Meta-Analysis and a Large Association Study Confirm a Role for Calpain-10 Variation in Type 2 Diabetes Susceptibility
2003; Elsevier BV; Volume: 73; Issue: 5 Linguagem: Inglês
10.1086/379285
ISSN1537-6605
AutoresMichael N. Weedon, Peter E. H. Schwarz, Yukio Horikawa, Naoko Iwasaki, Thomas Illig, Rolf Holle, Wolfgang Rathmann, T. Selisko, Jan Schulze, Katherine R. Owen, Julie Evans, Laura del Bosque‐Plata, G. A. Hitman, Mark Walker, J Levý, Mike Sampson, Graeme I. Bell, Mark I. McCarthy, Andrew T. Hattersley, Timothy M. Frayling,
Tópico(s)Gear and Bearing Dynamics Analysis
ResumoTo the Editor: Variation in the calpain-10 gene (CAPN10 [MIM 605286]) was recently linked and associated with type 2 diabetes mellitus (T2DM) susceptibility (Horikawa et al. Horikawa et al., 2000Horikawa Y Oda N Cox NJ Li X Orho-Melander M Hara M Hinokio Y Lindner TH Mashima H Schwarz PE del Bosque-Plata L 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 Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus.Nat Genet. 2000; 26: 163-175Crossref PubMed Scopus (1252) Google Scholar). The initial linkage of T2DM to chromosome 2 was found in a population of Mexican Americans from Starr County, Texas (Hanis et al. Hanis et al., 1996Hanis CL Boerwinkle E Chakraborty R Ellsworth DL Concannon P Stirling B Morrison VA et al.A genome wide search for human non-insulin dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2.Nat Genet. 1996; 13: 161-166Crossref PubMed Scopus (555) Google Scholar). Specific combinations of three intronic variants, designated "SNP-43," "SNP-19," and "SNP-63," that capture most of the haplotype diversity at CAPN10 were associated with a three-fold increased risk of T2DM in this population and could account for the observed linkage (Horikawa et al. Horikawa et al., 2000Horikawa Y Oda N Cox NJ Li X Orho-Melander M Hara M Hinokio Y Lindner TH Mashima H Schwarz PE del Bosque-Plata L 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 Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus.Nat Genet. 2000; 26: 163-175Crossref PubMed Scopus (1252) Google Scholar). Subsequent association and linkage studies of these three polymorphisms in other populations have produced conflicting results, with association being observed in some populations (Baier et al. Baier et al., 2000Baier LJ Permana PA Yang X Pratley RE Hanson RL Shen GQ Mott D Knowler WC Cox NJ Horikawa Y Oda N Bell GI Bogardus C A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance.J Clin Invest. 2000; 106: R69-R73Crossref PubMed Scopus (261) Google Scholar [Pima Indian]; Cassell et al. Cassell et al., 2002Cassell PG Jackson AE North BV Evans JC Syndercombe-Court D Phillips C Ramachandran A Snehalatha C Gelding SV Vijayaravaghan S Curtis D Hitman GA Haplotype combinations of calpain 10 gene polymorphisms associate with increased risk of impaired glucose tolerance and type 2 diabetes in South Indians.Diabetes. 2002; 51: 1622-1628Crossref PubMed Scopus (67) Google Scholar [South Indian]; Garant et al. Garant et al., 2002Garant MJ Kao WH Brancati F Coresh J Rami TM Hanis CL Boerwinkle E Shuldiner AR SNP43 of CAPN10 and the risk of type 2 diabetes in African-Americans: the atherosclerosis risk in communities study.Diabetes. 2002; 51: 231-237Crossref PubMed Scopus (79) Google Scholar [African American]; Malecki et al. Malecki et al., 2002Malecki MT Moczulski DK Klupa T Wanic K Cyganek K Frey J Sieradzki J Homozygous combination of calpain 10 gene haplotypes is associated with type 2 diabetes mellitus in a Polish population.Eur J Endocrinol. 2002; 146: 695-699Crossref PubMed Scopus (78) Google Scholar [Polish]; Orho-Melander et al. Orho-Melander et al., 2002Orho-Melander M Klannemark M Svensson MK Ridderstrale M Lindgren CM Groop L Variants in the calpain-10 gene predispose to insulin resistance and elevated free fatty acid levels.Diabetes. 2002; 51: 2658-2664Crossref PubMed Scopus (105) Google Scholar [Finnish/Botnia]), but not others (Evans et al. Evans et al., 2001Evans JC Frayling TM Cassell PG Saker PJ Hitman GA Walker M Levy JC et al.Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.Am J Hum Genet. 2001; 69: 544-552Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar [British]; Hegele et al. Hegele et al., 2001Hegele RA Harris SB Zinman B Hanley AJ Cao H Absence of association of type 2 diabetes with CAPN10 and PC-1 polymorphisms in Oji-Cree.Diabetes Care. 2001; 24: 1498-1499Crossref PubMed Scopus (52) Google Scholar [Oji-Cree Indians]; Tsai et al. Tsai et al., 2001Tsai HJ Sun G Weeks DE Kaushal R Wolujewicz M McGarvey ST Tufa J Viali S Deka R Type 2 diabetes and three calpain-10 gene polymorphisms in Samoans: no evidence of association.Am J Hum Genet. 2001; 69: 1236-1244Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar [Samoan]; Xiang et al. Xiang et al., 2001Xiang K Fang Q Zheng T Jia W Wang Y Zhang R Li J Shen K [The impact of calpain-10 gene combined-SNP variation on type 2 diabetes mellitus and its related metabolic traits].Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2001; 18: 426-430PubMed Google Scholar [Chinese]; Daimon et al. Daimon et al., 2002Daimon M Oizumi T Saitoh T Kameda W Yamaguchi H Ohnuma H Igarashi M Manaka H Kato T Calpain 10 gene polymorphisms are related, not to type 2 diabetes, but to increased serum cholesterol in Japanese.Diabetes Res Clin Pract. 2002; 56: 147-152Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar [Japanese]; Elbein et al. Elbein et al., 2002Elbein SC Chu W Ren Q Hemphill C Schay J Cox NJ Hanis CL Hasstedt SJ Role of calpain-10 gene variants in familial type 2 diabetes in Caucasians.J Clin Endocrinol Metab. 2002; 87: 650-654Crossref PubMed Scopus (74) Google Scholar [whites from Utah]; Fingerlin et al. Fingerlin et al., 2002Fingerlin 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 Variation in three single nucleotide polymorphisms in the calpain-10 gene not associated with type 2 diabetes in a large Finnish cohort.Diabetes. 2002; 51: 1644-1648Crossref PubMed Scopus (62) Google Scholar [Finnish]; Rasmussen et al. Rasmussen et al., 2002Rasmussen SK Urhammer SA Berglund L Jensen JN Hansen L Echwald SM Borch-Johnsen K Horikawa Y Mashima H Lithell H Cox NJ Hansen T Bell GI Pedersen O 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. 2002; 51: 3561-3567Crossref PubMed Scopus (69) Google Scholar [Danish and Swedish]; Horikawa et al. Horikawa et al., 2003Horikawa Y Oda N Yu L Imamura S Fujiwara K Makino M Seino Y Itoh M Takeda J Genetic variations in calpain-10 gene are not a major factor in the occurrence of type 2 diabetes in Japanese.J Clin Endocrinol Metab. 2003; 88: 244-247Crossref PubMed Scopus (58) Google Scholar [Japanese]). We previously reported that another variant, SNP-44 (designated "CAPN10-g4841T→C"; minor allele frequency 16%), located in intron 3 and 11 bp from SNP-43, was independently associated with T2DM in whites from the United Kingdom (Evans et al. Evans et al., 2001Evans JC Frayling TM Cassell PG Saker PJ Hitman GA Walker M Levy JC et al.Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.Am J Hum Genet. 2001; 69: 544-552Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). Further studies have provided tentative support for a role of SNP-44 in T2DM and related traits: associations with polycystic ovary syndrome (Gonzalez et al. Gonzalez et al., 2002Gonzalez A Abril E Roca A Aragon MJ Figueroa MJ Velarde P Royo JL Real LM Ruiz A Comment: CAPN10 alleles are associated with polycystic ovary syndrome.J Clin Endocrinol Metab. 2002; 87: 3971-3976Crossref PubMed Scopus (60) Google Scholar) and with measures of oral glucose tolerance (Wang et al. Wang et al., 2002Wang Y Xiang K Zheng T Jia W Shen K Li J [The UCSNP44 variation of calpain 10 gene on NIDDM1 locus and its impact on plasma glucose levels in type 2 diabetic patients].Zhonghua Yi Xue Za Zhi. 2002; 82: 613-616PubMed Google Scholar; Tschritter et al. Tschritter et al., 2003Tschritter O Fritsche A Shirkavand F Machicao F Haring H Stumvoll M Assessing the shape of the glucose curve during an oral glucose tolerance test.Diabetes Care. 2003; 26: 1026-1033Crossref PubMed Scopus (114) Google Scholar) have been reported. Functional studies suggest that SNP-44 is located in an enhancer element and might affect CAPN10 expression (Horikawa et al. Horikawa et al., 2000Horikawa Y Oda N Cox NJ Li X Orho-Melander M Hara M Hinokio Y Lindner TH Mashima H Schwarz PE del Bosque-Plata L 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 Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus.Nat Genet. 2000; 26: 163-175Crossref PubMed Scopus (1252) Google Scholar). Also, in the U.K., German, Japanese, and South Indian populations, SNP-44 is in perfect linkage disequilibrium (r2=1) with a missense mutation Thr504Ala (SNP-110) and two polymorphisms in the 5′-UTR (SNP-134 and SNP-135) (Evans et al. Evans et al., 2001Evans JC Frayling TM Cassell PG Saker PJ Hitman GA Walker M Levy JC et al.Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.Am J Hum Genet. 2001; 69: 544-552Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar; Cassell et al. Cassell et al., 2002Cassell PG Jackson AE North BV Evans JC Syndercombe-Court D Phillips C Ramachandran A Snehalatha C Gelding SV Vijayaravaghan S Curtis D Hitman GA Haplotype combinations of calpain 10 gene polymorphisms associate with increased risk of impaired glucose tolerance and type 2 diabetes in South Indians.Diabetes. 2002; 51: 1622-1628Crossref PubMed Scopus (67) Google Scholar; Y. Horikawa and P. E. Schwarz, unpublished data). To assess the association of SNP-44 with T2DM more comprehensively, we performed a meta-analysis of all published SNP-44/T2DM association study data. To identify all relevant published studies, we searched PubMed using the keywords "calpain 10," "diabetes," "44," "SNP 44," "CAPN10," and "type 2," in different combinations. When necessary, authors were contacted to obtain exact genotype numbers, so that precise odds ratios (ORs) from each study could be calculated. Our search identified 10 published case/control studies, consisting of 3,303 subjects. The studies were spread across a number of ethnic groups: British (three studies, Evans et al. Evans et al., 2001Evans JC Frayling TM Cassell PG Saker PJ Hitman GA Walker M Levy JC et al.Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.Am J Hum Genet. 2001; 69: 544-552Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar); Chinese (Wang et al. Wang et al., 2002Wang Y Xiang K Zheng T Jia W Shen K Li J [The UCSNP44 variation of calpain 10 gene on NIDDM1 locus and its impact on plasma glucose levels in type 2 diabetic patients].Zhonghua Yi Xue Za Zhi. 2002; 82: 613-616PubMed Google Scholar); Japanese (Daimon et al. Daimon et al., 2002Daimon M Oizumi T Saitoh T Kameda W Yamaguchi H Ohnuma H Igarashi M Manaka H Kato T Calpain 10 gene polymorphisms are related, not to type 2 diabetes, but to increased serum cholesterol in Japanese.Diabetes Res Clin Pract. 2002; 56: 147-152Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar; Horikawa et al. Horikawa et al., 2003Horikawa Y Oda N Yu L Imamura S Fujiwara K Makino M Seino Y Itoh M Takeda J Genetic variations in calpain-10 gene are not a major factor in the occurrence of type 2 diabetes in Japanese.J Clin Endocrinol Metab. 2003; 88: 244-247Crossref PubMed Scopus (58) Google Scholar); Finnish/Botnia (two studies, Orho-Melander et al. Orho-Melander et al., 2002Orho-Melander M Klannemark M Svensson MK Ridderstrale M Lindgren CM Groop L Variants in the calpain-10 gene predispose to insulin resistance and elevated free fatty acid levels.Diabetes. 2002; 51: 2658-2664Crossref PubMed Scopus (105) Google Scholar); South Indian (Cassell et al. Cassell et al., 2002Cassell PG Jackson AE North BV Evans JC Syndercombe-Court D Phillips C Ramachandran A Snehalatha C Gelding SV Vijayaravaghan S Curtis D Hitman GA Haplotype combinations of calpain 10 gene polymorphisms associate with increased risk of impaired glucose tolerance and type 2 diabetes in South Indians.Diabetes. 2002; 51: 1622-1628Crossref PubMed Scopus (67) Google Scholar); and Mexican American (Horikawa et al. Horikawa et al., 2000Horikawa Y Oda N Cox NJ Li X Orho-Melander M Hara M Hinokio Y Lindner TH Mashima H Schwarz PE del Bosque-Plata L 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 Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus.Nat Genet. 2000; 26: 163-175Crossref PubMed Scopus (1252) Google Scholar). The frequency of the T2DM-associated SNP-44 C allele (allele 2) ranged from 6% in Mexican Americans to 25% in the Botnia I control population. There was no evidence for OR heterogeneity (Q test P=.27), and, although these studies are only a small sample from the many existing T2DM genetic resources, a funnel-plot analysis (Egger et al. Egger et al., 1997Egger M Davey Smith G Schneider M Minder C Bias in meta-analysis detected by a simple, graphical test.Bmj. 1997; 315: 629-634Crossref PubMed Scopus (34429) Google Scholar) suggested an absence of publication bias (P=.44). A Mantel-Haenszel meta-analysis of these studies showed that the C allele was associated with increased risk of T2DM (OR 1.17 [1.02–1.34], P=.02). Three transmission/disequilibrium tests (TDT) had been performed (Evans et al. Evans et al., 2001Evans JC Frayling TM Cassell PG Saker PJ Hitman GA Walker M Levy JC et al.Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.Am J Hum Genet. 2001; 69: 544-552Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar; Cassell et al. Cassell et al., 2002Cassell PG Jackson AE North BV Evans JC Syndercombe-Court D Phillips C Ramachandran A Snehalatha C Gelding SV Vijayaravaghan S Curtis D Hitman GA Haplotype combinations of calpain 10 gene polymorphisms associate with increased risk of impaired glucose tolerance and type 2 diabetes in South Indians.Diabetes. 2002; 51: 1622-1628Crossref PubMed Scopus (67) Google Scholar; Orho-Melander et al. Orho-Melander et al., 2002Orho-Melander M Klannemark M Svensson MK Ridderstrale M Lindgren CM Groop L Variants in the calpain-10 gene predispose to insulin resistance and elevated free fatty acid levels.Diabetes. 2002; 51: 2658-2664Crossref PubMed Scopus (105) Google Scholar). The combined TDT results demonstrated that the C allele was significantly overtransmitted (117 transmitted vs. 77 not transmitted, P=.004) from heterozygous parents to diabetic offspring. Although this result cannot be considered independent replication, as proband data was included in the case/control meta-analysis from two of the TDT studies (Evans et al. Evans et al., 2001Evans JC Frayling TM Cassell PG Saker PJ Hitman GA Walker M Levy JC et al.Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.Am J Hum Genet. 2001; 69: 544-552Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar; Cassell et al. Cassell et al., 2002Cassell PG Jackson AE North BV Evans JC Syndercombe-Court D Phillips C Ramachandran A Snehalatha C Gelding SV Vijayaravaghan S Curtis D Hitman GA Haplotype combinations of calpain 10 gene polymorphisms associate with increased risk of impaired glucose tolerance and type 2 diabetes in South Indians.Diabetes. 2002; 51: 1622-1628Crossref PubMed Scopus (67) Google Scholar), it provides evidence that the association is not due to population stratification. Of the 10 studies in the meta-analysis, only 1 reported a significant (P<.05) association (Evans et al. Evans et al., 2001Evans JC Frayling TM Cassell PG Saker PJ Hitman GA Walker M Levy JC et al.Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.Am J Hum Genet. 2001; 69: 544-552Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). However, these studies were small and the mean power to detect an OR of 1.17 at P<.05 was ∼11% (range 5%–14%). In the context of genetic association studies, which test many polymorphisms in numerous candidate genes, a P value of .02 can only be considered evidence suggestive of a real association. We therefore genotyped SNP-44 in an additional 4,213 subjects: 3,274 white European subjects from four case/control studies (one British, two German, and one Czech); 691 Japanese subjects from two case/control studies; and 248 Mexican (mestizo) subjects from Mexico City and Orizaba City from one case/control study. Overall, this provided 2,056 subjects with T2DM and 2,157 controls, and a power of ∼80% to detect an OR of 1.17. Clinical details of the study subjects are presented in table 1; further details are available as supplementary information from the authors. All studies were approved by the relevant ethics committee, and all subjects gave their informed consent.Table 1Clinical Characteristics of Subjects in StudyFinding in StudyUK4German1German2CzechJapanese3Japanese4Mexican (Mestizo)CharacteristicControl EFSaEFS=Exeter Family Study.Control ECACCbECACC=European Collection of Cell Cultures.W2 T2DcW2 T2D=Warren 2 Type 2 Diabetes Collection. ProbandsYT2DdYT2D=Young-Onset Type 2 Diabetes Collection.ControlT2DMControlT2DMControlT2DMControlT2DMControlT2DMControlT2DMSNP-44 minor allele frequency.16.16.20.19.11.14.16.17.l2.14.09.06.12.14.04.09N [% males]994 [50]335 [56]399 [54]297 [55]73 [35]308 [38]235 [56]244 [59]110 [69]279 [36]206 [67]206 [59]90 [33]189 [57]114 [50]134 [42]Average age±SD (years)32.5±5.5NA70.6±8.6NA50.8±11.961.8±11.365±5.465.0±5.118.1±2.358.5±7.467.9±5.559.1±13.068.2±5.861.7±12.849.9±14.455.1±9.8Age at diagnosis±SD (years)NANA55.2±8.540.5±10.0NA49.2±12.4NANANA49.6±8.7NA45.8±12.8NA50.3±12.9NA44.8±7.5BMI (kg/m2)±SD26.7±3.8eMales only, as females were pregnant.NA28.9±5.430.9±4.524.9±4.428.7±4.827.5±3.831.0±4.724.3±4.030.1±5.323.0±2.523.5±3.623.0±2.923.7±4.726.5±3.827.4±4.1% Receiving treatment: DietNANA169NA13NA56NA26NA20NA12NANA OHAfOHA=oral hypoglycemia agents.NANA7038NA33NA28NA58NA40NA53NANA InsulinNANA1453NA53NA16NA16NA40NA35NANANote.—Continuous variables are presented as mean±SD. NA=not applicable or not available.a EFS=Exeter Family Study.b ECACC=European Collection of Cell Cultures.c W2 T2D=Warren 2 Type 2 Diabetes Collection.d YT2D=Young-Onset Type 2 Diabetes Collection.e Males only, as females were pregnant.f OHA=oral hypoglycemia agents. Open table in a new tab Note.— Continuous variables are presented as mean±SD. NA=not applicable or not available. When all the studies were combined, there was no evidence for between-studies OR heterogeneity (Q test P=.23); a Mantel-Haenszel fixed-effects model was therefore used for subsequent analysis. Meta-analysis of the new studies gave an OR for the SNP-44 C allele of 1.18 (1.04–1.34), P=.01 (fig. 1). A combined meta-analysis of all previously published data and our new data gave an OR of 1.17 (1.07–1.29), P=.0007. All study populations were in Hardy-Weinberg equilibrium except the T2DM cohort of Horikawa et al. Horikawa et al., 2003Horikawa Y Oda N Yu L Imamura S Fujiwara K Makino M Seino Y Itoh M Takeda J Genetic variations in calpain-10 gene are not a major factor in the occurrence of type 2 diabetes in Japanese.J Clin Endocrinol Metab. 2003; 88: 244-247Crossref PubMed Scopus (58) Google Scholar (P=.005) and the control population of the third Japanese study (P=.02). Although these deviations may be due to random fluctuation and multiple-hypothesis testing, they contributed a large amount to heterogeneity (27% of the Q statistic); excluding these studies, the SNP-44 C allele OR for the new studies was 1.23 (1.07–1.40), P=.003; the overall OR was 1.19 (1.08–1.31), P=.0005. This OR is of similar magnitude to that of E23K (Gloyn et al. Gloyn et al., 2003Gloyn AL Weedon MN Owen KR Turner MJ Knight BA Hitman G Walker M Levy JC Sampson M Halford S McCarthy MI Hattersley AT Frayling TM Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes.Diabetes. 2003; 52: 568-572Crossref PubMed Scopus (622) Google Scholar; Love-Gregory et al. Love-Gregory et al., 2003Love-Gregory L Wasson J Lin J Skolnick G Suarez B Permutt MA E23K single nucleotide polymorphism in the islet ATP-sensitive potassium channel gene (Kir6.2) contributes as much to the risk of type II diabetes in Caucasians as the PPARγ Pro12Ala variant.Diabetologia. 2003; 46: 136-137PubMed Google Scholar; Nielsen et al. Nielsen et al., 2003Nielsen EM Hansen L Carstensen B Echwald SM Drivsholm T Glumer C Thorsteinsson B Borch-Johnsen K Hansen T Pedersen O The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes.Diabetes. 2003; 52: 573-577Crossref PubMed Scopus (238) Google Scholar) and Pro12Ala (Altshuler et al. Altshuler et al., 2000Altshuler D Hirschhorn JN Klannemark M Lindgren CM Vohl M-C Nemesh J Lane CR Schaffner F Bolk S Brewer C Tuomi T Gaudet D Hudson TJ Daly M Groop L Lander ES The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes.Nat Genet. 2000; 26: 76-80Crossref PubMed Scopus (122) Google Scholar), the other common variants confirmed as T2DM-susceptibility polymorphisms. An OR of 1.17 is low and may help explain why there is little evidence for linkage of the CAPN10 region to T2DM in most populations. The haplotypes responsible for the CAPN10 linkage seen in the Mexican American population were associated with a higher T2DM OR (∼3.0) and were more likely to be detected by linkage analysis (Horikawa et al. Horikawa et al., 2000Horikawa Y Oda N Cox NJ Li X Orho-Melander M Hara M Hinokio Y Lindner TH Mashima H Schwarz PE del Bosque-Plata L 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 Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus.Nat Genet. 2000; 26: 163-175Crossref PubMed Scopus (1252) Google Scholar). These haplotypes are less common in other populations. SNP-44 is in perfect linkage disequilibrium (r2=1) with the missense mutation, Thr504Ala, and two SNPs (SNP-134 and SNP-135) in the 5′-UTR and therefore may not be the causal variant. Further haplotype and functional analyses are required to confirm which of these polymorphisms contribute to T2DM susceptibility. In conclusion, our results have confirmed that a CAPN10 haplotype defined by the SNP-44 polymorphism predisposes to T2DM. Meta-analyses of published genetic associations, combined with large replication studies, are a powerful approach to detecting susceptibility variants in common disease. This work was principally funded by Diabetes UK and the Warren 2 bequest. The funding for the Exeter Family Study of Childhood was provided by the South and West NHS Research Directorate for the UK4 normal population samples. This work was also supported by the Technical University, Dresden, funding grant MeDDrive and by the KORA study group: A. Döring, H. Löwel, C. Meisinger, B. Thorand, H. E. Wichmann (GSF National Research Center for Environment and Health, Institute of Epidemiology), and J. John (GSF National Research Center for Environment and Health, Institute of Health Economics and Health Care Management). Grants from the German National Genome Research Net (NGFN) platform 6 and from the GSF Research Center, as well as United States Public Health Service grants DK-20595 and DK-47486, also supported this work. T.M.F. is a career scientist of the South and West NHS Research Directorate. A.T.H. is a Wellcome Trust Career Leave Research Fellow. Accession numbers and URLs for data presented herein are as follows: Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for calpain-10, KCNJ11, and PPARγ) PubMed, http://www.ncbi.nlm.nih.gov/PubMed/
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