Our findings demonstrate that common variation at influences acute responses to both glipizide and metformin in people without diabetes and highlight altered incretin signaling as a potential mechanism by which variation increases T2D risk.
The prevalence in youth of T2D, once thought to be exclusively a disease of adults, has increased by over 35% since 2001. Youth with T2D tend to have higher rates of complications, more aggressive disease, with more rapid loss of beta-cell function and a less favorable response to treatment than adults. Obesity is the most important risk factor for T2D, and the rise in childhood overweight and obesity appears responsible for the dramatic increase in T2D in youth. However, some obese children do not develop T2D, consistent with genetic differences in susceptibility to the disease in the setting of obesity and insulin resistance, currently far less well characterized in youth than in adults. Recent studies have begun to show associations of several established adult T2D genetic risk variants with youth-onset T2D and related glycemic quantitative traits, including the strongest known cross-population T2D genetic contributor TCF7L2. Maturity-onset diabetes of the young (MODY), a diabetes subtype distinct from type 1 diabetes (T1D) and T2D, is now known to result from a highly penetrant gene mutation in one of several genes. MODY has been shown to account for or contribute to at least 4.5% of clinically diagnosed T2D, even among those who are overweight or obese, impacting treatment decisions. The recently formed ProDiGY (Progress in Diabetes Genetics in Youth) Consortium is using genome-wide association studies and whole exome sequencing to understand the genetic architecture of T2D in youth, including how it differs from that of adults. The limited amount of research conducted to date on the genetics of youth-onset T2D, which tends to be a more aggressive disease than adult T2D, suggests some overlap with genes involved in adult T2D and a sizeable influence of highly penetrant monogenic diabetes variants. The ProDiGY Consortium is expected to provide a more comprehensive understanding of youth T2D genetics.
The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multiethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth case subjects with type 2 diabetes (mean age 15.1 6 2.9 years) and 6,061 diabetes-free adult control subjects (mean age 54.2 6 12.4 years). After stratifying by principal componentclustered ethnicity, we performed association analyses on ∼10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified seven genome-wide significant loci, including the novel locus rs10992863 in PHF2 (P 5 3.2 3 10 28 ; odds ratio [OR] 5 1.23). Known loci identified in our analysis include rs7903146 in TCF7L2 (
The prevalence of type 2 diabetes in youth has
increased substantially, yet the genetic underpinnings remain largely
unexplored. To identify genetic variants predisposing to youth-onset type 2
diabetes, we formed ProDiGY, a multi-ethnic collaboration of three studies (TODAY,
SEARCH, and T2D-GENES) with 3,006 youth type 2 diabetes cases (mean age
15.1±2.9 y) and 6,061 diabetes-free adult controls (mean age 54.2±12.4 y). After stratifying by principal
component-clustered ethnicity, we performed association analyses on ~10 million
imputed variants using a generalized linear mixed model incorporating a genetic
relationship matrix to account for population structure and adjusting for sex. We
identified 7 genome-wide significant loci, including the novel locus rs10992863
in <i>PHF2 </i>(<i>P</i>=3.2´10<sup>-8</sup>,
odds ratio [OR]=1.23). Known loci identified in our analysis include rs7903146 in
<i>TCF7L2 </i>(<i>P</i>=8.0´10<sup>-20</sup>,
OR 1.58), rs72982988 near <i>MC4R </i>(<i>P</i>=4.4´10<sup>-14</sup>, OR=1.53), rs200893788 in <i>CDC123</i> (<i>P</i>=1.1´10<sup>-12</sup>,
OR= 1.32), rs2237892 in <i>KCNQ1</i> (<i>P</i>=4.8´10<sup>-11</sup>, OR=1.59), rs937589119 in <i>IGF2BP2</i> (<i>P</i>=3.1´10<sup>-9</sup>,
OR=1.34) and rs113748381 in <i>SLC16A11 </i>(<i>P</i>=4.1´10<sup>-8</sup>, OR=1.04). Secondary analysis with 856
diabetes-free youth controls uncovered an additional locus in <i>CPEB2</i> (<i>P</i>=3.2´10<sup>-8</sup>,
OR=2.1) and consistent direction of effect for diabetes risk. In conclusion, we
identified both known and novel loci in the first genome wide association study
(GWAS) of youth-onset type 2 diabetes.
Context
There is substantial heterogeneity in insulin sensitivity, and genetics may suggest possible mechanisms by which common variants influence this trait.
Objectives
We aimed to evaluate an 11-variant polygenic lipodystrophy genetic risk score (GRS) for association with anthropometric, glycemic and metabolic traits in the Diabetes Prevention Program (DPP). In secondary analyses, we tested the association of the GRS with cardiovascular risk factors in the DPP.
Design
In 2713 DPP participants, we evaluated a validated GRS of 11 common variants associated with fasting insulin-based measures of insulin sensitivity discovered through genome-wide association studies that cluster with a metabolic profile of lipodystrophy, conferring high metabolic risk despite low body mass index (BMI).
Results
At baseline, a higher polygenic lipodystrophy GRS was associated with lower weight, BMI, and waist circumference measurements, but with worse insulin sensitivity index (ISI) values. Despite starting at a lower weight and BMI, a higher GRS was associated with less weight and BMI reduction at one year and less improvement in ISI after adjusting for baseline values but was not associated with diabetes incidence. A higher GRS was also associated with more atherogenic low-density lipoprotein peak-particle-density at baseline but was not associated with coronary artery calcium scores in the Diabetes Prevention Program Outcomes Study.
Conclusions
In the DPP, a higher polygenic lipodystrophy GRS for insulin resistance with lower BMI was associated with diminished improvement in insulin sensitivity and potential higher cardiovascular disease risk. This GRS helps characterize insulin resistance in a cohort of individuals at high risk for diabetes, independent of adiposity.
<p>Objective:
Maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type
1 or type 2 diabetes. Correct diagnosis may result in a change in clinical
treatment and impacts prediction of complications and familial risk. In this
study, we aimed to assess the prevalence of MODY in multi-ethnic youth under
age 20 years with a clinical diagnosis of type 2 diabetes.</p>
<p> </p>
<p>Research
design and methods: We evaluated whole-exome sequence data of youth with a clinical diagnosis of type
2 diabetes. We considered participants
to have MODY if they carried a MODY gene variant classified as likely
pathogenic (LP) or pathogenic (P) according to current guidelines.</p>
<p> </p>
<p>Results:
93 of 3,333 participants (2.8%) carried an LP/P variant in <i>HNF4A </i>(16 participants)<i>, GCK </i>(23)<i>, HNF1A </i>(44), <i>PDX1</i> (5), <i>INS</i> (4), and <i>CEL</i> (1).
Compared with those with no LP/P variants, youth with MODY had a younger
age at diagnosis (12.9 ±
2.5 <i>vs</i> 13.6 ± 2.3 years, <i>P</i>=0.002) and lower fasting C-peptide
levels (3.0 ±
1.7 <i>vs</i> 4.7 ± 3.5 ng/mL, <i>P</i><0.0001). Youth with MODY were less likely to have
hypertension (6.9% <i>vs</i> 19.5%, <i>P</i>=0.007) and had higher HDL cholesterol
(43.8 <i>vs</i> 39.7 mg/dL, <i>P=</i>0.006). </p>
<p> </p>
Conclusions: By comprehensively sequencing the
coding regions of all MODY genes, we identified MODY in 2.8% of youth with
clinically diagnosed type 2 diabetes; importantly, in 89% (n=83) the specific
diagnosis would have changed clinical management. No clinical criterion reliably separated the
two groups. New tools are needed to find
ideal criteria to select individuals for genetic testing.
Under controlled conditions, pediatric endocrinologists and radiologists displayed nearly identical consistencies in reading bone ages. The GR atlas performed similarly to the GP atlas, except for an increased number of outliers, and might be suitable as a replacement for GP.
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