Abstract
Common
diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a
major risk factor for type 2 diabetes, but patients vary appreciably in body
mass index. We hypothesized that the genetic predisposition to the disease may
be different in lean (BMI<25 Kg/m2) compared to obese cases
(BMI≥30 Kg/m2). We performed two case-control genome-wide studies
using two accepted cut-offs for defining individuals as overweight or obese. We
used 2,112 lean type 2 diabetes cases (BMI<25 kg/m2) or 4,123
obese cases (BMI≥30 kg/m2), and 54,412 un-stratified controls.
Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957
un-stratified controls. To assess the effects of known signals, we tested the
individual and combined effects of SNPs representing 36 type 2 diabetes loci.
After combining data from discovery and replication datasets, we identified two
signals not previously reported in Europeans. A variant (rs8090011) in the
LAMA1 gene was associated with type 2 diabetes in lean cases (P =
8.4×10−9, OR = 1.13 [95% CI 1.09–1.18]), and this association was
stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00–1.06]). A
variant in HMG20A—previously identified in South Asians but not
Europeans—was associated with type 2 diabetes in obese cases (P =
1.3×10−8, OR = 1.11 [95% CI 1.07–1.15]), although this association
was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95%
CI 1.02–1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in
the lean compared to obese (binomial P = 0.0002). In the lean analysis, we
observed a weighted per-risk allele OR = 1.13 [95% CI 1.10–1.17], P =
3.2×10−14. This was larger than the same model fitted in the obese
analysis where the OR = 1.06 [95% CI 1.05–1.08], P = 2.2×10−16. This
study provides evidence that stratification of type 2 diabetes cases by BMI may
help identify additional risk variants and that lean cases may have a stronger
genetic predisposition to type 2 diabetes.
It's not only down to genetics!
ReplyDeleteI was diagnosed T2 after a very traumatic time which ended up on me being prescribed anti depressants, these with the stress ultimately I believe brought on my diagnosis. Prior to this there had been no history of diabetes in my family, my mother was diagnosed T2 at the age of 94 a full 2 years after me which is more an age related thing.
Graham