky KS 2003 A 48-hour exposure of pancreatic islets to calpain inhibitors impairs mitochondrial fuel metabolism and the exocytosis of insulin. Metabolism 5:528–534
  7. Groop L, Forsblom C, Lehtovirta M, Tuomi T, Karanko S, Nissen M, Ehrnström BO, Forsen B, Isomaa B, Snickars B, Taskinen MR 1996 Metabolic consequences of a family history of NIDDM (the Botnia study): evidence for sex-specific parental effects. Diabetes 45:1585–1593[Abstract]
  8. Beck-Nielsen H, Groop L 1994 Metabolic and genetic characterization of prediabetic states: sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 94:1714–1721
  9. Groop L, Orho-Melander M 2001 The dysmetabolic syndrome. J Intern Med 250:105–120[CrossRef][Medline]
  10. Boden G 1997 Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46:3–10[Abstract]
  11. Jacob S, Machann J, Rett K, Brechtel K, Volk A, Renn W, Maerker E, Matthaei S, Schick F, Claussen CD, Haring HU 1999 Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects. Diabetes 48:1113–1119[Abstract]
  12. Perseghin G, Scifo P, De Cobelli F, Pagliato E, Battezzati A, Arcelloni C, Vanzulli A, Testolin G, Pozza G, Del Maschio A, Luzi L 1999 Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans. Diabetes 48:1600–1606[Abstract]
  13. Orho-Melander M, Klannemark M, Svensson M, Ridderstråle M, Lindgren C, Groop L 2002 Variants in the calpain-10 gene predispose to insulin resistance and elevated free fatty acid levels. Diabetes 51:2658–2664[Abstract/Free Full Text]
  14. Hoffstedt J, Näslund E, Arner P 2002 Calpain-10 gene polymorphism is associated with reduced ß3-adrenoceptor function in human fat cells. J Clin Endocrinol Metab 87:3362–3367[Abstract/Free Full Text]
  15. Daimon M, Oizumi T, Saitoh T, Kameda W, Yamaguchi H, Ohnuma H, Igarashi M, Manaka H, Kato T 2002 Calpain 10 gene polymorphisms are related, not to type 2 diabetes, but to increased serum cholesterol in Japanese. Diabetes Res Clin Pract 56:147–152[CrossRef][Medline]
  16. Vandenplas S, Wiid I, Grobler-Rabie A, Brebner K, Ricketts M, Wallis G, Bester A, Boyd C, Mathew C 1984 Blot hybridisation analysis of genomic DNA. J Med Genet 21:164–172[Abstract/Free Full Text]
  17. Yang X, Pratley RE, Baier LJ, Horikawa Y, Bell GI, Bogardus C, Permana PA 2001 Reduced skeletal muscle calpain-10 transcript level is due to cumulative decrease in major isoforms. Mol Genet Metab 73:111–113[CrossRef][Medline]
  18. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES1996 Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363
  19. Stumvoll M, Fritsche A, Madaus A, Stefan N, Weisser M, Machicao F, Haring H 2001 Functional significance of the UCSNP-43 polymorphism in the CAPN10 gene for proinsulin processing and insulin secretion in nondiabetic Germans. Diabetes 50:2161–2163[Abstract/Free Full Text]
  20. Tsai HJ, Sun G, Weeks DE, Kaushal R, Wolujewicz M, McGarvey ST, Tufa J, Viali S, Deka R 2001 Type 2 diabetes and three calpain-10 gene polymorphisms in Samoans: no evidence of association. Am J Hum Genet 69:1236–1244[CrossRef][Medline]
  21. Garant MJ, Kao WHL, Brancati F, Coresh J, Rami TM, Hanis CL, Boerwinkle E, Shuldiner AR 2002 SNP43 of CAPN10 and the risk of type 2 diabetes in African-Americans. Diabetes 51:231–237[Abstract/Free Full Text]
  22. Hoffstedt J, Ryden M, Löfgren P, Orho-Melander M, Groop L, Arner P 2002 Polymorphism in the calpain 10 gene influences glucose metabolism in human fat cells. Diabetologia 45:276–282[CrossRef][Medline]
  23. Fingerlin TE, Erdos MR, Watanabe RM, Wiles KR, Stringham HM, Mohlke KL, Silander K, Valle TT, Buchanan TA, Tuomilehto J, Bergman RN, Boehnke M, Collins FS 2002 Variation in three single nucleotide polymorphisms in the calpain-10 gene not associated with type 2 diabetes in a large Finnish cohort. Diabetes 51:1644–1648[Abstract/Free Full Text]
  24. Malecki MT, Moczulski DK, Klupa T, Wanic K, Cyganek K, Frey J, Sieradzki J 2002 Homozygous combination of calpain 10 gene haplotype is associated with type 2 diabetes mellitus in a Polish population. Eur J Endocrinol 146:695–699[Abstract]
  25. Shore AC, Evans JC, Frayling TM, Clark PM, Lee BC, Horikawa Y, Hattersley AT, Tooke JE 2002 Association of the calpain-10 gene with microvascular function. Diabetologia 45:899–904[CrossRef][Medline]
  26. Lynn S, Evans JC, White C, Frayling TM, Hattersley AT, Turnbull DM, Horikawa Y, Cox NJ, Bell GI, Walker M 2002 Variation in the calpain-10 gene affects blood glucose levels in the British population. Diabetes 51:247–250[Abstract/Free Full Text]
  27. Rasmussen SK, Urhammer SA, Berglund L, Jensen JN, Hansen L, Echwald SM, Borch-Johnsen K, Horikawa Y, Mashima H, Lethell H, Cox NJ, Hansen T, Mell GI, Pedersen O 2002 Variants within the calpain-10 gene on chromosome 2q37 (NIDDM1) and relationships to type 2 diabetes, insulin resistance, and impaired acute insulin secretion among Scandinavian Caucasians. Diabetes 51:3561–3567[Abstract/Free Full Text]
  28. Hinnley A, Antwerpen B, Geller F, Schäfer H, Siegfried W, Goldschmidt H, Remschmidt H, Ziegel A, Hebebrand J 2002 No evidence for involvement of the calpain-10 gene "high-risk" haplotype combination for non-insulin-dependent diabetes mellitus in early onset diabetes. Mol Genet Metab 76:152–156[CrossRef][Medline]
  29. Evans JC, Frayling TM, Cassell PG, Saker PJ, Hitman GA, Walker M, Levy JC, O’Rahilly S, Subba Rao PV, Bennett AJ, Jones EC, Menzel S, Prestwich P, Simecek N, Wishart M, Dhillon R, Fletcher C, Millward A, Demaine A, Wilkin T, Horikawa Y, Cox NJ, Bell GI, Ellard S, McCarthy MI, Hattersley A 2001 Studies of association between the gene for calpain-10 and type 2 diabetes in the United Kingdom. Am J Hum Genet 69:544–552[CrossRef][Medline]
  30. Cassell P, Jackson AE, North BV, Evans JC, Syndercombe-Court D, Phillips C, Ramachandran A, Snehalatha C, Gelding SV, Vijayaravaghan S, Curtis D, Hitman GA 2002 Haplotype combinations of calpain 10 gene polymorphisms associate with increase risk of impaired glucose tolerance and type 2 diabetes in South Indians. Diabetes 51:1622–1628[Abstract/Free Full Text]
  31. Stumvoll M, Wahl HG, Machicao WF, Häring H 2002 Insulin sensitivity of glucose disposal and lipolysis: no influence of common genetic variants in IRS-1 and CAPN10. Diabetologia 45:651–656[CrossRef][Medline]
  32. Shima Y, Nakanishi K, Odawara M, Kobayashi T, Ohta H 2003 Association of the SNP-19 genotype 22 in the calpain-10 gene with elevated body mass index and hemoglobin A1c levels in Japanese. Clin Chim Acta 336:89–96[CrossRef][Medline]
  33. Yan H, Yuan W, Velculescu VE, Vogelstein B, Kinzler KW 2002 Allelic variation in human gene expression. Science 297:1143[Free Full Text]
  34. Arner P 1997 Regional adipocity in man. J Endocrinol 155:191–192[Free Full Text]



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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals