Genetic interactions of KIR and G1M immunoglobulin allotypes differ in obese from non-obese individuals with type 2 diabetes.
We analyzed the natural killer cell immunoglobulin-like receptor (KIR) genes and immunoglobulin allotypes in the development of type 2 diabetes (T2D) based on body mass index (BMI) measurements (obese vs. non-obese) in Puerto Rican Americans. Genetic interactions between the KIR haplotype A homozygotes (HAH) and its fraction containing two inhibitory receptors 2DL3 and 2DL1 and the activating receptor 2DS4 with immunoglobulin allotypes were studied. We found a significant association between the HAH and T2D (p=0.002; OR=7.97) and its interaction with the immunoglobulin allotype z: GM f/f (-) (p=<0.0001; OR, not determined) only in non-obese individuals. This association were due to the interactions between the 2DL3/2DL3, 2DL1/2DL1, and 2DS4 fragment with GM f/f (-) in T2D patients (p=0.0017; OR=3.45). Analysis based on BMI demonstrated associations in both obese (p=0.037; OR=2.43; 95% CI=0.97-6.31) and non-obese individuals (p=<0.0001; OR=8.38; 95% CI=2.49-29.31). By contrast, the interaction of the GM allotype f/f (-) with the HAH fragment was associated with T2D only in non-obese individuals (p=<0.0001; OR=18.2; 95% CI=3.71-113.4). As expected, interaction of both HAH and its fragment with HLA-C group's ligands were significant. We used informative short tandem repeats (STRs) that distinguish major populations to determine genetic admixture and found that there was no genetic stratification in our cohort. Our findings are consistent with the possibility of an autoimmune and/or innateimmune component in the pathogenesis of T2D: NK receptors with chronic inflammation in obese and genetic interactions with G1M allotype in T2D non-obese possibly mediating autoimmunity.
Romero
Viviana
V
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Zúñiga
Joaquin
J
Azocar
Jose
J
Clavijo
Olga P
OP
Terreros
Daniel
D
Kidwai
Hassan
H
Pandey
Janardan P
JP
Yunis
Edmond J
EJ
D000368:Aged; D015992:Body Mass Index; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006630:Hispanic or Latino / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007126:Immunoglobulin Allotypes / Q000235:genetics*; D007129:Immunoglobulin Gm Allotypes / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020559:Monomeric GTP-Binding Proteins; D009765:Obesity / Q000235:genetics*; D011647:Puerto Rico / Q000208:ethnology; D054340:Receptors, KIR / Q000032:analysis / Q000235:genetics*; D014481:United States
D007126:Immunoglobulin Allotypes; D007129:Immunoglobulin Gm Allotypes; D054340:Receptors, KIR; C490245:GEM protein, human; D020559:Monomeric GTP-Binding Proteins