Association of INSIG2 rs9308762 with ALT level independent of BMI.
OBJECTIVE
An increasing number of people are at risk for developing nonalcoholic fatty liver disease (NAFLD). Because obesity is a risk factor for NAFLD, the common variants of obesity-susceptible genes may be associated with NAFLD. Our aim was to identify whether the obesity-susceptible gene variants (rs9939609, rs9930506, and rs4783819 in fat mass and obesity-associated gene (FTO); rs12970134 and rs17782313 in melanocortin-4 receptor gene (MC4R); and rs7566605, rs13428113, and rs9308762 in insulin-induced gene 2 [INSIG2]) were associated with NAFLD.


METHODS
The case-control study recruited 1027 Chinese children ages 7 to 18 years, including 162 children with NAFLD and 865 children without NAFLD. Anthropometric measurements, alanine transaminase (ALT) detection, liver ultrasound examination, and genotyping of 8 gene variants were performed.


RESULTS
The A-allele of FTO rs9939609 was associated with increased NAFLD risk (P = 0.029, odds ratio  1.43), but was not significant after being adjusted for body mass index (BMI) (P = 0.268). We also found an association between the 2 variants (rs12970134 in MC4R and rs9308762 in INSIG2) and ALT level. For rs12970134, each additional A-allele increased ALT level by 1.87 IU/L (P = 0.032). For rs9308762, the homozygotes of the C-allele had a higher ALT level than the T-allele carriers (β = 3.19, P = 0.007). After adjustment for BMI, the former association did not exist, whereas the latter reminded significant (P = 0.003).


CONCLUSIONS
The FTO rs9939609 A-allele increased risk of NAFLD and MC4R rs12970134 was associated with ALT level through an effect on BMI. The association between INSIG2 rs9308762 and ALT level was independent of BMI. The results provided evidence for identifying genetic factors of NAFLD and may be useful for risk assessment and personalized medicine of NAFLD.
*Institute of Child and Adolescent Health †Division of Maternal and Child Health, School of Public Health, Peking University, Beijing, China.
Li
L
Guan
Xiao-Rui
XR
Shang
Fang-Hong
FH
Liu
Jie-Yun
JY
Song
Jun
J
Ma
Hai-Jun
HJ
Wang
D000293:Adolescent; D000410:Alanine Transaminase / Q000097:blood / Q000235:genetics*; D000483:Alleles; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D044466:Asian People / Q000235:genetics; D015992:Body Mass Index; D016022:Case-Control Studies; D002648:Child; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics*; D009765:Obesity / Q000150:complications / Q000235:genetics; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics
C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; D000410:Alanine Transaminase