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.
Diabetes Molecular Genetics Section and, Diabetes Epidemiology, the National Institute of Diabetes and Digestive andKidney Disease, the National Institutes of Health, Phoenix, Arizona, USA.
Yunhua L
YL
Muller
Robert L
RL
Hanson
Li
L
Bian
Janel
J
Mack
Xiaolian
X
Shi
Ruth
R
Pakyz
Alan R
AR
Shuldiner
William C
WC
Knowler
Clifton
C
Bogardus
Leslie J
LJ
Baier
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