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Functional Variants in MBL2 Are Associated With Type 2 Diabetes and Pre-Diabetes Traits in Pima Indians and the Old Order Amish

Published on Aug 1, 2010in Diabetes7.199
· DOI :10.2337/db09-1593
Yunhua L. Muller15
Estimated H-index: 15
,
Robert L. Hanson72
Estimated H-index: 72
+ 7 AuthorsLeslie J. Baier36
Estimated H-index: 36
Abstract
Abstract Objective- MBL2 encodes the mannose-binding lectin which is a key player in the innate immune system, and has recently been found to play a role in insulin resistance and development of type 1 diabetes and gestational diabetes. To assess the role of MBL2 in diabetes susceptibility, this gene was analyzed in the Pima Indian population which has a high prevalence of type 2 diabetes. Research design and methods- Nineteen tag Single Nucleotide Polymorphisms (SNPs) were genotyped in a population-based sample of 3501 full-heritage Pima Indians and selected SNPs were further genotyped in independent samples of Native Americans (n=3723) and the Old Order Amish (n=486) subjects. Results- Two variants, a promoter SNP (rs11003125) at -550bp with a risk allele frequency of 0.77 and a Gly54Asp (rs1800450) with a risk allele frequency of 0.83 were associated with type 2 diabetes in the full-heritage Pima Indians [odds ratio (OR)=1.30 per copy of the G allele for rs1103125, P=0.0007; OR=1.30 per copy of the glycine allele for rs1800450, P=0.002, adjusted for age, sex, birth-year and family membership]. These associations replicated in an independent Native American sample (OR=1.19, P=0.04 for rs11003125) and a Caucasian sample, the Old Order Amish (OR=1.51, P=0.004 for rs1103125; OR=2.38, P=0.003 for rs1800450). Among Pima Indians with normal glucose tolerance, the diabetes risk allele glycine of Gly54Asp was associated with a decreased acute insulin response to an intravenous glucose bolus infusion (P=0.004, adjusted for age, sex, percent body fat, glucose disposal under physiological insulin stimulation and family membership). Conclusions- Our data suggest that the functional variants in MBL2 contribute to type 2 diabetes susceptibility in both Native Americans and the Old Order Amish.
  • References (31)
  • Citations (15)
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References31
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#1Lyle G. BestH-Index: 39
#2Robert E. Ferrell (University of Pittsburgh)H-Index: 89
Last. Peter Garred (UCPH: University of Copenhagen)H-Index: 55
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Background Mannose-binding lectin (MBL) forms an integral part of the innate immune system. Persistent, subclinical infections and chronic inflammatory states are hypothesized to contribute to the pathogenesis of atherosclerosis. MBL gene (MBL2) variants with between 12 to 25% allele frequency in Caucasian and other populations, result in markedly reduced expression of functional protein. Prospective epidemiologic studies, including a nested, case-control study from the present population, have ...
9 CitationsSource
#1Eleftheria Zeggini (Wellcome Trust Centre for Human Genetics)H-Index: 71
#2Laura J. Scott (UM: University of Michigan)H-Index: 62
Last. David AltshulerH-Index: 145
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Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)(1-11). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and similar to 2.2 million...
1,559 CitationsSource
This article reports that the magazine's award for Research Leader of the Year was given to the Wellcome Trust Case Control Consortium which conducted a huge genetic study to look at the genetic causes for various diseases. Their research will enable physicians to calculate the chances of a patient developing a disease that was inherited. The goal of the project is to have a patient submit a blood sample so treatment and prevention can be personalized to the patient's genetic makeup.
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#1Evadnie RampersaudH-Index: 24
#2Coleen M. DamcottH-Index: 26
Last. Alan R. ShuldinerH-Index: 92
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OBJECTIVE— We sought to identify type 2 diabetes susceptibility genes through a genome-wide association scan (GWAS) in the Amish. RESEARCH DESIGN AND METHODS— DNA from 124 type 2 diabetic case subjects and 295 control subjects with normal glucose tolerance were genotyped on the Affymetrix 100K single nucleotide polymorphism (SNP) array. A total of 82,485 SNPs were tested for association with type 2 diabetes. Type 2 diabetes–associated SNPs were further prioritized by the following: 1 ) associati...
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#1Robert L. HansonH-Index: 72
#2Clifton BogardusH-Index: 75
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#2Lucas André Cavalcanti Brandão (UFPE: Federal University of Pernambuco)H-Index: 13
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Summary Mannose-binding lectin is an important constituent of the innate immune system, the serum levels of which are greatly affected by polymorphisms of the MBL2 gene: three polymorphims in exon 1, as well as nucleotide variations in the promoter region of the gene, have been associated with protein deficiency and some infectious and autoimmune disease. The aim of this study was to investigate a possible association between MBL2 gene polymorphisms in patients who have developed type 1 diabetes...
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#1Jakob Appel Østergaard (Aarhus University Hospital)H-Index: 5
#2Steffen Thiel (AU: Aarhus University)H-Index: 69
Last. Allan Flyvbjerg (Aarhus University Hospital)H-Index: 69
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#1Richa SaxenaH-Index: 52
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New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D - in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2...
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Last. Michael F. Seldin (UC Davis: University of California, Davis)H-Index: 87
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For admixture mapping studies in Mexican Americans (MAM), we define a genomewide single-nucleotide–polymorphism (SNP) panel that can distinguish between chromosomal segments of Amerindian (AMI) or European (EUR) ancestry. These studies used genotypes for >400,000 SNPs, defined in EUR and both Pima and Mayan AMI, to define a set of ancestry-informative markers (AIMs). The use of two AMI populations was necessary to remove a subset of SNPs that distinguished genotypes of only one AMI subgroup from...
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The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci i...
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Abstract Since the early 20th century, a marked increase in obesity, diabetes, and chronic kidney disease has occurred in the American Indian population, especially the Pima Indians of the Southwest. Here, we review the current epidemic and attempt to identify remediable causes. A search was performed using PubMed and the search terms American Indian and obesity, American Indian and diabetes, American Indian and chronic kidney disease, and American Indian and sugar or fructose, Native American, ...
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