Genome-Wide Search for Type 2 Diabetes/Impaired Glucose Homeostasis Susceptibility Genes in the Chinese

Abstract

This genome-wide search for susceptibility genes to type 2 diabetes/impaired glucose homeostasis (IGH) was performed on a relatively homogenous 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. T ype 2 diabetes is a complex disease that develops in individuals with genetic susceptibility to impaired insulin secretion, as well as to impaired insulin sensitivity, in the presence of appropriate environmental factors, particularly those leading to obesity (1). Marked increases in the prevalence of type 2 diabetes occur in those societies or countries that have experienced tremendous economic development from a starting point of an impoverished economic base (2). Along with the economic development in China, nationwide surveys have revealed an increase in the prevalence of diabetes in the adult population from 0.9 to 2.4% over the years 1980 -1994 (3). In Shanghai, China, the prevalence of diabetes was only 1.0% in 1978 but had reached 9.8% by the turn of the last century, i.e., there has been a 10-fold increase within the last two decades in the Shanghai population alone (4,5).Genetic heterogeneity of type 2 diabetes has been suggested among ethnic groups (6). This may be one of the reasons for the different locations of susceptibility loci reported to be linked to type 2 diabetes among ethnic groups in genome-wide scans (7-22). In the large geographic area of China, 56 ethnic groups are officially recognized, the Han being the largest. The Chinese of Han ethnicity reside throughout China, mostly in the eastern and central regions. Studies of the origin of the East Asian population revealed that, even within the Han ethnic group, considerable genetic heterogeneity might exist according to geographical location (23)(24)(25). Because appropriate definition of a more homogenous sample set is one of the issues for a genome-wide screen for type 2 diabetes susceptibility genes, geographical genetic heterogeneity should be considered when conducting such a study on the Chinese population. Thus, the genome-wide screen reported in this study was performed with Chinese pedigrees recruited from a limited geographic area in China. RESEARCH DESIGN AND METHODSPedigrees for this study were selected from a sampling scheme for the collection of multiplex diabetic families aimed at the genetic studies of type 2 Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org. ASP, affected sibpair; IA-2, protein tyrosine phosphatase-like protein; IGH, impaired glucose homeostasis; LOD, logarithm of odds; MLS, maximum likelihood score; MODY, maturity-onset diabetes of the young; NPL, nonparametric linkage.

Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects

“…The involvement of PC-1 in insulin-resistant states is further supported by recent studies revealing evidence for linkage between the chromosomal region 6q22-q23 of the gene encoding PC-1 (ENPP1) and insulin resistance [9], obesity [10,11] and type 2 diabetes [12][13][14][15]. Furthermore, the minor Q allele of a K121Q variant (rs1044498) of ENPP1 has been shown to influence PC-1 protein function by inhibiting insulin receptor function and insulin signalling more effectively than the major K allele [16,17].…”

The ENPP1 K121Q polymorphism is not associated with type 2 diabetes or obesity in the Chinese Han population

“…[1][2] Genetic and genome-wide association studies in recent decades have identified many different candidate genes that are related to susceptibility in various populations. [3][4][5] The ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene, also known as plasma cell membrane glycoprotein 1, localizes on chromosome 6q23.2, a region that has been reported to be being linked to obesity, 6 serum insulin levels 7 and T2D 8,9 in different populations. ENPP1 encodes for a type II transmembrane glycoprotein that inhibits insulin receptor (IR) tyrosine kinase activity 10 and subsequent insulin signaling by a likely direct interaction with the a-subunit of IR.…”

Variation in the Lamin A/C Gene

“…20 This region is approximately 160 to 180 cM from p-telomere and corresponds to a region of chromosome 1 that has been linked to T2DM in several other populations, including Pima Indians, 21 Utah Mormons, 22 British whites, 23 French whites, 24 and Chinese. 25 Familial partial lipodystrophy is a condition associated with severe insulin resistance, diabetes, dyslipidemia, and atherosclerosis, 26 making LMNA an excellent positional candidate gene for metabolic syndrome, T2DM, and related traits. LMNA, located on chromosome 1q21.2, encodes a nuclear envelope protein that exists as a heterodimer of lamin A and lamin C and is expressed in several cell types including liver, fat, muscle, and pancreas.…”