Variation in the calpain-10 gene (CAPN10 [MIM 605286]) was recently linked and associated with type 2 diabetes mellitus (T2DM) susceptibility (Horikawa et al. 2000). The initial linkage of T2DM to chromosome 2 was found in a population of Mexican Americans from Starr County, Texas (Hanis et al. 1996). 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. 2000). 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. 2000 [Pima Indian]; Cassell et al. 2002 [South Indian]; Garant et al. 2002 [African American]; Malecki et al. 2002 [Polish]; Orho-Melander et al. 2002 [Finnish/Botnia]), but not others (Evans et al. 2001 [British]; Hegele et al. 2001 [Oji-Cree Indians]; Tsai et al. 2001 [Samoan]; Xiang et al. 2001 [Chinese]; Daimon et al. 2002 [Japanese]; Elbein et al. 2002 [whites from Utah]; Fingerlin et al. 2002 [Finnish]; Rasmussen et al. 2002 [Danish and Swedish]; Horikawa et al. 2003 [Japanese]). We previously reported that another variant, SNP-44 (designated “CAPN10-g4841TrC”; 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. 2001). 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. 2002) and with measures of oral glucose tolerance (Wang et al. 2002; Tschritter et al. 2003) have been reported. Functional studies suggest that SNP-44 is located in an enhancer element and might affect CAPN10 expression (Horikawa et al. 2000). Also, in the UK, German, Japanese, and South Indian populations, SNP-44 is in perfect linkage disequilibrium () with a missense mu-2 r p 1 tation Thr504Ala (SNP-110) and two polymorphisms in the 5-UTR (SNP-134 and SNP-135)(Evans et al. 2001; Cassell et al. 2002; Y. Horikawa and PE Schwarz, unpublished data).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. 2001); Chinese (Wang et al. 2002); Japanese (Daimon et al. 2002; Horikawa et al. 2003); Finnish/Botnia (two studies, Orho-Melander et al. 2002); South Indian (Cassell et al. 2002); and Mexican American (Horikawa et al. 2000). 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), and, although these studies are only a small P p. 27 sample from the many existing T2DM genetic resources, a funnel-plot analysis (Egger et al. 1997) suggested an absence of publication bias (). A Mantel-Haen-P p. 44 szel 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 p. 02 …