Haplotype Structure and Genotype-Phenotype Correlations of the Sulfonylurea Receptor and the Islet ATP-Sensitive Potassium
Channel Gene Region
Jose C. Florez 1 2 3 4 ,
Noël Burtt 3 ,
Paul I.W. de ...Bakker 1 3 5 ,
Peter Almgren 6 ,
Tiinamaija Tuomi 7 ,
Johan Holmkvist 6 ,
Daniel Gaudet 8 ,
Thomas J. Hudson 9 ,
Steve F. Schaffner 3 ,
Mark J. Daly 3 ,
Joel N. Hirschhorn 3 5 10 ,
Leif Groop 6 and
David Altshuler 1 2 3 4 5
1 Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
2 Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts
3 Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
4 Department of Medicine, Harvard Medical School, Boston, Massachusetts
5 Department of Genetics, Harvard Medical School, Boston, Massachusetts
6 Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden
7 Department of Medicine, Helsinki University Central Hospital and Folkhalsan Research Institute, Helsinki, Finland
8 University of Montreal Community Genomic Center, Chicoutimi Hospital, Quebec, Canada
9 McGill University and Genome Quebec Innovation Centre, Montreal, Canada
10 Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts
Leif Groop, Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden. E-mail: leif.groop{at}endo.mas.lu.se
Address correspondence and reprint requests to David Altshuler, Department of Molecular Biology, Massachusetts General Hospital,
Boston, MA 02114. E-mail: altshuler{at}molbio.mgh.harvard.edu
Abstract
The genes for the sulfonylurea receptor (SUR1; encoded by ABCC8 ) and its associated islet ATP-sensitive potassium channel (Kir6.2; encoded by KCNJ11 ) are adjacent to one another on human chromosome 11. Multiple studies have reported association of the E23K variant of Kir6.2
with risk of type 2 diabetes. Whether and how E23K itself—or other variant(s) in either of these two closely linked genes—influences
type 2 diabetes remains to be fully determined. To better understand genotype-phenotype correlation at this important candidate
gene locus, we 1 ) characterized haplotype structures across the gene region by typing 77 working, high-frequency markers spanning 207 kb and
both genes; 2 ) performed association studies of E23K and nearby markers in >3,400 patients (type 2 diabetes and control) not previously
reported in the literature; and 3 ) analyzed the resulting data for measures of insulin secretion. These data independently replicate the association of E23K
with type 2 diabetes with an odds ratio (OR) in the new data of 1.17 ( P = 0.003) as compared with an OR of 1.14 provided by meta-analysis of previously published, nonoverlapping data ( P = 0.0002). We find that the E23K variant in Kir6.2 demonstrates very strong allelic association with a coding variant (A1369S)
in the neighboring SUR1 gene ( r 2 > 0.9) across a range of population samples, making it difficult to distinguish which gene and polymorphism in this region
are most likely responsible for the reported association. We show that E23K is also associated with decreased insulin secretion
in glucose-tolerant control subjects, supporting a mechanism whereby β-cell dysfunction contributes to the common form of
type 2 diabetes. Like peroxisome proliferator–activated receptor γ, the SUR1/Kir6.2 gene region both contributes to the inherited
risk of type 2 diabetes and encodes proteins that are targets for hypoglycemic medications, providing an intriguing link between
the underlying mechanism of disease and validated targets for pharmacological treatment.
CEPH, Centre d’Etude du Polymorphisme Humain
ISI, insulin sensitivity index
LD, linkage disequilibrium
OGTT, oral glucose tolerance test
SNP, single-nucleotide polymorphism
SUR1, sulfonylurea receptor
TDT, transmission disequilibrium test
Footnotes
Additional information for this article can be found in an online appendix at http://www.diabetes.diabetesjournals.org .
L.G. and D.A. jointly supervised the project.
Accepted January 26, 2004.
Received January 12, 2004.
DIABETES
Evaluation of Common Variants in the Six Known Maturity-Onset Diabetes of the Young (MODY) Genes for Association With Type
2 Diabetes
Wendy Winckler 1 2 3 ,
Michael N. Weedon 4 ,
Robert R. Graham 1 2 ...3 ,
Steven A. McCarroll 1 2 3 ,
Shaun Purcell 3 ,
Peter Almgren 5 ,
Tiinamaija Tuomi 6 7 ,
Daniel Gaudet 8 ,
Kristina Bengtsson Boström 9 ,
Mark Walker 10 ,
Graham Hitman 11 ,
Andrew T. Hattersley 4 ,
Mark I. McCarthy 12 ,
Kristin G. Ardlie 13 ,
Joel N. Hirschhorn 2 3 14 ,
Mark J. Daly 3 ,
Timothy M. Frayling 4 ,
Leif Groop 5 and
David Altshuler 1 2 3 15 16
1 Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
2 Department of Genetics, Harvard Medical School, Boston, Massachusetts
3 Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard University,
Cambridge, Massachusetts
4 Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K
5 Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden
6 Department of Medicine, Helsinki University Central Hospital
7 Folkhalsan Genetic Institute, Folkhalsan Research Center and Research Program for Molecular Medicine, University of Helsinki,
Helsinki, Finland
8 University of Montreal Community Genomic Center, Chicoutimi Hospital, Quebec, Canada
9 Department of Clinical Science, University Hospital MAS, Lund University, Malmö, Sweden
10 Department of Medicine, School of Medicine, University of Newcastle, Newcastle Upon Tyne, U.K
11 Department of Diabetes and Metabolic Medicine, Barts and The London, Queen Mary School of Medicine and Dentistry, University
of London, London, U.K
12 Department of Endocrinology and Metabolism, Diabetes Research Laboratories, Oxford Centre for Diabetes, Churchill Hospital,
Oxford, U.K
13 Genomics Collaborative, Cambridge, Massachusetts
14 Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts
15 Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts
16 Department of Medicine, Harvard Medical School, Boston, Massachusetts
Address correspondence and reprint requests to David Altshuler, Program in Medical and Population Genetics, Broad Institute
of Harvard and MIT, Cambridge, MA, 02142. E-mail: altshuler{at}molbio.mgh.harvard.edu
Abstract
An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants
that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common
variation in the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes,
is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding
Gck, Ipf1, Tcf2, and NeuroD1 (MODY2 and MODY4–MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide
polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden,
Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value <0.1 for association to type 2 diabetes in this initial screen were then genotyped in an additional 4,470 subjects
from North America and Poland. Of 30 nominally significant SNPs from the initial sample, 8 achieved consistent results in
the replication sample. We found the strongest effect at rs757210 in intron 2 of TCF2, with corrected P values <0.01 for an odds ratio (OR) of 1.13. This association was observed again in an independent sample of 5,891 unrelated
case and control subjects and 500 families from the U.K., for an overall OR of 1.12 and a P value <10 −6 in >15,000 samples. We combined these results with our previous studies on HNF4α and TCF1 and explicitly tested for gene-gene
interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions
between these six genes. We conclude that although rare variants in these six genes explain most cases of MODY, common variants
in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes.
CEPH, Centre d’Etude du Polymorphisme Humain
LD, linkage disequilibrium
MODY, maturity-onset diabetes of the young
SNP, single nucleotide polymorphism
Footnotes
L.G. has been a consultant for and served on the advisory boards for Aventis-Sanofi, Bristol Myers Squibb, GKS, Kowa, and
Roche. D.A. is a paid consultant and member of the scientific advisory board of Genomics Collaborative.
L.G. and D.A. jointly supervised the project.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-0202 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted December 4, 2006.
Received February 10, 2006.
DIABETES
Testosterone levels are linked with diverse characteristics of human health, yet, whether these associations reflect correlation or causation remains debated. Here, we provide a broad perspective on ...the role of genetically determined testosterone on complex diseases in both sexes.
Leveraging genetic and health registry data from the UK Biobank and FinnGen (total N = 625,650), we constructed polygenic scores (PGS) for total testosterone, sex-hormone binding globulin (SHBG) and free testosterone, associating these with 36 endpoints across different disease categories in the FinnGen. These analyses were combined with Mendelian Randomization (MR) and cross-sex PGS analyses to address causality.
We show testosterone and SHBG levels are intricately tied to metabolic health, but report lack of causality behind most associations, including type 2 diabetes (T2D). Across other disease domains, including 13 behavioral and neurological diseases, we similarly find little evidence for a substantial contribution from normal variation in testosterone levels. We nonetheless find genetically predicted testosterone affects many sex-specific traits, with a pronounced impact on female reproductive health, including causal contribution to PCOS-related traits like hirsutism and post-menopausal bleeding (PMB). We also illustrate how testosterone levels associate with antagonistic effects on stroke risk and reproductive endpoints between the sexes.
Overall, these findings provide insight into how genetically determined testosterone correlates with several health parameters in both sexes. Yet the lack of evidence for a causal contribution to most traits beyond sex-specific health underscores the complexity of the mechanisms linking testosterone levels to disease risk and sex differences.
Parent-of-origin effects (POE) and sex-specific parental effects have been reported for plasma lipid levels, and a strong relationship exists between dyslipidemia and obesity. We aim to explore ...whether genetic variants previously reported to have an association to lipid traits also show POE on blood lipid levels and obesity. Families from the Botnia cohort and the Hungarian Transdanubian Biobank (HTB) were genotyped for 12 SNPs, parental origin of alleles were inferred, and generalized estimating equations were modeled to assess parental-specific associations with lipid traits and obesity. POE were observed for the variants at the
,
,
, and
on lipid traits, the latter replicated in HTB. Sex-specific parental effects were also observed; variants at
showed POE on lipid traits and obesity in daughters only, while those at
and
showed POE on lipid traits in sons. Variants at
and
showed POE on obesity-related traits in Botnia and HTB, and POE effects on obesity were seen to a higher degree in daughters. This highlights the need to include analysis of POEs in genetic studies of complex traits.
Urinary extracellular vesicles (uEV) are a largely unexplored source of kidney-derived mRNAs with potential to serve as a liquid kidney biopsy. We assessed ∼200 uEV mRNA samples from clinical studies ...by genome-wide sequencing to discover mechanisms and candidate biomarkers of diabetic kidney disease (DKD) in Type 1 diabetes (T1D) with replication in Type 1 and 2 diabetes. Sequencing reproducibly showed >10,000 mRNAs with similarity to kidney transcriptome. T1D DKD groups showed 13 upregulated genes prevalently expressed in proximal tubules, correlated with hyperglycemia and involved in cellular/oxidative stress homeostasis. We used six of them (GPX3, NOX4, MSRB, MSRA, HRSP12, and CRYAB) to construct a transcriptional “stress score” that reflected long-term decline of kidney function and could even identify normoalbuminuric individuals showing early decline. We thus provide workflow and web resource for studying uEV transcriptomes in clinical urine samples and stress-linked DKD markers as potential early non-invasive biomarkers or drug targets.
Display omitted
•NGS reveals robust expression of >10,000 mRNAs in clinical uEV samples•uEV transcriptome enriches kidney mRNAs and shows global similarity with the kidney•In DKD, uEV express elevated levels of cellular/oxidative stress-linked genes•uEV stress score associates with long-term decline of eGFR in early and late DKD
Medicine; Clinical finding; Disease; Specimen; Biopsy sample
Type 2 diabetes (T2D) is a multifactorial disease in which environmental triggers interact with genetic variants in the predisposition to the disease. A number of common variants have been associated ...with T2D but our knowledge of their ability to predict T2D prospectively is limited.
By using a Cox proportional hazard model, common variants in the PPARG (P12A), CAPN10 (SNP43 and 44), KCNJ11 (E23K), UCP2 (-866G>A), and IRS1 (G972R) genes were studied for their ability to predict T2D in 2,293 individuals participating in the Botnia study in Finland. After a median follow-up of 6 y, 132 (6%) persons developed T2D. The hazard ratio for risk of developing T2D was 1.7 (95% confidence interval CI 1.1-2.7) for the PPARG PP genotype, 1.5 (95% CI 1.0-2.2) for the CAPN10 SNP44 TT genotype, and 2.6 (95% CI 1.5-4.5) for the combination of PPARG and CAPN10 risk genotypes. In individuals with fasting plasma glucose > or = 5.6 mmol/l and body mass index > or = 30 kg/m(2), the hazard ratio increased to 21.2 (95% CI 8.7-51.4) for the combination of the PPARG PP and CAPN10 SNP43/44 GG/TT genotypes as compared to those with the low-risk genotypes with normal fasting plasma glucose and body mass index < 30 kg/m(2).
We demonstrate in a large prospective study that variants in the PPARG and CAPN10 genes predict future T2D. Genetic testing might become a future approach to identify individuals at risk of developing T2D.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Type 1 and Type 2 Diabetes Tuomi, Tiinamaija
Diabetes (New York, N.Y.),
12/2005, Letnik:
54, Številka:
suppl 2
Journal Article
Recenzirano
Odprti dostop
Type 1 and type 2 diabetes frequently co-occur in the same families, suggesting common genetic susceptibility. Such mixed family history is associated with an intermediate phenotype of diabetes: ...insulin resistance and cardiovascular complications in type 1 diabetic patients and lower BMI and less cardiovascular complications as well as lower C-peptide concentrations in type 2 diabetic patients. GAD antibody positivity is more common in type 2 diabetic patients from mixed families than from common type 2 diabetes families. The mixed family history is associated with more type 1–like genetic (HLA and insulin gene) and phenotypic characteristics in type 2 diabetic patients, especially in the GAD antibody–positive subgroup. Leaving out the extreme ends of diabetes phenotypes, young children progressing rapidly to total insulin deficiency and strongly insulin-resistant subjects mostly with non-Europid ethnic origin, a large proportion of diabetic patients may have both type 1 and type 2 processes contributing to their diabetic phenotype.
A substantial proportion of patients with adult-onset diabetes share features of both type 1 diabetes (T1D) and type 2 diabetes (T2D). These individuals, at diagnosis, clinically resemble T2D ...patients by not requiring insulin treatment, yet they have immunogenetic markers associated with T1D. Such a slowly evolving form of autoimmune diabetes, described as latent autoimmune diabetes of adults (LADA), accounts for 2-12% of all patients with adult-onset diabetes, though they show considerable variability according to their demographics and mode of ascertainment. While therapeutic strategies aim for metabolic control and preservation of residual insulin secretory capacity, endotype heterogeneity within LADA implies a personalized approach to treatment. Faced with a paucity of large-scale clinical trials in LADA, an expert panel reviewed data and delineated one therapeutic approach. Building on the 2020 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus for T2D and heterogeneity within autoimmune diabetes, we propose "deviations" for LADA from those guidelines. Within LADA, C-peptide values, proxy for β-cell function, drive therapeutic decisions. Three broad categories of random C-peptide levels were introduced by the panel:
) C-peptide levels <0.3 nmol/L: a multiple-insulin regimen recommended as for T1D;
) C-peptide values ≥0.3 and ≤0.7 nmol/L: defined by the panel as a "gray area" in which a modified ADA/EASD algorithm for T2D is recommended; consider insulin in combination with other therapies to modulate β-cell failure and limit diabetic complications;
) C-peptide values >0.7 nmol/L: suggests a modified ADA/EASD algorithm as for T2D but allowing for the potentially progressive nature of LADA by monitoring C-peptide to adjust treatment. The panel concluded by advising general screening for LADA in newly diagnosed non-insulin-requiring diabetes and, importantly, that large randomized clinical trials are warranted.
Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes
Johan Holmkvist 1 ,
Peter Almgren 1 ,
Valeriya Lyssenko 1 ,
Cecilia M. Lindgren 2 3 ,
Karl-Fredrik ...Eriksson 1 ,
Bo Isomaa 4 5 ,
Tiinamaija Tuomi 5 6 ,
Peter Nilsson 7 and
Leif Groop 1 5
1 Department of Clinical Sciences—Diabetes and Endocrinology, CRC, Malmö University Hospital MAS, Lund University, Malmö, Sweden
2 Wellcome Trust Centre for Human Genetics and Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University,
Oxford, U.K
3 Clinical Research Centre, Karolinska Institute, Stockholm, Sweden
4 Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland
5 Folkhalsan Research Centre, Helsinki, Finland
6 Department of Medicine, Helsinki University Central Hospital, and Research Program of Molecular Medicine, University of Helsinki,
Helsinki, Finland
7 Department of Medicine, Malmö University Hospital MAS, Lund University, Malmö, Sweden
Corresponding author: Johan Holmkvist, Department of Clinical Sciences—Diabetes and Endocrinology, CRC Malmö University Hospital
MAS, Lund University, S-205 02 Malmö, Sweden. E-mail: johan.holmkvist{at}med.lu.se
Abstract
OBJECTIVE— Mutations in the hepatocyte nuclear factor ( HNF ) -1 α, HNF-4 α, glucokinase ( GCK ), and HNF-1 β genes cause maturity-onset diabetes of the young (MODY), but it is not known whether common variants in these genes predict
future type 2 diabetes.
RESEARCH DESIGN AND METHODS— We tested 14 previously associated polymorphisms in HNF-1 α, HNF-4 α, GCK , and HNF-1 β for association with type 2 diabetes–related traits and future risk of type 2 diabetes in 2,293 individuals from the Botnia
study (Finland) and in 15,538 individuals from the Malmö Preventive Project (Sweden) with a total follow-up >360,000 years.
RESULTS— The polymorphism rs1169288 in HNF-1 α strongly predicted future type 2 diabetes (hazard ratio HR 1.2, P = 0.0002). Also, SNPs rs4810424 and rs3212198 in HNF-4 α nominally predicted future type 2 diabetes (HR 1.3 95% CI 1.0–1.6, P = 0.03; and 1.1 1.0–1.2, P = 0.04). The rs2144908 polymorphism in HNF-4 α was associated with elevated rate of hepatic glucose production during a hyperinsulinemic-euglycemic clamp ( P = 0.03) but not with deterioration of insulin secretion over time. The SNP rs1799884 in the GCK promoter was associated with elevated fasting plasma glucose (fPG) concentrations that remained unchanged during the follow-up
period ( P = 0.4; SE 0.004 −0.003–0.007) but did not predict future type 2 diabetes (HR 0.9 0.8–1.0, P = 0.1). Polymorphisms in HNF-1 β (transcription factor 2 TCF2 ) did not significantly influence insulin or glucose values nor did they predict future type 2 diabetes.
CONCLUSIONS— In conclusion, genetic variation in both HNF-1 α and HNF-4 α predict future type 2 diabetes, whereas variation in the GCK promoter results in a sustained but subtle elevation of fPG that is not sufficient to increase risk for future type 2 diabetes.
EGP, endogenous glucose production
FFM, fat-free mass
fPG, fasting plasma glucose
G6Pase, glucose-6-phosphatase
GCK, glucokinase
GEE, general estimation equation
HNF, hepatocyte nuclear factor
HOMA, homeostasis model assessment
IFG, impaired fasting glucose
IGT, impaired glucose tolerance
MPP, Malmö Preventive Project
MODY, maturity-onset diabetes of the young
OGTT, oral glucose tolerance test
PCK-1, phosphoenolpyruvate carboxykinase 1
PGC-1α, peroxisome proliferator–activated receptor-γ coactivator-1α
PPAR, peroxisome proliferator–activated receptor
TCF, transcription factor
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 10 March 2008. DOI: 10.2337/db06-1464.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1464 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted February 27, 2008.
Received October 18, 2006.
DIABETES
OBJECTIVE: To develop a model for the prediction of type 2 diabetes mellitus (T2DM) risk on the basis of a multivariate logistic model and 1-h plasma glucose concentration (1-h PG). RESEARCH DESIGN ...AND METHODS: The model was developed in a cohort of 1,562 nondiabetic subjects from the San Antonio Heart Study (SAHS) and validated in 2,395 nondiabetic subjects in the Botnia Study. A risk score on the basis of anthropometric parameters, plasma glucose and lipid profile, and blood pressure was computed for each subject. Subjects with a risk score above a certain cut point were considered to represent high-risk individuals, and their 1-h PG concentration during the oral glucose tolerance test was used to further refine their future T2DM risk. RESULTS: We used the San Antonio Diabetes Prediction Model (SADPM) to generate the initial risk score. A risk-score value of 0.065 was found to be an optimal cut point for initial screening and selection of high-risk individuals. A 1-h PG concentration >140 mg/dL in high-risk individuals (whose risk score was >0.065) was the optimal cut point for identification of subjects at increased risk. The two cut points had 77.8, 77.4, and 44.8% (for the SAHS) and 75.8, 71.6, and 11.9% (for the Botnia Study) sensitivity, specificity, and positive predictive value, respectively, in the SAHS and Botnia Study. CONCLUSIONS: A two-step model, based on the combination of the SADPM and 1-h PG, is a useful tool for the identification of high-risk Mexican-American and Caucasian individuals.
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