Functional variants in MBL2 are associated with type 2 diabetes and pre-diabetes traits in Pima Indians and the old order Amish.
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 mellitus. 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.


METHODS
Nineteen tag single nucleotide polymorphisms (SNPs) were genotyped in a population-based sample of 3,501 full-heritage Pima Indians, and selected SNPs were further genotyped in independent samples of Native American (n = 3,723) and Old Order Amish (n = 486) subjects.


RESULTS
Two variants, a promoter SNP (rs11003125) at -550 bp 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 1.30 per copy of the G allele for rs1103125, P = 0.0007, and 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 (1.19, P = 0.04, for rs11003125) and a Caucasian sample, the Old Order Amish (1.51, P = 0.004, for rs1103125 and 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.
Muller
Yunhua L
YL
Diabetes Molecular Genetics Section and, Diabetes Epidemiology, the National Institute of Diabetes and Digestive andKidney Disease, the National Institutes of Health, Phoenix, Arizona, USA.
Hanson
Robert L
RL
Bian
Li
L
Mack
Janel
J
Shi
Xiaolian
X
Pakyz
Ruth
R
Shuldiner
Alan R
AR
Knowler
William C
WC
Bogardus
Clifton
C
Baier
Leslie J
LJ
D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005951:Glucose Tolerance Test; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008297:Male; D037601:Mannose-Binding Lectin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011236:Prediabetic State / Q000453:epidemiology / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D033303:Protestantism; D018570:Risk Assessment; D044465:White People / Q000235:genetics; D055815:Young Adult
C445619:MBL2 protein, human; D037601:Mannose-Binding Lectin