Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes.
We identified a locus on chromosome 6q16.3-q24.2 (ref. 1) associated with childhood obesity that includes 2.4 Mb common to eight genome scans for type 2 diabetes (T2D) or obesity. Analysis of the gene ENPP1 (also called PC-1), a candidate for insulin resistance, in 6,147 subjects showed association between a three-allele risk haplotype (K121Q, IVS20delT-11 and A-->G+1044TGA; QdelTG) and childhood obesity (odds ratio (OR) = 1.69, P = 0.0006), morbid or moderate obesity in adults (OR = 1.50, P = 0.006 or OR = 1.37, P = 0.02, respectively) and T2D (OR = 1.56, P = 0.00002). The Genotype IBD Sharing Test suggested that this obesity-associated ENPP1 risk haplotype contributes to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesity-associated A-->G+1044TGA SNP, was specific for pancreatic islet beta cells, adipocytes and liver. These findings suggest that several variants of ENPP1 have a primary role in mediating insulin resistance and in the development of both obesity and T2D, suggesting that an underlying molecular mechanism is common to both conditions.
Meyre
David
D
CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France.
Bouatia-Naji
Nabila
N
Tounian
Agnès
A
Samson
Chantal
C
Lecoeur
Cécile
C
Vatin
Vincent
V
Ghoussaini
Maya
M
Wachter
Christophe
C
Hercberg
Serge
S
Charpentier
Guillaume
G
Patsch
Wolfgang
W
Pattou
François
F
Charles
Marie-Aline
MA
Tounian
Patrick
P
Clément
Karine
K
Jouret
Béatrice
B
Weill
Jacques
J
Maddux
Betty A
BA
Goldfine
Ira D
ID
Walley
Andrew
A
Boutin
Philippe
P
Dina
Christian
C
Froguel
Philippe
P
D000328:Adult; D016022:Case-Control Studies; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test; D006239:Haplotypes; D006801:Humans; D009765:Obesity / Q000235:genetics*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D011755:Pyrophosphatases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics
D012333:RNA, Messenger; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases