Genome-wide search for type 2 diabetes/impaired glucose homeostasis susceptibility genes in the Chinese: significant linkage to chromosome 6q21-q23 and chromosome 1q21-q24.

This genome-wide search for susceptibility genes to type 2 diabetes/impaired glucose homeostasis (IGH) was performed on a relatively homogeneous Chinese sample with a total number of 257 pedigrees and 385 affected sibpairs. Two regions showed significant linkage to type 2 diabetes/IGH in the Chinese. The region showing linkage to type 2 diabetes/IGH from the entire sample group analysis was located on chromosome 6q21-q23 (128.93 cM, 1-LOD [logarithm of odds] support interval between 124 and 142 cM, according to the Marshfield genetic map), with a maximum likelihood score of 6.23, a nonparametric linkage (all) score of 4.48, and empirical P value <0.001. With a subanalysis based on 101 affected sibpairs with age at diagnosis of type 2 diabetes/IGH <40 years, we detected significant evidence for linkage to chromosome 1q21-q24 (192.1 cM, 1-LOD support interval between 182 and 197 cM), with a maximum likelihood score of 8.91, a nonparametric linkage (all) score of 5.70, and empirical P value <0.001. No interaction was observed between these two regions. Our independent replication of the region on chromosome 1q that has been shown to be linked significantly to type 2 diabetes/IGH in Chinese supports the notion that gene(s) in this region may be universally important in the development of human type 2 diabetes.

[The UCSNP44 variation of calpain 10 gene on NIDDM1 locus and its impact on plasma glucose levels in type 2 diabetic patients].

OBJECTIVE: To study the contribution of single nucleotide polymorphism-UCSNP44 at calpain-10 gene (CAPN-10) on NIDDM1 locus to type 2 diabetes mellitus (T2DM) in Chinese. METHODS: 276 Chinese living in Shanghai, 148 with normal glucose tolerance (NGT) and 128 with T2DM were given 75 g glucose. O, 30, 60, 120, and 180 minutes later their plasma glucose (PG), insulin (INS), C-peptide (CP), and free fatty acids (FFA) were measured and the areas under curve (AUC) were calculated. The islet beta-cell insulin secretion and tissue insulin sensitivity were estimated by formulae of homeostasis model assessment and increment ratio of insulin to glucose levels 30 minutes after glucose challenge. The CAPN-10 UCSNP44 as well as UCSNP43 were genotyped by automated DNA direct sequencing. RESULTS: (1) The major genotype of CAPN-10 UCSNP44 in persons with NGT was TT (with a frequency of 0.82); the major allele was T (0.91). The most frequent genotype combination between UCSNP44 and UCSNP43 was TT-GG (corresponding to haplotype combination TG/TG) (0.64). The most frequent haplotype was TG (0.80). The D value for linkage disequilibrium between UCSNP44 and UCSNP43 was -0.11. (2) The frequencies of UCSNP44 and UCSNP44/UCSNP43 haplotype combination did not differ significantly between subjects with NGT and those with T2DM. (3) The PG levels in T2DM subjects with UCSNP44 TT genotype both at fasting and after glucose challenge were statistically significantly higher than those in subjects with non-TT (TC + CC) genotype, especially the PG levels 0, 60, 120, and 180 minutes after glucose challenge (P = 0.036, 0.040, 0.020, and 0.017) and the PG-AUC (P = 0.013). The PG levels and PG-AUC 0 and 120 minutes after glucose challenge were still significant after adjusted with age, sex, and body mass index and waist circumference. Similar results were observed in comparison between the TG/TG and TG/CG subgroups of UCSNP44/UCSNP43 haplotype combination. In addition, T2DM subjects with UCSNP44 TT genotype had lower CP levels after glucose challenge than those with non-TT genotype. However, the difference became not statistically significant after adjusted with above-mentioned variables. CONCLUSION: The variation of CAPN-10 UCSNP44 has an impact on plasma glucose levels at fasting and after glucose challenge in subjects with type 2 diabetes. The relevant mechanism remains to be elucidated.