Effect of Common Genetic Variants of Growth Arrest-Specific 6 Gene on Insulin Resistance, Obesity and Type 2 Diabetes in an Asian Population.
OBJECTIVE
Growth arrest-specific 6 (Gas6), a vitamin K-dependent protein, has been implicated in systemic inflammation, obesity, and insulin resistance (IR). Data from recent studies suggest that polymorphisms in the Gas6 gene are associated with cardiovascular disorders and type 2 diabetes (T2D). However, the association of Gas6 gene variants with obesity, IR, and T2D development has not been explored.


METHODS
Four common single nucleotide polymorphisms (SNPs) in the Gas6 gene were genotyped in 984 participants from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family cohort. An insulin suppression test was performed to determine IR based on steady-state plasma glucose (SSPG). Associations between IR indices and obesity, and SNP genotypes, based on previously-reported data for this cohort (Phase I), were analyzed. In the present follow-up study (Phase II), the effects of gene variants of Gas6 on the progression to T2D were explored in individuals who were free of T2D in Phase I. The mean follow-up period for Phase II was 5.7 years.


RESULTS
The mean age of the study population in Phase I was 49.5 years and 16.7% of individuals developed T2D during follow-up. After adjusting for covariates, three SNPs (rs8191973, rs8197974, and rs7323932) were found to be associated with SSPG levels (p = 0.007, p = 0.03, and p = 0.011, respectively). This association remained significant after multiple testing and showed a significant interaction with physical activity for SNP rs8191973. However, no other significant correlations were observed between Gas6 polymorphisms and other indices of IR or obesity. A specific haplotype, AACG (from rs8191974, rs7323932, rs7331124, and rs8191973), was positively associated with SSPG levels (p = 0.0098). None of the polymorphisms were associated with an increased risk of T2D development.


CONCLUSIONS
Our results suggest that Gas6 gene variants are associated with IR, although their effects on subsequent progression to T2D were minimal in this prospective Asian cohort.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Chang-Hsun
CH
Hsieh
Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences National Health Research Institutes, Miaoli Country, Taiwan.
Ren-Hua
RH
Chung
Department of Medical Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan.
Wen-Jane
WJ
Lee
Institute of Public Health, National Yang-Ming University, Taipei, Taiwan, and Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.
Ming-Wei
MW
Lin
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, and Graduate Institute of Preventive Medicine, National Taiwan University School of Public Health, Taipei, Taiwan.
Lee-Ming
LM
Chuang
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America; Stanford Cardiovascular Institute, Stanford University, Stanford, California, United States of America.
Thomas
T
Quertermous
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America; Stanford Cardiovascular Institute, Stanford University, Stanford, California, United States of America.
Themistocles
T
Assimes
Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Yi-Jen
YJ
Hung
Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences National Health Research Institutes, Miaoli Country, Taiwan.
Ya-Wen
YW
Yu
D044466:Asian People / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D000099255:Growth Arrest-Specific Protein 6