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The HNF1A G319S variant is associated with C-reactive protein in an Aboriginal population
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CANADIAN JOURNAL OF DIABETES
this block we identified 35 novel and 14 known SNPs which were genotyped in 1033 cases and 1106 controls along with the SSTR marker DG10S478. SNP rs7903146 was by far the most strongly associated (admixture adjusted, additive P=1.59x10-6; OR 1.39) suggesting this is a functional polymorphism. Admixture in these samples has been evaluated by genotyping 70 Ancestry Informative Markers in all samples. In contrast to TCF7L2, other SNPs associated with T2DM in European-derived samples showed little or no evidence of association with T2DM even in an enlarged sample of 2841 cases and 1964 controls. Only SNPs in CDKAL1 showed even modest evidence of association (P-values 0.06-0.07). Evaluation of these SNPs in the Human Genome Diversity Panel, however, suggests some of these SNPs may be fixed in the African population since Yoruba are monomorphic for the risk allele observed in Europeans. We have carried out a GWAS analysis on 966 cases and 1033 controls using the Affymetrix 6.0 chip. After extensive quality control 835,042 SNPs were evaluated in admixture-adjusted association analysis focusing on the additive model. Approximately 40 SNPs had P-values < 10-6. In addition, SNPs in two previously identified T2DM genes from studies of European-derived populations were among the top hits. SNPs rs17703228 (P=7.42x10-5) in “juxtaposed with another zinc finger gene 1” (JAZF1) and rs10906180 (P=6.38x10-5) in the calcium calmodulin-dependent protein kinase 1D (CAMK1D) were associated with T2DM in African Americans. These SNPs are different from SNPs previously observed to be associated with T2DM in Europeans. Replication studies of African American SNPs are underway in a two stage replication analysis totaling over 4,000 cases and 4,000 controls, and evaluation of imputed SNPs and copy number variation is also in progress. Discussion: While some elements of diabetes risk in African Americans are similar to those in European-derived populations, clear differences are observed that will be of great interest for future investigation. Genetics of type 2 diabetes No conflict of interest O-0230 the HNF1a G319s variant is associated with c-reactive protein in an aboriginal population S.H. Ley1, R.A. Hegele2, P.W. Connelly3, S.B. Harris4, M. Mamakeesick5, J. Gittelsohn6, R. Retnakaran7, B. Zinman7, A.J. Hanley1 1 University of Toronto, Nutritional Sciences, Toronto, Canada 2 University of Western Ontario, Robarts Research Institute, London, Canada 3 University of Toronto, Laboratory Medicine and Pathobiology, Toronto, Canada 4 University of Western Ontario, Center for Studies in Family Medicine, London, Canada 5 Sandy Lake Health and Diabetes Project, Sandy Lake, Canada 6 Johns Hopkins Bloomberg School of Public Health, Center for Human Nutrition, Baltimore, USA 7 Mount Sinai Hospital, Leadership Sinai Centre for Diabetes, Toronto, Canada aims: Common variants of the hepatocyte nuclear factor 1A (HNF1A) gene encoding HNF-1a have been associated with plasma C-reactive protein (CRP) concentration, which is elevated among individuals with diabetes and metabolic abnormalities. HNF-1 binding to promoter regions of the CRP gene is known to be involved in regulation of CRP synthesis in the liver. A glycine to serine substitution at codon 319 (G319S) of the HNF1A gene has been identified and linked with increased risk for type 2 diabetes - not maturity-onset-diabetes-of-theyoung - in a Canadian First Nations population. The aim of this study was to determine the association between the HNF1A G319S variant and plasma CRP among individuals with and without type 2 diabetes. Methods: Between 1993 and 1995, 728 members of Sandy Lake First Nation participated in a diabetes prevalence and risk factor
survey. Fasting glucose and a 75-g oral glucose tolerance test were obtained to determine type 2 diabetes, according to the 1998 World Health Organization criteria. Participants were genotyped for the HNF1A G319S mutation. Fasting blood samples were analyzed for CRP, interleukin (IL)-6, and serum lipids. Interviewers administered questionnaires to obtain demographic and medical history information. Anthropometry and blood pressure were measured. results: The prevalence rates of type 2 diabetes were 14.0% (77/550) in homozygous G319, 29.2% (42/144) in heterozygous, and 83.3% (5/6) in homozygous S319 carriers (p<0.001). Under a dominant model, least squares mean CRP levels were higher among the homozygous G319 carriers (1.90 [95% confidence interval 1.55-2.33] mg/l) compared to S319 allele carriers (1.37 [1.12-1.68] mg/l) (p=0.0016), after adjustment for age, sex, hypertension, triglyceride, waist circumference, HDL cholesterol, 2-h postload glucose, and IL-6. When participants were stratified by diabetes status, CRP remained strongly associated with the G319S mutation among people without type 2 diabetes (1.66 [1.33-2.08] mg/l in homozygous G319 vs. 1.18 [0.95-1.48] mg/l in S319 allele carriers, p=0.0030) with similar adjustment. Among participants with diabetes, the CRP levels were elevated in both S319 allele carriers and non-carriers. The association between the G319S variant and CRP was not statistically significant among individuals with diabetes potentially due to the small sample size (4.90 [3.12-7.71] mg/l in homozygous G319 vs. 3.76 [2.39-5.91] mg/l in S319 allele carriers, p=0.25). There was no sex or age interaction with HNF1A G319S variant on plasma CRP levels (p>0.5). conclusion: We conclude that the HNF1A G319S variant, which is clearly dysfunctional and a risk marker of type 2 diabetes, is also associated with variation in CRP levels in this population, supporting a mechanistic relationship between HNF1A and plasma CRP. Epidemiology No conflict of interest O-0232 Effect of cd36 deficiency on carbohydrate and lipid metabolism is contextually determined by genomic background and reflected in transcriptomic profile O. Seda1, L. Sedova2, F. Liska2, L. Kazdova3, J. Tremblay1, D. Krenova2, P. Hamet1, V. Kren2 1 Research Centre CHUM (CR CHUM), Technopole Angus, Montreal, Canada 2 First Faculty of Medicine Charles University, Institute of Biology and Medical Genetics, Prague, Czech Republic 3 Institute for Clinical and Experimental Medicine, Dept of Metabolism and Diabetes, Prague, Czech Republic aims: Deficiency of fatty acid translocase Cd36 has been shown to play a major role in pathogenesis of metabolic syndrome in spontaneously hypertensive rats (SHR). We have tested the hypothesis that its effects on metabolism and genome-wide transcription profile are contextual with genomic background. Methods: We have derived 4 new congenic strains: 2 BN-Lx.SHR4 and 2 PD.SHR4 by introgression of chromosome (chr.) 4 region of SHR origin including defective Cd36 gene into genetic background of highly inbred models of insulin resistance and dyslipidemia, PD and BN-Lx strains, respectively. We have compared the metabolic profile of BN-Lx.SHR4 congenic strains under standard diet conditions and after 3-day administration of dexamethasone to that of progenitor strains BN-Lx and SHR (n=6 adult males/strain).We have subjected standard diet-fed adult males of PD and PD.SHR4 strains (n=8/strain) to metabolic, morphometric and transcriptomic (Affymetrix Rat 1.0 ST Exon array) profiling. results: The BN-Lx.SHR4 strains showed markedly blunted reaction to diabetogenic action of dexamethasone compared both to BN-Lx and SHR. We observed significantly improved glucose tolerance and lower fasting insulin in both PD.SHR4 strains compared to PD. In contrast,
CANADIAN JOURNAL OF DIABETES
this block we identified 35 novel and 14 known SNPs which were genotyped in 1033 cases and 1106 controls along with the SSTR marker DG10S478. SNP rs7903146 was by far the most strongly associated (admixture adjusted, additive P=1.59x10-6; OR 1.39) suggesting this is a functional polymorphism. Admixture in these samples has been evaluated by genotyping 70 Ancestry Informative Markers in all samples. In contrast to TCF7L2, other SNPs associated with T2DM in European-derived samples showed little or no evidence of association with T2DM even in an enlarged sample of 2841 cases and 1964 controls. Only SNPs in CDKAL1 showed even modest evidence of association (P-values 0.06-0.07). Evaluation of these SNPs in the Human Genome Diversity Panel, however, suggests some of these SNPs may be fixed in the African population since Yoruba are monomorphic for the risk allele observed in Europeans. We have carried out a GWAS analysis on 966 cases and 1033 controls using the Affymetrix 6.0 chip. After extensive quality control 835,042 SNPs were evaluated in admixture-adjusted association analysis focusing on the additive model. Approximately 40 SNPs had P-values < 10-6. In addition, SNPs in two previously identified T2DM genes from studies of European-derived populations were among the top hits. SNPs rs17703228 (P=7.42x10-5) in “juxtaposed with another zinc finger gene 1” (JAZF1) and rs10906180 (P=6.38x10-5) in the calcium calmodulin-dependent protein kinase 1D (CAMK1D) were associated with T2DM in African Americans. These SNPs are different from SNPs previously observed to be associated with T2DM in Europeans. Replication studies of African American SNPs are underway in a two stage replication analysis totaling over 4,000 cases and 4,000 controls, and evaluation of imputed SNPs and copy number variation is also in progress. Discussion: While some elements of diabetes risk in African Americans are similar to those in European-derived populations, clear differences are observed that will be of great interest for future investigation. Genetics of type 2 diabetes No conflict of interest O-0230 the HNF1a G319s variant is associated with c-reactive protein in an aboriginal population S.H. Ley1, R.A. Hegele2, P.W. Connelly3, S.B. Harris4, M. Mamakeesick5, J. Gittelsohn6, R. Retnakaran7, B. Zinman7, A.J. Hanley1 1 University of Toronto, Nutritional Sciences, Toronto, Canada 2 University of Western Ontario, Robarts Research Institute, London, Canada 3 University of Toronto, Laboratory Medicine and Pathobiology, Toronto, Canada 4 University of Western Ontario, Center for Studies in Family Medicine, London, Canada 5 Sandy Lake Health and Diabetes Project, Sandy Lake, Canada 6 Johns Hopkins Bloomberg School of Public Health, Center for Human Nutrition, Baltimore, USA 7 Mount Sinai Hospital, Leadership Sinai Centre for Diabetes, Toronto, Canada aims: Common variants of the hepatocyte nuclear factor 1A (HNF1A) gene encoding HNF-1a have been associated with plasma C-reactive protein (CRP) concentration, which is elevated among individuals with diabetes and metabolic abnormalities. HNF-1 binding to promoter regions of the CRP gene is known to be involved in regulation of CRP synthesis in the liver. A glycine to serine substitution at codon 319 (G319S) of the HNF1A gene has been identified and linked with increased risk for type 2 diabetes - not maturity-onset-diabetes-of-theyoung - in a Canadian First Nations population. The aim of this study was to determine the association between the HNF1A G319S variant and plasma CRP among individuals with and without type 2 diabetes. Methods: Between 1993 and 1995, 728 members of Sandy Lake First Nation participated in a diabetes prevalence and risk factor
survey. Fasting glucose and a 75-g oral glucose tolerance test were obtained to determine type 2 diabetes, according to the 1998 World Health Organization criteria. Participants were genotyped for the HNF1A G319S mutation. Fasting blood samples were analyzed for CRP, interleukin (IL)-6, and serum lipids. Interviewers administered questionnaires to obtain demographic and medical history information. Anthropometry and blood pressure were measured. results: The prevalence rates of type 2 diabetes were 14.0% (77/550) in homozygous G319, 29.2% (42/144) in heterozygous, and 83.3% (5/6) in homozygous S319 carriers (p<0.001). Under a dominant model, least squares mean CRP levels were higher among the homozygous G319 carriers (1.90 [95% confidence interval 1.55-2.33] mg/l) compared to S319 allele carriers (1.37 [1.12-1.68] mg/l) (p=0.0016), after adjustment for age, sex, hypertension, triglyceride, waist circumference, HDL cholesterol, 2-h postload glucose, and IL-6. When participants were stratified by diabetes status, CRP remained strongly associated with the G319S mutation among people without type 2 diabetes (1.66 [1.33-2.08] mg/l in homozygous G319 vs. 1.18 [0.95-1.48] mg/l in S319 allele carriers, p=0.0030) with similar adjustment. Among participants with diabetes, the CRP levels were elevated in both S319 allele carriers and non-carriers. The association between the G319S variant and CRP was not statistically significant among individuals with diabetes potentially due to the small sample size (4.90 [3.12-7.71] mg/l in homozygous G319 vs. 3.76 [2.39-5.91] mg/l in S319 allele carriers, p=0.25). There was no sex or age interaction with HNF1A G319S variant on plasma CRP levels (p>0.5). conclusion: We conclude that the HNF1A G319S variant, which is clearly dysfunctional and a risk marker of type 2 diabetes, is also associated with variation in CRP levels in this population, supporting a mechanistic relationship between HNF1A and plasma CRP. Epidemiology No conflict of interest O-0232 Effect of cd36 deficiency on carbohydrate and lipid metabolism is contextually determined by genomic background and reflected in transcriptomic profile O. Seda1, L. Sedova2, F. Liska2, L. Kazdova3, J. Tremblay1, D. Krenova2, P. Hamet1, V. Kren2 1 Research Centre CHUM (CR CHUM), Technopole Angus, Montreal, Canada 2 First Faculty of Medicine Charles University, Institute of Biology and Medical Genetics, Prague, Czech Republic 3 Institute for Clinical and Experimental Medicine, Dept of Metabolism and Diabetes, Prague, Czech Republic aims: Deficiency of fatty acid translocase Cd36 has been shown to play a major role in pathogenesis of metabolic syndrome in spontaneously hypertensive rats (SHR). We have tested the hypothesis that its effects on metabolism and genome-wide transcription profile are contextual with genomic background. Methods: We have derived 4 new congenic strains: 2 BN-Lx.SHR4 and 2 PD.SHR4 by introgression of chromosome (chr.) 4 region of SHR origin including defective Cd36 gene into genetic background of highly inbred models of insulin resistance and dyslipidemia, PD and BN-Lx strains, respectively. We have compared the metabolic profile of BN-Lx.SHR4 congenic strains under standard diet conditions and after 3-day administration of dexamethasone to that of progenitor strains BN-Lx and SHR (n=6 adult males/strain).We have subjected standard diet-fed adult males of PD and PD.SHR4 strains (n=8/strain) to metabolic, morphometric and transcriptomic (Affymetrix Rat 1.0 ST Exon array) profiling. results: The BN-Lx.SHR4 strains showed markedly blunted reaction to diabetogenic action of dexamethasone compared both to BN-Lx and SHR. We observed significantly improved glucose tolerance and lower fasting insulin in both PD.SHR4 strains compared to PD. In contrast,