Examination of Candidate Chromosomal Regions for Type 2 Diabetes Reveals a Susceptibility Locus on Human Chromosome 8p23.1
Marcus G. Pezzolesi 1 ,
Moonsuk Nam 1 2 4 ,
Terumasa Nagase 1 2 ,
Tomasz ...Klupa 1 2 ,
Jonathon S. Dunn 1 ,
Wojciech M. Mlynarski 1 2 ,
Stephen S. Rich 3 ,
James H. Warram 1 and
Andrzej S. Krolewski 1 2
1 Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts
2 Department of Medicine, Harvard Medical School, Boston, Massachusetts
3 Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
4 Department of Internal Medicine, College of Medicine, Inha University, Incheon, Republic of Korea
Address correspondence and reprint requests to Andrzej S. Krolewski, MD, PhD, Section on Genetics and Epidemiology, Joslin
Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: andrzej.krolewski{at}joslin.harvard.edu
Abstract
In a panel of large Caucasian pedigrees, we genotyped markers in eight chromosomal regions previously reported as supporting
linkage with type 2 diabetes. We previously reported significant linkage on chromosome 20q (maximum logarithm of odds score
MLS = 2.79) in this panel. In the present analysis, candidate regions on 1q, 2q, 3q, 5q, 9q, and 10q yielded little evidence
for linkage; a region on 2p (MLS = 1.64, P = 0.01 at position 9.0 cM) gave suggestive evidence of linkage; and a region on 8p (MLS = 3.67, P = 2.8 × 10 −5 , at position 7.6 cM) gave significant evidence of linkage. Conditional analyses were performed for both 2p and 8p regions
and the region reported on 20q. The MLS for 2p increased from 1.64 to 1.79 (empirical P = 0.142) when conditioned for heterogeneity on 20q. The case was similar for 8p, where the MLS increased from 3.67 to 4.51
(empirical P = 0.023) when conditioned on families without evidence of linkage at 20q. In conclusion, our data support a type 2 diabetes
susceptibility locus on chromosome 8p that appears to be independent from other susceptibility loci. Although we were able
to replicate linkage in our pedigrees on chromosome 2p, we did not find evidence of linkage for regions on 1q, 2q, 3q, 5q,
9q, or 10q.
IGT, impaired glucose tolerance
LOD, logarithm of odds
MLS, maximum LOD score
PPase, protein phosphatase
Footnotes
M.G.P. and M.N. contributed equally to this work.
Additional information for this article can be found in online appendixes available at http://diabetes.diabetesjournals.org .
Accepted October 29, 2003.
Received March 24, 2003.
DIABETES
Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide ...significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10
at rs8018720 in SEC23A, and P = 1.9×10
at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury
. These substances are used ...across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries
. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.
Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 ...HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.
Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.
As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
GLUT10 (gene symbol SLC2A10) is a facilitative glucose transporter within the type 2 diabetes (T2DM)-linked region on chromosome 20q12-13.1. Therefore, we evaluated GLUT10 as a positional candidate ...gene for T2DM in Caucasian Americans.
Twenty SNPs including 4 coding, 10 intronic and 6 5' and 3' to the coding sequence were genotyped across a 100 kb region containing the SLC2A10 gene in DNAs from 300 T2DM cases and 310 controls using the Sequenom MassArray Genotyping System. Allelic association was evaluated, and linkage disequilibrium (LD) and haplotype structure of SLC2A10 were also determined to assess whether any specific haplotypes were associated with T2DM.
Of these variants, fifteen had heterozygosities greater than 0.80 and were analyzed further for association with T2DM. No evidence of significant association was observed for any variant with T2DM (all P > or = 0.05), including Ala206Thr (rs2235491) which was previously reported to be associated with fasting insulin. Linkage disequilibrium analysis suggests that the SLC2A10 gene is contained in a single haplotype block of 14 kb. Haplotype association analysis with T2DM did not reveal any significant differences between haplotype frequencies in T2DM cases and controls.
From our findings, we can conclude that sequence variants in or near GLUT10 are unlikely to contribute significantly to T2DM in Caucasian Americans.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. In an attempt to map the genes predisposing to the common, complex aetiologies of end-stage renal disease (ESRD), we performed a genome-wide scan in 1023 individuals with chronic kidney ...disease (946 dialysis dependent and 77 with advanced chronic renal failure) from 483 African American families. Methods. The study sample comprised 563 ESRD-affected sibling pairs, with nephropathy attributed to diabetes mellitus, chronic glomerular disease or hypertension. Multipoint non-parametric linkage (NPL) analysis methods were employed. Results. NPL regression provided modest evidence of linkage to 13q33.3 near D13S796 log of the odds (LOD) = 1.72, 9q34.3 near D9S1826 (LOD = 1.22), 4p15.32 near D4S2639 (LOD = 1.11) and 1q25.1 near D1S1589 (LOD = 1.01). Adjusting for the evidence of linkage at the other loci using NPL regression analysis provided evidence for linkage to 4p15.32, 9q34.3 and 13q33.3. NPL regression interaction and ordered subset analysis (OSA) suggested that the evidence for linkage to ESRD significantly increased with higher body mass index (BMI) at 13q33.3 (LOD = 4.94 in 61% of families with the highest BMI). Additionally, OSA suggested that linkage significantly improved in the 13% of families with earliest age at ESRD onset (LOD = 3.05 at 2q32.1) and in the 16% of families with latest age at ESRD onset (LOD = 2.47 at 10q26.3). Conclusions. Multipoint single-locus linkage analysis provided modest evidence of linkage to all-cause ESRD in African Americans on 13q33.3, and NPL regression and OSA suggested that evidence for linkage in this region markedly increased in obese families. This region, as well as 9q34.3, 4p15.32 and 1q25.1, should receive priority in the search for loci contributing to ESRD susceptibility in African Americans.
Using the Immunochip custom SNP array, which was designed for dense genotyping of 186 loci identified through genome-wide association studies (GWAS), we analyzed 11,475 individuals with rheumatoid ...arthritis (cases) of European ancestry and 15,870 controls for 129,464 markers. We combined these data in a meta-analysis with GWAS data from additional independent cases (n = 2,363) and controls (n = 17,872). We identified 14 new susceptibility loci, 9 of which were associated with rheumatoid arthritis overall and five of which were specifically associated with disease that was positive for anticitrullinated peptide antibodies, bringing the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at 6 loci and identified association to low-frequency variants at 4 loci. Bioinformatic analyses generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a ...large (n = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haplotypes, we demonstrated accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT) populations). Applying HLA imputation to genome-wide association study data for HIV-1 viral load in three populations (EUR, AA and LAT), we obviated effects of previously reported associations from population-specific HIV studies and discovered a novel association at position 156 in HLA-B. We pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide-binding groove, explaining 12.9% of trait variance.
Introduction: TrialNet TN07, a randomized controlled trial, assessed oral insulin for preventing type 1 diabetes (T1D) in autoantibody-positive relatives of individuals with T1D. Of 560 participants, ...the stratum characterized by low first-phase insulin release (LFIR) (n=57) showed a positive response to oral insulin, while others (n=503) did not. We aimed to understand genetic differences between participants with and without LFIR, and between responders and non-responders to oral insulin in the LFIR stratum. Methods: 552 participants were genotyped using the TEDDY T1DExome array. We compared T1D and insulin associated single nucleotide polymorphisms (SNPs), human leukocyte antigen (HLA) alleles, and T1D genetic risk scores (T1DGRS) in the LFIR stratum vs others using Fisher's tests and t tests. In the LFIR stratum, we used Cox models to examine genetic factors that identify participants with slower T1D progression in response to treatment. Results: Participants with LFIR had higher T1DGRS than those without LFIR (mean 14.2 vs 13.7, p=0.04); higher frequencies of INS rs1004446 susceptible allele (63% vs 48%, p=0.04), higher frequencies of homozygosity for IL27 rs4788084 susceptible allele (18% vs 7%, p=0.04), and lower frequencies of the HLA DRB1*13/DQA1*01 protective haplotype (5% vs 17%, p=0.02). In participants with LFIR, hazard ratio (HR) of response to oral insulin treatment compared to placebo was different in participants with vs without GLIS3 rs7020673 protective allele (respectively, HR: 0.90 vs 0.08, p=0.003), with vs without PXK/PDHB rs11705721 susceptible allele (HR: 0.26 vs 1.09, p=0.05) and with vs without the HLA DRB1*0401/DQA1*0301 susceptible haplotype (HR: 0.23 vs 1.36, p=0.01). Conclusion: Genetic differences exist in autoantibody-positive relatives with and without LFIR, and in LFIR stratum, between responders and non-responders to oral insulin for T1D prevention. Genetics may help precision medicine by identifying candidates responsive to T1D-modifying therapies. Disclosure L. You: None. H.M. Parikh: None. T.M. Triolo: None. L.A. Ferrat: Consultant; Johnson & Johnson Medical Devices Companies. E. Templeman: None. R.A. Oram: Research Support; Randox R & D. Consultant; Provention Bio, Inc., Sanofi. P. Gottlieb: Other Relationship; IM Therapeutics. Research Support; Imcyse. Advisory Panel; Imcyse. Consultant; Juvenile Diabetes Research Foundation (JDRF). Research Support; Hemsley Charitable Trust, Novartis AG, Provention Bio, Inc., Precigen, Inc. Advisory Panel; ViaCyte, Inc. Research Support; Nova Pharmaceuticals. S.S. Rich: None. S. Onengut-Gumuscu: None. A. Steck: None. J. Krischer: None. M.J. Redondo: None. Funding This research was funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK121843). The Type 1 Diabetes TrialNet Study Group is a clinical trials network currently funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, through the cooperative agreements U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085461, U01 DK085465, U01 DK085466, U01 DK085476, U01 DK085499, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK106993, UC4DK117009, and the JDRF.
Introduction & Objective: Teplizumab has shown efficacy at delaying the onset of type 1 diabetes (T1D) but markers of response to treatment are needed to evaluate risk-benefit ratio. The T1D genetic ...risk score-2 (GRS2) combines 67 HLA and non-HLA single nucleotide polymorphisms (SNPs) that increase T1D risk. We tested the hypothesis that the likelihood of response to immunotherapies for T1D prevention increases with higher T1D GRS2. Methods: We studied autoantibody-positive participants in the TrialNet trials TN10 (n=44 teplizumab, n=32 placebo), TN18 (n=101 abatacept, n=111 placebo) and TN07 (n=283 oral insulin, n=277 placebo). Martingale residual scatterplots (MRS) based on the Cox Model were employed to assess T1D risk. Analyses were adjusted for age. Results: Except for TN10, MRS smoothing curves demonstrated that GRS2 is directly correlated with T1D risk. Analyzing TN10 by arm, the smoothing curve showed that, with higher GRS2, T1D risk increases for the placebo arm while, for the treated arm, the risk appears to decrease, creating a crossover point at GRS=12.8 near zero (relative risk=1). We then fitted a Cox Model including GRS2 dichotomized at 13, treatment arm and an interaction term. The interaction term was significant (p=0.03) and the hazard ratio of T1D risk (teplizumab to placebo) for GRS2 ≥13 was 0.263 (95%CI=0.123-0.562) but 0.898 (95th% CI=0.295, 2.74) for GRS2<13. Conclusion: In clinical trials with agents that failed to prevent progression to stage 3 T1D (e.g., abatacept and oral insulin), higher T1D GRS (reflecting higher genetic burden of T1D risk) was associated with higher risk of progression, as expected. However, teplizumab modified the relationship between GRS2 and T1D risk suggesting a greater beneficial therapeutic effect in participants with T1D GRS2 ≥13. In contrast, participants with lower T1D GRS2 had worse response to teplizumab. These results support that genetics can help select individuals who will respond to treatments to prevent T1D. Disclosure M.J. Redondo: None. B.N. Bundy: None. H.M. Parikh: None. L. You: None. T.M. Triolo: None. L.A. Ferrat: Consultant; Johnson & Johnson Medical Devices Companies. E. Templeman: None. M. Tosur: None. A. Steck: None. P. Gottlieb: Other Relationship; IM Therapeutics. Research Support; Imcyse. Advisory Panel; Imcyse. Consultant; Juvenile Diabetes Research Foundation (JDRF). Research Support; Hemsley Charitable Trust, Novartis AG, Provention Bio, Inc., Precigen, Inc. Advisory Panel; ViaCyte, Inc. Research Support; Nova Pharmaceuticals. S. Onengut-Gumuscu: None. S.S. Rich: None. R.A. Oram: Research Support; Randox R & D. Consultant; Provention Bio, Inc., Sanofi. K.C. Herold: Consultant; Sanofi. J. Krischer: None. Funding National Institutes of Health NIDDK 1R01DK121843
PDF
