Transcription factor 7-like 2 polymorphisms and type 2 diabetes, glucose homeostasis traits and gene expression in US participants of European and African descent.
OBJECTIVE
We sought to determine: (1) the role of previously described transcription factor 7-like 2 (TCF7L2) variants in type 2 diabetes in African American individuals and in participants of European ancestry; (2) the physiological impact of these variants on glucose homeostasis; and (3) whether the non-coding variants altered TCF7L2 expression in adipocytes and transformed lymphocytes.


METHODS
Association studies were conducted by genotyping 932 Europid and African American diabetic and control participants. Family studies were conducted in 673 members of 68 Europid families ascertained for at least two diabetic siblings. Metabolic studies were conducted in 585 non-diabetic individuals who had undergone frequently sampled intravenous glucose tolerance tests to determine insulin sensitivity and insulin secretion. Gene expression studies were conducted in 74 adipose samples and 64 muscle samples from non-diabetic individuals with known genotypes and also in 55 lymphoblastoid cell lines.


RESULTS
TCF7L2 variants were associated with type 2 diabetes in a Europid case-control population and in families, but not in African Americans. Risk alleles increased the 60 min post-challenge glucose value in Europid families and reduced insulin sensitivity by 45% in Europids, but did not alter insulin secretion. TCF7L2 expression was not altered by genotype and did not correlate with insulin sensitivity or BMI.


CONCLUSIONS
We confirmed TCF7L2 as a risk factor in a population of European descent, where it reduced glucose tolerance and insulin sensitivity, but not insulin secretion. We found no role in African Americans and could not explain the association by altered adipocyte or muscle gene expression.
Elbein
S C
SC
Endocrine Section, Medicine and Research Services, Central Arkansas Veterans Healthcare System, John L. McClellan Memorial Veterans Hospital, 4700 W. 7th Street, Little Rock, AR 72205, USA. elbeinstevenc@uams.edu
Chu
W S
WS
Das
S K
SK
Yao-Borengasser
A
A
Hasstedt
S J
SJ
Wang
H
H
Rasouli
N
N
Kern
P A
PA
D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005838:Genotype; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein; D044465:White People / Q000235:genetics
D001786:Blood Glucose; D007328:Insulin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D005947:Glucose