Latino populations have one of the highest prevalences of type 2 diabetes worldwide.
To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a ...large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships.
Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14,276 participants and characterized in experimental assays.
Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function.
A single rare missense variant (c.1522G>A p.E508K) was associated with type 2 diabetes prevalence (odds ratio OR, 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10(-7)) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19).
Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.
Aims/hypothesis
Type 2 diabetes is highly polygenic and influenced by multiple biological pathways. Rapid expansion in the number of type 2 diabetes loci can be leveraged to identify such pathways.
...Methods
We developed a high-throughput pipeline to enable clustering of type 2 diabetes loci based on variant–trait associations. Our pipeline extracted summary statistics from genome-wide association studies (GWAS) for type 2 diabetes and related traits to generate a matrix of 323 variants × 64 trait associations and applied Bayesian non-negative matrix factorisation (bNMF) to identify genetic components of type 2 diabetes. Epigenomic enrichment analysis was performed in 28 cell types and single pancreatic cells. We generated cluster-specific polygenic scores and performed regression analysis in an independent cohort (
N
=25,419) to assess for clinical relevance.
Results
We identified ten clusters of genetic loci, recapturing the five from our prior analysis as well as novel clusters related to beta cell dysfunction, pronounced insulin secretion, and levels of alkaline phosphatase, lipoprotein A and sex hormone-binding globulin. Four clusters related to mechanisms of insulin deficiency, five to insulin resistance and one had an unclear mechanism. The clusters displayed tissue-specific epigenomic enrichment, notably with the two beta cell clusters differentially enriched in functional and stressed pancreatic beta cell states. Additionally, cluster-specific polygenic scores were differentially associated with patient clinical characteristics and outcomes. The pipeline was applied to coronary artery disease and chronic kidney disease, identifying multiple overlapping clusters with type 2 diabetes.
Conclusions/interpretation
Our approach stratifies type 2 diabetes loci into physiologically interpretable genetic clusters associated with distinct tissues and clinical outcomes. The pipeline allows for efficient updating as additional GWAS become available and can be readily applied to other conditions, facilitating clinical translation of GWAS findings. Software to perform this clustering pipeline is freely available.
Graphical abstract
To identify potential subtypes of type 2 diabetes (T2D) anchored in genetics but informed by physiology, we previously used a soft clustering method to cluster T2D single nucleotide variants (SNVs) ...by their associated metabolic traits. The resulting European-based clusters represent likely disease mechanistic pathways. However, ancestry-specific SNVs, phenotype characteristics and prevalence rates suggest that a portion of the T2D’s heterogeneity is population-based, requiring expansion of this work to non-European populations.
We created a semi-automated Bayesian non-negative matrix factorization (bNMF) pipeline to generate new ancestry-specific clusters in European (EUR, 390 SNVs), East Asian (EAS, 326 SNVs) and African (AFR, 172 SNVs), as well as trans-ancestry (TA, 498 SNVs), using up to 89 T2D-related traits. We validated the clusters by replicating their trait associations in the Mass General Brigham Biobank cohort (MGBB, N=62,252).
The new ancestry-specific and TA clusters captured previously identified clusters, as well as novel clusters related to possible mechanisms of insulin resistance. In the 11 TA clusters, 127/498 SNVs were from non-EUR T2D studies, with 87 SNVs not represented in the EUR clusters. In the non-European subset of MGBB (N=8,990), 8 of 10 TA cluster pPS were more strongly associated with T2D compared to the corresponding EUR cluster pPS. We assessed in MGBB whether the proportion of cumulative genetic risk attributed to each cluster differed between sub populations. A significantly higher proportion was attributed to the Lipodystrophy cluster in EAS, to the Obesity cluster in EUR, and to the Liver/Lipid cluster in AFR (all t-test P<10-15).
By expanding our previous clusters to include non-European SNVs, we were able to identify new genetic clusters and improve the predictive ability of cluster pPS. Our results suggest that polygenic processes contribute in different proportions across populations.
Disclosure
K.Smith: None. A.Manning: None. J.M.Mercader: None. M.Udler: None. H.Kim: None. K.E.Westerman: None. S.Hsu: None. R.Mandla: None. P.H.Schroeder: None. T.Majarian: Employee; Vertex Pharmaceuticals Incorporated. V.Kaur: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc.
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R03DK131249)
The Middle to Later Stone Age transition in Africa has been debated as a significant shift in human technological, cultural, and cognitive evolution. However, the majority of research on this ...transition is currently focused on southern Africa due to a lack of long-term, stratified sites across much of the African continent. Here, we report a 78,000-year-long archeological record from Panga ya Saidi, a cave in the humid coastal forest of Kenya. Following a shift in toolkits ~67,000 years ago, novel symbolic and technological behaviors assemble in a non-unilinear manner. Against a backdrop of a persistent tropical forest-grassland ecotone, localized innovations better characterize the Late Pleistocene of this part of East Africa than alternative emphases on dramatic revolutions or migrations.
Naringenin and hesperetin are two of the most abundant flavanones found in citrus with beneficial effects on human health. However, their poor water solubility imposes considerable limitations to ...their use in functional foods or nutraceuticals development. In order to increase their aqueous solubility and find a new stable system, the effect of different factors as temperature, pH or complexation agents as cyclodextrins has been studied. The solubility of both flavanones increased exponentially with temperature (25–90 °C): 10-fold in the case of naringenin and 20-fold for hesperetin. The solubility of both flavanones also increased with the media pH (3.5–8.5): 314-fold in the case of naringenin and 3.5-fold for hesperetin. Flavanones solubility also increased with β- or HP-β-CDs concentration. By the addition of β-CDs 13 mM naringenin solubility increased 9.3-fold and hesperetin solubility 30-fold. Using HP-β-CDs 100 mM naringenin solubility increased 143-fold and hesperetin 467-fold. In summary, the higher increase in naringenin solubility was reached by increasing pH up 8.5. However, in the case of hesperetin, the higher increase was obtained by complexation with HP-β-CDs 100 mM. Moreover, the presence of CDs, not only increased the aqueous solubility of flavanones, but also improved the stability of hesperetin at pHs 3.5 and 6.5.
•Effect of temperature on aqueous solubility of flavanones.•Effect of pH in the complexation and solubility of flavanones.•Effect of CDs on aqueous solubility of flavanones.•Stability of naringenin and hesperetin in the presence of cyclodextrins at different pHs.
Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D ...prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D.
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•The T2D-risk haplotype contains a cis-eQTL for lower SLC16A11 expression in liver•T2D-risk variants disrupt a SLC16A11-BSG interaction and cell-surface localization•Reduced SLC16A11 induces metabolic changes associated with increased T2D risk•Therapeutics that enhance SLC16A11 levels or activity may be beneficial for T2D
Genetic variants associated with type 2 diabetes impair function of a monocarboxylate transporter that in turn impacts the metabolic state of the cell.
Cloquet's node, located at the junction between the deep inguinal nodes and the external iliac chain, is easily accessible and commonly excised during pelvic lymph node dissection for prostate ...cancer. However, we hypothesize that Cloquet's node is not part of lymphatic metastatic spread of prostate cancer.
Between September 2016 and June 2019, 105 consecutive patients with high-risk prostate cancer (cT3a or Grade Group 4/5, or prostate specific antigen >20 ng/ml) underwent a laparoscopic radical prostatectomy and pelvic lymph node dissection. First, Cloquet's node was identified, retrieved and submitted separately to pathology as right and left Cloquet's node. Next, a pelvic lymph node dissection was completed including the external iliac, obturator fossa and hypogastric nodal packets. Each lymph node was cut into 3 mm slices which were separately embedded in paraffin, stained with hematoxylin and eosin, and examined microscopically.
The final analysis included 95 patients. In this high-risk population, the median number of nodes removed was 22 (IQR 18-29); 39/95 patients (41%) had lymph node metastasis. The median number of Cloquet's nodes removed was 2 (IQR 2-3). Cloquet's node was negative in all but 1 patient (1.1%), who had very high-risk features and high metastatic burden in the lymph nodes.
In high-risk prostate cancer, metastasis to the ilioinguinal node of Cloquet is rare. Given this low prevalence, Cloquet's node can be safely excluded from the pelvic lymph node dissection template.
The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes ...(T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches.
Type 2 diabetes (T2D) is a multifactorial disease with substantial genetic risk, for which the underlying biological mechanisms are not fully understood. In this study, we identified multi-ancestry ...T2D genetic clusters by analyzing genetic data from diverse populations in 37 published T2D genome-wide association studies representing more than 1.4 million individuals. We implemented soft clustering with 650 T2D-associated genetic variants and 110 T2D-related traits, capturing known and novel T2D clusters with distinct cardiometabolic trait associations across two independent biobanks representing diverse genetic ancestral populations (African, n = 21,906; Admixed American, n = 14,410; East Asian, n =2,422; European, n = 90,093; and South Asian, n = 1,262). The 12 genetic clusters were enriched for specific single-cell regulatory regions. Several of the polygenic scores derived from the clusters differed in distribution among ancestry groups, including a significantly higher proportion of lipodystrophy-related polygenic risk in East Asian ancestry. T2D risk was equivalent at a body mass index (BMI) of 30 kg m
in the European subpopulation and 24.2 (22.9-25.5) kg m
in the East Asian subpopulation; after adjusting for cluster-specific genetic risk, the equivalent BMI threshold increased to 28.5 (27.1-30.0) kg m
in the East Asian group. Thus, these multi-ancestry T2D genetic clusters encompass a broader range of biological mechanisms and provide preliminary insights to explain ancestry-associated differences in T2D risk profiles.
Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack ...disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP’s comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.
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•Human genetic and genomic data offer valuable insights to diabetes research•The T2DKP aggregates and integrates multiple T2D-relevant data types•Defined workflows help non-geneticist researchers get started with the T2DKP•Interactive tools in the T2DKP allow genetic experts to do custom analyses
The Type 2 Diabetes Knowledge Portal (T2DKP) is an innovative resource that democratizes access to human genetic and genomic data. In this issue, Costanzo et al. describe how both novice and expert users can use the T2DKP in their research.
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