1. Identification and functional analysis of glycemic trait loci in the China Health and Nutrition Survey
- Author
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Penny Gordon-Larsen, Ying Wang, Ethan M. Lange, Shi Jinxiu, Shufa Du, Wentao Yuan, Meng Zou, Cassandra N. Spracklen, Leslie A. Lange, Chelsea K. Raulerson, Wei Huang, Karen L. Mohlke, Jingchun Luo, Haifeng Wang, Swarooparani Vadlamudi, Barry M. Popkin, Weihua Shou, James P. Davis, Ying Wu, Kayla Jackson, and Monica Zeynalzadeh
- Subjects
Blood Glucose ,Male ,0301 basic medicine ,Cancer Research ,Heredity ,Genome-wide association study ,QH426-470 ,Biochemistry ,Endocrinology ,Cell Signaling ,Medicine and Health Sciences ,Insulin ,Genetics (clinical) ,2. Zero hunger ,Genetics ,education.field_of_study ,Fasting ,Genomics ,Nutrition Surveys ,Type 2 Diabetes ,3. Good health ,Genetic Mapping ,Female ,Genomic Signal Processing ,Research Article ,Signal Transduction ,China ,Endocrine Disorders ,Quantitative Trait Loci ,Population ,Mutation, Missense ,Locus (genetics) ,Biology ,Quantitative trait locus ,Glucose Signaling ,Islets of Langerhans ,03 medical and health sciences ,Genome-Wide Association Studies ,Diabetes Mellitus ,Humans ,Allele ,education ,Molecular Biology ,Allele frequency ,Alleles ,Ecology, Evolution, Behavior and Systematics ,Glycemic ,Diabetic Endocrinology ,Biology and Life Sciences ,Computational Biology ,Human Genetics ,Cell Biology ,Genome Analysis ,Health Surveys ,Hormones ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Haplotypes ,Genetic Loci ,Metabolic Disorders ,Expression quantitative trait loci ,Genome-Wide Association Study - Abstract
To identify genetic contributions to type 2 diabetes (T2D) and related glycemic traits (fasting glucose, fasting insulin, and HbA1c), we conducted genome-wide association analyses (GWAS) in up to 7,178 Chinese subjects from nine provinces in the China Health and Nutrition Survey (CHNS). We examined patterns of population structure within CHNS and found that allele frequencies differed across provinces, consistent with genetic drift and population substructure. We further validated 32 previously described T2D- and glycemic trait-loci, including G6PC2 and SIX3-SIX2 associated with fasting glucose. At G6PC2, we replicated a known fasting glucose-associated variant (rs34177044) and identified a second signal (rs2232326), a low-frequency (4%), probably damaging missense variant (S324P). A variant within the lead fasting glucose-associated signal at SIX3-SIX2 co-localized with pancreatic islet expression quantitative trait loci (eQTL) for SIX3, SIX2, and three noncoding transcripts. To identify variants functionally responsible for the fasting glucose association at SIX3-SIX2, we tested five candidate variants for allelic differences in regulatory function. The rs12712928-C allele, associated with higher fasting glucose and lower transcript expression level, showed lower transcriptional activity in reporter assays and increased binding to GABP compared to the rs12712928-G, suggesting that rs12712928-C contributes to elevated fasting glucose levels by disrupting an islet enhancer, resulting in reduced gene expression. Taken together, these analyses identified multiple loci associated with glycemic traits across China, and suggest a regulatory mechanism at the SIX3-SIX2 fasting glucose GWAS locus., Author summary Type 2 diabetes risk and levels of glucose, insulin, and HbA1c are heritable traits correlated with risk of other diseases and mortality. To identify genetic variants associated with these traits, we studied up to 7,178 men and women from nine provinces in China. We found established variants that could affect fasting glucose located in or near genes named G6PC2 and SIX3. One of the variants at G6PC2 changes the protein sequence and is predicted to affect how the protein functions. Variants located near SIX3 that are associated with levels of glucose are also associated with levels of expression of the genes SIX3 and SIX2 in pancreatic islets. These variants are located in a genomic region predicted to enhance gene expression. We used laboratory assays to show that alleles at one variant, rs12712928, demonstrate significant differences in transcriptional activity, suggesting that this variant influences levels of the SIX3 and SIX2 genes in islets, ultimately increasing glucose levels.
- Published
- 2018