The influence of genetic variations in HHEX gene on insulin metabolism in the German MESYBEPO cohort.
BACKGROUND
In the present study, we aimed to validate the type 2 diabetes (T2DM) susceptibility alleles identified in the first genome-wide association study in the hematopoietically expressed homeobox protein (HHEX) gene region (rs1111875 and rs7923837). Furthermore, we investigated quantitative metabolic risk phenotypes of these two variants for association with three key components of the insulin metabolism: insulin secretion, insulin sensitivity and insulin degradation.


METHODS
Two HHEX polymorphisms were genotyped in 1026 subjects from the German MESYBEPO cohort. Complete OGTT data were available for a subset of 420 with normal glucose tolerance (NGT), 282 with impaired glucose tolerance/impaired fasting glucose (IGT/IFG) and 146 diabetic subjects.


RESULTS
We validated association of both HHEX polymorphisms with T2DM. In the non-diabetic subcohort including NGT and IFG/IGT subjects, the risk alleles of rs7923837 and rs1111875 were significantly associated with decreased first and second phases of insulin secretion and lower insulinogenic index after oral glucose loading. In healthy, normal glucose-tolerant subjects, the same association of HHEX SNP rs1111875 with OGTT-derived phases of insulin secretion were detectable, however, rs7923837 was only weakly associated with reduced insulinogenic index. For both polymorphisms, no significant correlations with insulin sensitivity were obtained. Reduced insulin clearance was also observed in heterozygous carriers of rs1111875.


CONCLUSIONS
We validated the association of polymorphisms of the HHEX gene with T2DM in the MESYBEPO cohort. Importantly, variations within the HHEX gene conferred the impaired insulin secretion and changes of insulin degradation but no alteration in insulin sensitivity in carriers of risk alleles.
Pivovarova
Olga
O
Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam, Germany. olga.pivovarova@dife.de
Nikiforova
Victoria J
VJ
Pfeiffer
Andreas F H
AF
Rudovich
Natalia
N
D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D005858:Germany; D018149:Glucose Intolerance / Q000235:genetics; D005951:Glucose Tolerance Test; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D014157:Transcription Factors / Q000235:genetics*
C078492:HHEX protein, human; D018398:Homeodomain Proteins; D007328:Insulin; D014157:Transcription Factors