Functional SOCS1 polymorphisms are associated with variation in obesity in whites.
OBJECTIVE
The suppressor of cytokine signalling 1 (SOCS1) is a natural inhibitor of cytokine and insulin signalling pathways and may also play a role in obesity. In addition, SOCS1 is considered a candidate gene in the pathogenesis of both type 1 diabetes (T1D) and type 2 diabetes (T2D). The objective was to perform mutation analysis of SOCS1 and to test the identified variations for association to T2D-related quantitative traits, T2D or T1D.


METHODS
Mutation scanning was performed by direct sequencing in 27 white Danish subjects. Genotyping was carried out by TaqMan allelic discrimination. A total of more than 8100 individuals were genotyped.


RESULTS
Eight variations were identified in the 5' untranslated region (UTR) region. Two of these had allele frequencies below 1% and were not further examined. The six other variants were analysed in groups of T1D families (n = 1461 subjects) and T2D patients (n = 1430), glucose tolerant first-degree relatives of T2D patients (n = 212) and normal glucose tolerant (NGT) subjects. The rs33977706 polymorphism (-820G > T) was associated with a lower body mass index (BMI) (p = 0.004). In a second study (n = 4625 NGT subjects), significant associations of both the rs33977706 and the rs243330 (-1656G > A) variants to obesity were found (p = 0.047 and p = 0.015) respectively. The rs33977706 affected both binding of a nuclear protein to and the transcriptional activity of the SOCS1 promoter, indicating a relationship between this polymorphism and gene regulation.


CONCLUSIONS
This study demonstrates that functional variations in the SOCS1 promoter may associate with alterations in BMI in the general white population.
Gylvin
T
T
Steno Diabetes Center, Gentofte, Denmark.
Ek
J
J
Nolsøe
R
R
Albrechtsen
A
A
Andersen
G
G
Bergholdt
R
R
Brorsson
C
C
Bang-Berthelsen
C H
CH
Hansen
T
T
Karlsen
A E
AE
Billestrup
N
N
Borch-Johnsen
K
K
Jørgensen
T
T
Pedersen
O
O
Mandrup-Poulsen
T
T
Nerup
J
J
Pociot
F
F
D000328:Adult; D015992:Body Mass Index; D003922:Diabetes Mellitus, Type 1 / Q000208:ethnology / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics*
C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins