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Identification and Functional Analysis of Glycemic Trait Loci in the China Health and Nutrition Survey

Citation

Spracklen, Cassandra N.; Shi, Jinxiu; Vadlamudi, Swarooparani; Wu, Ying; Zou, Meng; Raulerson, Chelsea K.; Davis, James P.; Zeynalzadeh, Monica; Jackson, Kayla; & Yuan, Wentao, et al. (2018). Identification and Functional Analysis of Glycemic Trait Loci in the China Health and Nutrition Survey. PLOS Genetics, 14(4), 1007275. PMCID: PMC5886383

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.

URL

http://dx.doi.org/10.1371/journal.pgen.1007275

Reference Type

Journal Article

Year Published

2018

Journal Title

PLOS Genetics

Author(s)

Spracklen, Cassandra N.
Shi, Jinxiu
Vadlamudi, Swarooparani
Wu, Ying
Zou, Meng
Raulerson, Chelsea K.
Davis, James P.
Zeynalzadeh, Monica
Jackson, Kayla
Yuan, Wentao
Wang, Haifeng
Shou, Weihua
Wang, Ying
Luo, Jingchun
Lange, Leslie A.
Lange, Ethan M.
Popkin, Barry M.
Gordon-Larsen, Penny
Du, Shufa
Huang, Wei
Mohlke, Karen L.

PMCID

PMC5886383