- Email: [email protected]
DWP6-2 Association between R325W zinc transporter-8 gene polymorphism (SLC30A8)and Type 2 diabetes
DIABETES RESEARCH A N D CLINICAL PRACTICE
79 (2008) S1 – S127
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Table 2. Odds ratio (95% CI) for a renal event
Type 2 Diabetes Maori (European=1) Male (Female=1) Type 1 Diabetes Maori (European=1) Male (Female=1) Overall Maori (European=1) Male (Female=1) Duration of diabetes
†
Univariate Odds
Multivariate Odds
11.4 (7–18)* 1.4 (0.9–2)
11.7 (7–19)* 1.5 (0.9–2)
7.3 (3–18)* 1.8 (0.8–5)
7.1 (3–18)* 2.1 (0.9–5)
8.2 (6–12)* 1.5 (1–2)* 1.03 (1–1.1)*
8.4 (6–12)* 1.7 (1–2.5)* 1.03 (1–1.1)*
*Significant at 5% level. † Adjusted for duration of diabetes, gender and ethnicity. Includes only European and Maori patients
Conclusion: Present findings indicate that Maori with diabetes have extremely high odds of developing renal disease compared with Europeans with diabetes. The progression of coronary artery disease (CAD) among Maori with diabetes is similar to that among European diabetes patients. The reason for this ethnic difference in renal event is not explained and needs further investigation.
DWP6-1 Identifying a genomic signature for diabetes risk Donia Macartney 1 , David Hall 1 , Lisa McCallum 1 , Jeremy Krebs 2 , Richard Stubbs 3 , Rod Lea 1 1 Institute of Environmental Health & Science Research Ltd, NZ, 2 Capital and Coast, Wellington, NZ, 3 Wakefield Hospital and The Wakefield Gastroenterology Research Institute, Wellington, New Zealand Aims: The utility of genomics in clinical medicine depends on how accurately a DNA-based test can predict disease risk, outcome or patient response to drug (pharmacogenomics). The development of useful genomic tests has been hampered by the fact that many diseases and drug responses are complex traits, which are explained by the synergistic effects of environmental factors and multiple genes. In an effort to address the latter we are developing strategies to identify genomic signatures of disease which capture more of the genetic variation, and as such, better predict disease. A small proportion of morbidly obese patients presenting for gastric bypass surgery are insulin sensitive and normoglycemic (fasting glucose ≤ 5.5). We hypothesise that these patients are somehow genetically protected against insulin resistance and Type 2 diabetes despite their morbid obesity. These patients should facilitate our identification of a genomic signature predictive for insulin sensitivity and may provide additional insight into the mechanisms of insulin resistance and development of Type 2 diabetes. Methods: We used an extreme phenotype case control design to look for genomic differences between insulin sensitive (HOMA <2.0, McAuley index >6.3) and insulin resistant (HOMA > 3.0 and McAuley index < 6.0) morbidly obese (BMI > 35kg/m2 ) individuals matched for BMI, sex, gender, age and ethnicity. We employed single nucleotide polymorphism (SNP) chip technology and bioinformative algorithms to identify a characteristic multi-SNP set that best predicts insulin sensitivity/resistance in a morbidly obese cohort. Results: The first phase of the project was to perform SNP array analysis on pooled DNA from the two groups to estimate trait heritability. A comparison of the groups revealed genome-wide differences in SNP allele frequencies which exceeded the random chance threshold. Having established that the two groups did indeed appear to be genetically distinct we performed SNP array analysis on samples from 15 insulin sensitive and 30 insulin
Figure 1
resistant individuals. Using this data we identified a genomic signature which distinguished the insulin sensitive study subjects from the insulin resistant ones (Figure 1). Conclusions/Comments: We have demonstrated the power of our approach to identify a genomic signature for insulin sensitivity/resistance in a cohort of morbidly obese individuals and are in the process of validating this in another small independent cohort. The mechanism of insulin resistance remains elusive and this signature may highlight novel avenues for future research into insulin resistance and the development of Type 2 diabetes. Our primary goal is to develop DNA-based tests for use in clinical practise. For instance, to apply our methodology to Type 2 diabetes and to develop tests which enable us to better predict patient disease risk and response to gastric bypass surgery and/or drug treatment.
DWP6-2 Association between R325W zinc transporter-8 gene polymorphism (SLC30A8) and Type 2 diabetes Yong Ho Lee 1 , Eun Seok Kang 1,2,3 , So Hun Kim 4 , Seung Jin Han 1 , Kyu Yeon Hur 2 , Chul Hoon Kim 2,5 , Chul Woo Ahn 1,2,3 , Bong Soo Cha 1,2,3 , Moonsuk Nam 4 , Hyun Chul Lee 1,2,3 1 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 2 Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, 3 Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, 4 Department of Internal Medicine, Inha University College of Medicine, Inchon, 5 Department of Pharmacology, Yonsei University College of Medicine, Seoul, South Korea Aim: Type 2 Diabetes (T2DM) is a growing major health problem and insulin secretory defects play an important role in the pathogenesis of T2DM in Korea. The R325W (rs13266634) nonsynonymous polymorphism in the islet-specific zinc transporter protein gene, SLC30A8 has been reported to be associated with T2DM and possibly with a defect in insulin secretion. This study investigated the association between genetic variations in SLC30A8 and T2DM in a Korean population. Methods: A total of 1,410 subjects were enrolled in this study. There were 908 T2DM patients and 502 control subjects. The genotyping of the SLC30A8 polymorphism was performed using real-time PCR. Results: There was no significant difference in age, sex, body weight, and duration of diabetes in patients with T2DM according to genotype. In control subjects, 31.1% had the RR genotype, 49.4% had the RW genotype, and 19.5% had the WW genotype. There were 35.7% with the RR genotype, 50.6% with the RW
S30
DIABETES RESEARCH A N D CLINICAL PRACTICE
genotype, and 13.8% of the WW genotype in T2DM patients (chi-square p=0.012. linear trend p=0.006). This genetic effect remained statistically significant after adjustment for age and sex (odds ratio=0.822, p=0.018, 95% confidence interval 0.699 0.967). Conclusion: These data provide evidence that the SLC30A8 rs13266634 gene variation is associated with protection from the development of T2DM in the Korean population.
DWP6-3 Meta-analysis of the association of TCF7L2 with Type 2 diabetes in the Asian population Linong Ji, Yingying Luo, Hongyuan Wang, Qian Ren, Xueyao Han Peking University Peoples’ Hospital, Beijing, China Objective: Variants of transcription factor 7-like 2 (TCF7L2) genes have shown a consistent association with Type 2 diabetes (T2DM) in Caucasians and European populations. Among them, the rs7903146 T allele and the rs12255372 T allele are probably the best two proxies to evaluate the effect of this gene on the risk of T2DM. However, the effect of these previously reported two high risk alleles contribution to T2DM in Asian ancestry is uncertain. In this study, we aimed to clarify the possible association of rs7903146 and rs12255372 with T2DM in Asian populations by using meta-analysis. Research design and methods: Articles evaluating the association between rs7903146 T allele or rs12255372 T allele of the TCF7L2 gene on the risk of T2DM in Asian population were identified from PubMed and CNKI database since Mar, 2006 to Sep, 2007. Unpublished articles were found from the abstracts of 2006 ADA, EASD, IDF annual meeting and abstracts of Chinese diabetes society annual meeting in 2006 and 2007. After extraction of relevant data, main and sub-group meta-analysis was performed to assess the association of rs7903146 and rs12255372 with the risk of T2DM. Results: Nine eligible papers containing 11 subgroups were included in the meta analysis of rs7903146, while 6 eligible papers containing 8 subgroups were included in the meta analysis of rs12255372. Among the total of 24774 subjects analyzed for rs7903146, 14956 people had T2DM and 9818 people were healthy controls. No heterogeneity was found between each subgroup of population by heterogeneity chi-squared test. A fixed model was performed to provide a pooled allelic odds ratio (OR) of rs7903146 high risk T allele of 1.37 [95% confidence interval (CI), 1.24 to 1.52, p<0.001]. The pooled OR of genotype with T allele for T2DM was 1.53 (95% CI, 1.35 to 1.74, p<0.001 ). The ORs of TT genotype and TC genotype compared with CC genotype were 1.87 (95% CI, 1.39 to 2.51, p<0.001) and 1.49 (95% CI, 1.31 to 1.70, p<0.001) respectively. When compared with the association of rs7903146 TC genotype on the risk of T2DM, there was no significant difference with rs7903146 TT genotype (OR=1.30, 95% CI 0.96 to 1.76, p=0.085). Among the total of 19656 subjects analyzed for rs12255372, 11938 people had T2DM and 7718 people were healthy controls. No heterogeneity was found between each subgroup of population by heterogeneity chi-squared test. A fixed model was performed to provide a pooled allelic odds ratio (OR) of rs12255372 high risk T allele of 1.40 [95% confidence interval (CI), 1.23 to 1.58, p<0.001 ]. The pooled OR of genotype with T allele for T2DM was 1.49 (95% CI, 1.29 to 1.72, p<0.001). The ORs of TT genotype and TC genotype compared with CC genotype were 1.86 (95% CI, 1.31 to 2.63, p<0.001) and 1.44 (95% CI, 1.24 to 1.68, p<0.001) respectively. The rs12255372 TC genotype and TT genotype carried similar risk. Conclusion: Rs7903146 and rs12255372 of TCF7L2 gene are associated with the risk of T2DM in Asian population.
79 (2008) S1 – S127
DWP6-4 Novel hepatocyte nuclear factor 4-alpha (HNF4A) promoter mutation in a New Zealand family Rinki Murphy 1 , Tim Cundy 1 , Sian Ellard 2 Auckland Diabetes Centre, Greenlane Clinical Centre, Auckland, NZ, 2 Insitute of Clinical & Biomedical Sciences, Peninsula Medical School, Exeter, United Kingdom 1
Mutations in the HNF4A gene encoding the transcription factor HNF-4α were first described as a cause of dominantly inherited maturity onset diabetes of the young (MODY) in 1996. 31 HNF4A gene mutations in 40 families have been described to date. There are two recognized promoters: the hepatic P1, and the pancreatic-specific P2, identified in 2001. Only two MODYassociated mutations in the P2 promoter have been described: -146T>C in an IPF1 binding site and -181G>A in an HNF1A binding site, but several common polymorphisms near this P2 promoter have been associated with type 2 diabetes. We describe a novel HNF4A mutation of the P2 promoter at -169C>T within the HNF-1α/HNF-1β binding site in a New Zealand European family with early adult-onset diabetes, macrosomia, normal lipids and variable requirement for sulfonylurea therapy. The proband was diagnosed with diabetes at the age of 16. She was not overweight (BMI 22.5) and was negative for GAD-antibodies. She was treated initially with insulin and subsequently with metformin and glibenclamide. Her older brother (also heterozygous for -169C>T) was diagnosed with diabetes at the age of 33 years and is managed on diet alone. He was macrosomic (birth weight 4.44kg at term, +2.2 SDS). Their mother (also carrying -169C>T) was diagnosed with diabetes only at the age of 57 and is also treated with diet only. The proband’s firstborn child was macrosomic (birth weight +3.2 SDS) despite excellent maternal glycemic control, and is heterozygous for the mutation. Her second child, who did not inherit the mutation, was less macrosomic (birth weight +2.2 SDS, despite poorer maternal glucose control). HNF4A mutations have recently been reported to cause neonatal hypoglycaemia, increased birth weight and macrosomia. This contrasts to most monogenic causes of diabetes that result in β-cell deficiency (such as those resulting from mutations in the genes GCK, IPF1, HNF1B, KCNJ11 and ABCC8) where neonates have reduced birth weight. The dyslipidemia described in HNF4A mutation carriers (lower HDL and higher LDL) is thought to be due to defects in hepatic P1-regulated HNF4A expression, hence those with a pancreatic P2 promoter mutation would be predicted to have normal circulating lipids. Approximately half of HNF4A mutation carriers have a good, long-term hypoglycemic response to sulfonylurea therapy.
Clinical diabetes CD1-1 Glycemic index, glycemic load and diabetes risk: a meta-analysis Alan Barclay 1 , Peter Petocz 2 , Joanna McMillan-Price 1 , Victoria Flood 1,3 , Tania Prvan 2 , Paul Mitchell 3 , Jennie Brand-Miller 1 1 Human Nutrition Unit, University of Sydney, NSW, 2006, Australia, 2 Department of Statistics, Macquarie University, NSW, 2109, Australia, 3 Department of Ophthalmology (Centre for Vision Research, Westmead Millennium Institute, Westmead Hospital), University of Sydney, NSW, Australia Inconsistent findings from observational studies have continued the controversy over the effects of glycemic index (GI), glycemic
79 (2008) S1 – S127
S29
Table 2. Odds ratio (95% CI) for a renal event
Type 2 Diabetes Maori (European=1) Male (Female=1) Type 1 Diabetes Maori (European=1) Male (Female=1) Overall Maori (European=1) Male (Female=1) Duration of diabetes
†
Univariate Odds
Multivariate Odds
11.4 (7–18)* 1.4 (0.9–2)
11.7 (7–19)* 1.5 (0.9–2)
7.3 (3–18)* 1.8 (0.8–5)
7.1 (3–18)* 2.1 (0.9–5)
8.2 (6–12)* 1.5 (1–2)* 1.03 (1–1.1)*
8.4 (6–12)* 1.7 (1–2.5)* 1.03 (1–1.1)*
*Significant at 5% level. † Adjusted for duration of diabetes, gender and ethnicity. Includes only European and Maori patients
Conclusion: Present findings indicate that Maori with diabetes have extremely high odds of developing renal disease compared with Europeans with diabetes. The progression of coronary artery disease (CAD) among Maori with diabetes is similar to that among European diabetes patients. The reason for this ethnic difference in renal event is not explained and needs further investigation.
DWP6-1 Identifying a genomic signature for diabetes risk Donia Macartney 1 , David Hall 1 , Lisa McCallum 1 , Jeremy Krebs 2 , Richard Stubbs 3 , Rod Lea 1 1 Institute of Environmental Health & Science Research Ltd, NZ, 2 Capital and Coast, Wellington, NZ, 3 Wakefield Hospital and The Wakefield Gastroenterology Research Institute, Wellington, New Zealand Aims: The utility of genomics in clinical medicine depends on how accurately a DNA-based test can predict disease risk, outcome or patient response to drug (pharmacogenomics). The development of useful genomic tests has been hampered by the fact that many diseases and drug responses are complex traits, which are explained by the synergistic effects of environmental factors and multiple genes. In an effort to address the latter we are developing strategies to identify genomic signatures of disease which capture more of the genetic variation, and as such, better predict disease. A small proportion of morbidly obese patients presenting for gastric bypass surgery are insulin sensitive and normoglycemic (fasting glucose ≤ 5.5). We hypothesise that these patients are somehow genetically protected against insulin resistance and Type 2 diabetes despite their morbid obesity. These patients should facilitate our identification of a genomic signature predictive for insulin sensitivity and may provide additional insight into the mechanisms of insulin resistance and development of Type 2 diabetes. Methods: We used an extreme phenotype case control design to look for genomic differences between insulin sensitive (HOMA <2.0, McAuley index >6.3) and insulin resistant (HOMA > 3.0 and McAuley index < 6.0) morbidly obese (BMI > 35kg/m2 ) individuals matched for BMI, sex, gender, age and ethnicity. We employed single nucleotide polymorphism (SNP) chip technology and bioinformative algorithms to identify a characteristic multi-SNP set that best predicts insulin sensitivity/resistance in a morbidly obese cohort. Results: The first phase of the project was to perform SNP array analysis on pooled DNA from the two groups to estimate trait heritability. A comparison of the groups revealed genome-wide differences in SNP allele frequencies which exceeded the random chance threshold. Having established that the two groups did indeed appear to be genetically distinct we performed SNP array analysis on samples from 15 insulin sensitive and 30 insulin
Figure 1
resistant individuals. Using this data we identified a genomic signature which distinguished the insulin sensitive study subjects from the insulin resistant ones (Figure 1). Conclusions/Comments: We have demonstrated the power of our approach to identify a genomic signature for insulin sensitivity/resistance in a cohort of morbidly obese individuals and are in the process of validating this in another small independent cohort. The mechanism of insulin resistance remains elusive and this signature may highlight novel avenues for future research into insulin resistance and the development of Type 2 diabetes. Our primary goal is to develop DNA-based tests for use in clinical practise. For instance, to apply our methodology to Type 2 diabetes and to develop tests which enable us to better predict patient disease risk and response to gastric bypass surgery and/or drug treatment.
DWP6-2 Association between R325W zinc transporter-8 gene polymorphism (SLC30A8) and Type 2 diabetes Yong Ho Lee 1 , Eun Seok Kang 1,2,3 , So Hun Kim 4 , Seung Jin Han 1 , Kyu Yeon Hur 2 , Chul Hoon Kim 2,5 , Chul Woo Ahn 1,2,3 , Bong Soo Cha 1,2,3 , Moonsuk Nam 4 , Hyun Chul Lee 1,2,3 1 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 2 Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, 3 Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, 4 Department of Internal Medicine, Inha University College of Medicine, Inchon, 5 Department of Pharmacology, Yonsei University College of Medicine, Seoul, South Korea Aim: Type 2 Diabetes (T2DM) is a growing major health problem and insulin secretory defects play an important role in the pathogenesis of T2DM in Korea. The R325W (rs13266634) nonsynonymous polymorphism in the islet-specific zinc transporter protein gene, SLC30A8 has been reported to be associated with T2DM and possibly with a defect in insulin secretion. This study investigated the association between genetic variations in SLC30A8 and T2DM in a Korean population. Methods: A total of 1,410 subjects were enrolled in this study. There were 908 T2DM patients and 502 control subjects. The genotyping of the SLC30A8 polymorphism was performed using real-time PCR. Results: There was no significant difference in age, sex, body weight, and duration of diabetes in patients with T2DM according to genotype. In control subjects, 31.1% had the RR genotype, 49.4% had the RW genotype, and 19.5% had the WW genotype. There were 35.7% with the RR genotype, 50.6% with the RW
S30
DIABETES RESEARCH A N D CLINICAL PRACTICE
genotype, and 13.8% of the WW genotype in T2DM patients (chi-square p=0.012. linear trend p=0.006). This genetic effect remained statistically significant after adjustment for age and sex (odds ratio=0.822, p=0.018, 95% confidence interval 0.699 0.967). Conclusion: These data provide evidence that the SLC30A8 rs13266634 gene variation is associated with protection from the development of T2DM in the Korean population.
DWP6-3 Meta-analysis of the association of TCF7L2 with Type 2 diabetes in the Asian population Linong Ji, Yingying Luo, Hongyuan Wang, Qian Ren, Xueyao Han Peking University Peoples’ Hospital, Beijing, China Objective: Variants of transcription factor 7-like 2 (TCF7L2) genes have shown a consistent association with Type 2 diabetes (T2DM) in Caucasians and European populations. Among them, the rs7903146 T allele and the rs12255372 T allele are probably the best two proxies to evaluate the effect of this gene on the risk of T2DM. However, the effect of these previously reported two high risk alleles contribution to T2DM in Asian ancestry is uncertain. In this study, we aimed to clarify the possible association of rs7903146 and rs12255372 with T2DM in Asian populations by using meta-analysis. Research design and methods: Articles evaluating the association between rs7903146 T allele or rs12255372 T allele of the TCF7L2 gene on the risk of T2DM in Asian population were identified from PubMed and CNKI database since Mar, 2006 to Sep, 2007. Unpublished articles were found from the abstracts of 2006 ADA, EASD, IDF annual meeting and abstracts of Chinese diabetes society annual meeting in 2006 and 2007. After extraction of relevant data, main and sub-group meta-analysis was performed to assess the association of rs7903146 and rs12255372 with the risk of T2DM. Results: Nine eligible papers containing 11 subgroups were included in the meta analysis of rs7903146, while 6 eligible papers containing 8 subgroups were included in the meta analysis of rs12255372. Among the total of 24774 subjects analyzed for rs7903146, 14956 people had T2DM and 9818 people were healthy controls. No heterogeneity was found between each subgroup of population by heterogeneity chi-squared test. A fixed model was performed to provide a pooled allelic odds ratio (OR) of rs7903146 high risk T allele of 1.37 [95% confidence interval (CI), 1.24 to 1.52, p<0.001]. The pooled OR of genotype with T allele for T2DM was 1.53 (95% CI, 1.35 to 1.74, p<0.001 ). The ORs of TT genotype and TC genotype compared with CC genotype were 1.87 (95% CI, 1.39 to 2.51, p<0.001) and 1.49 (95% CI, 1.31 to 1.70, p<0.001) respectively. When compared with the association of rs7903146 TC genotype on the risk of T2DM, there was no significant difference with rs7903146 TT genotype (OR=1.30, 95% CI 0.96 to 1.76, p=0.085). Among the total of 19656 subjects analyzed for rs12255372, 11938 people had T2DM and 7718 people were healthy controls. No heterogeneity was found between each subgroup of population by heterogeneity chi-squared test. A fixed model was performed to provide a pooled allelic odds ratio (OR) of rs12255372 high risk T allele of 1.40 [95% confidence interval (CI), 1.23 to 1.58, p<0.001 ]. The pooled OR of genotype with T allele for T2DM was 1.49 (95% CI, 1.29 to 1.72, p<0.001). The ORs of TT genotype and TC genotype compared with CC genotype were 1.86 (95% CI, 1.31 to 2.63, p<0.001) and 1.44 (95% CI, 1.24 to 1.68, p<0.001) respectively. The rs12255372 TC genotype and TT genotype carried similar risk. Conclusion: Rs7903146 and rs12255372 of TCF7L2 gene are associated with the risk of T2DM in Asian population.
79 (2008) S1 – S127
DWP6-4 Novel hepatocyte nuclear factor 4-alpha (HNF4A) promoter mutation in a New Zealand family Rinki Murphy 1 , Tim Cundy 1 , Sian Ellard 2 Auckland Diabetes Centre, Greenlane Clinical Centre, Auckland, NZ, 2 Insitute of Clinical & Biomedical Sciences, Peninsula Medical School, Exeter, United Kingdom 1
Mutations in the HNF4A gene encoding the transcription factor HNF-4α were first described as a cause of dominantly inherited maturity onset diabetes of the young (MODY) in 1996. 31 HNF4A gene mutations in 40 families have been described to date. There are two recognized promoters: the hepatic P1, and the pancreatic-specific P2, identified in 2001. Only two MODYassociated mutations in the P2 promoter have been described: -146T>C in an IPF1 binding site and -181G>A in an HNF1A binding site, but several common polymorphisms near this P2 promoter have been associated with type 2 diabetes. We describe a novel HNF4A mutation of the P2 promoter at -169C>T within the HNF-1α/HNF-1β binding site in a New Zealand European family with early adult-onset diabetes, macrosomia, normal lipids and variable requirement for sulfonylurea therapy. The proband was diagnosed with diabetes at the age of 16. She was not overweight (BMI 22.5) and was negative for GAD-antibodies. She was treated initially with insulin and subsequently with metformin and glibenclamide. Her older brother (also heterozygous for -169C>T) was diagnosed with diabetes at the age of 33 years and is managed on diet alone. He was macrosomic (birth weight 4.44kg at term, +2.2 SDS). Their mother (also carrying -169C>T) was diagnosed with diabetes only at the age of 57 and is also treated with diet only. The proband’s firstborn child was macrosomic (birth weight +3.2 SDS) despite excellent maternal glycemic control, and is heterozygous for the mutation. Her second child, who did not inherit the mutation, was less macrosomic (birth weight +2.2 SDS, despite poorer maternal glucose control). HNF4A mutations have recently been reported to cause neonatal hypoglycaemia, increased birth weight and macrosomia. This contrasts to most monogenic causes of diabetes that result in β-cell deficiency (such as those resulting from mutations in the genes GCK, IPF1, HNF1B, KCNJ11 and ABCC8) where neonates have reduced birth weight. The dyslipidemia described in HNF4A mutation carriers (lower HDL and higher LDL) is thought to be due to defects in hepatic P1-regulated HNF4A expression, hence those with a pancreatic P2 promoter mutation would be predicted to have normal circulating lipids. Approximately half of HNF4A mutation carriers have a good, long-term hypoglycemic response to sulfonylurea therapy.
Clinical diabetes CD1-1 Glycemic index, glycemic load and diabetes risk: a meta-analysis Alan Barclay 1 , Peter Petocz 2 , Joanna McMillan-Price 1 , Victoria Flood 1,3 , Tania Prvan 2 , Paul Mitchell 3 , Jennie Brand-Miller 1 1 Human Nutrition Unit, University of Sydney, NSW, 2006, Australia, 2 Department of Statistics, Macquarie University, NSW, 2109, Australia, 3 Department of Ophthalmology (Centre for Vision Research, Westmead Millennium Institute, Westmead Hospital), University of Sydney, NSW, Australia Inconsistent findings from observational studies have continued the controversy over the effects of glycemic index (GI), glycemic