Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.
Dimas AS., Lagou V., Barker A., Knowles JW., Mägi R., Hivert M-F., Benazzo A., Rybin D., Jackson AU., Stringham HM., Song C., Fischer-Rosinsky A., Boesgaard TW., Grarup N., Abbasi FA., Assimes TL., Hao K., Yang X., Lecoeur C., Barroso I., Bonnycastle LL., Böttcher Y., Bumpstead S., Chines PS., Erdos MR., Graessler J., Kovacs P., Morken MA., Narisu N., Payne F., Stancakova A., Swift AJ., Tönjes A., Bornstein SR., Cauchi S., Froguel P., Meyre D., Schwarz PEH., Häring H-U., Smith U., Boehnke M., Bergman RN., Collins FS., Mohlke KL., Tuomilehto J., Quertemous T., Lind L., Hansen T., Pedersen O., Walker M., Pfeiffer AFH., Spranger J., Stumvoll M., Meigs JB., Wareham NJ., Kuusisto J., Laakso M., Langenberg C., Dupuis J., Watanabe RM., Florez JC., Ingelsson E., McCarthy MI., Prokopenko I., MAGIC Investigators None.
Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.