Association of hypoxia inducible factor-1 alpha gene polymorphism with both type 1 and type 2 diabetes in a Caucasian (Hungarian) sample.
BACKGROUND
Hypoxia inducible factor-1 alpha (HIF-1alpha) is a transcription factor that plays an important role in neo-vascularisation, embryonic pancreas beta-cell mass development, and beta cell protection. Recently a non synonymous single nucleotide polymorphism (g.C45035T SNP, rs11549465) of HIF-1alpha gene, resulting in the p.P582S amino acid change has been shown to be associated with type 2 diabetes (T2DM) in a Japanese population. Our aim was to replicate these findings on a Caucasian (Hungarian) population, as well as to study whether this genetic effect is restricted to T2DM or can be expanded to diabetes in general.


METHODS
A large Caucasian sample (N = 890) was recruited including 370 T2DM, 166 T1DM and 354 healthy subjects. Genotyping was validated by two independent methods: a restriction fragment analysis (RFLP) and a real time PCR using TaqMan probes. An overestimation of heterozygotes by RFLP was observed as a consequence of a nearby SNP (rs34005929). Therefore genotyping results of the justified TaqMan system were accepted. The measured genotype distribution corresponded to Hardy-Weinberg equilibrium (P = 0.740)


RESULTS
As the TT genotype was extremely rare in the population (0.6% in clinical sample and 2.5% in controls), the genotypes were grouped as T absent (CC) and T present (CT and TT). Genotype-wise analysis showed a significant increase of T present group in controls (24.0%) as compared to patients (16.8%, P = 0.008). This genetic effect was demonstrated in the separated samples of type 1 (15.1%, P = 0.020), and also in type 2 (17.6%, P = 0.032) diabetes. Allele-wise analysis gave identical results showing a higher frequency of the T allele in the control sample (13.3%) than in the clinical sample (8.7%, P = 0.002) with similar results in type 1 (7.8%, P = 0.010) and type 2 (9.1%, P = 0.011) diabetes. The odds ratio for diabetes (either type 1 or 2) was 1.56 in the presence of the C allele.


CONCLUSIONS
We confirmed the protective effect of a rare genetic variant of HIF-1alpha gene against type 2 diabetes in a Caucasian sample. Moreover we demonstrated a genetic contribution of the same polymorphism in type 1 diabetes as well, supporting a possible overlap in pathomechanism for T2DM and a T1DM.
Nagy
Geza
G
2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary. ngeza@bel2.sote.hu
Kovacs-Nagy
Reka
R
Kereszturi
Eva
E
Somogyi
Aniko
A
Szekely
Anna
A
Nemeth
Nora
N
Hosszufalusi
Nora
N
Panczel
Pal
P
Ronai
Zsolt
Z
Sasvari-Szekely
Maria
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D054458:Amplified Fragment Length Polymorphism Analysis; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006814:Hungary; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014162:Transfection; D044465:White People / Q000235:genetics; D055815:Young Adult
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
Carcinogenesis. 2003 Nov;24(11):1779-83
12919954
Nat Genet. 2007 Sep;39(9):1074-82
17676041
Diabetes. 2004 Mar;53(3):821-9
14988269
Diabetes. 2001 Jun;50(6):1290-301
11375329
Cell. 2001 Oct 5;107(1):43-54
11595184
Hum Immunol. 2008 Apr-May;69(4-5):279-83
18486763
Cardiovasc Res. 2005 Feb 15;65(3):564-73
15664382
Diabetologia. 2001 Jan;44(1):3-15
11206408
Mol Cancer. 2003 Sep 09;2:31
14521712
Transplant Proc. 2004 May;36(4):1178-80
15194408
Circ Res. 1995 Sep;77(3):638-43
7641334
Mol Cell Biol. 1996 Sep;16(9):4604-13
8756616
Nature. 2001 Dec 13;414(6865):782-7
11742409
Proc Natl Acad Sci U S A. 1993 May 1;90(9):4304-8
8387214
Diabetologia. 2008 Jul;51(7):1100-10
18504548
Diabetologia. 2007 Oct;50(10):2218-20
17657473
Science. 2001 Oct 19;294(5542):564-7
11577200
Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4
7539918
Clin Chim Acta. 2008 Jan;387(1-2):9-17
17963738
Curr Opin Clin Nutr Metab Care. 2008 Jul;11(4):500-4
18542013
J Clin Endocrinol Metab. 2001 Feb;86(2):574-82
11158011
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7987-92
9653127
Nature. 2001 Dec 13;414(6865):792-8
11742411
Diabetes. 1999 Apr;48(4):738-44
10102689
Oncogene. 2001 Aug 16;20(36):5067-74
11526493
Diabetologia. 2001 Jul;44(7):914-22
11508279
Prostate. 2005 May 15;63(3):215-21
15538748
Lancet. 2001 Jul 21;358(9277):221-9
11476858
Diabetologia. 2007 Jan;50(1):212-3
17063324
Curr Med Chem. 2002 Apr;9(8):793-7
11966444
Diabetes. 2004 Apr;53(4):963-70
15047611
Diabetologia. 1989 Jan;32(1):2-6
2707516
J Biol Chem. 1996 Jul 26;271(30):17771-8
8663540
Immunogenetics. 2006 Apr;58(2-3):107-12
16508738
Behav Res Methods. 2007 May;39(2):175-91
17695343
Immunol Today. 1990 Apr;11(4):122-9
2187469
J Biol Chem. 1997 Apr 25;272(17):11205-14
9111021
J Clin Endocrinol Metab. 2005 Oct;90(10):5841-7
16046581
J Biol Chem. 1998 Dec 11;273(50):33501-7
9837930
J Biol Chem. 1997 Aug 1;272(31):19253-60
9235919
Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12217-8
16894143
Diabetes Obes Metab. 2006 Jan;8(1):75-82
16367885
Rev Endocr Metab Disord. 2003 Sep;4(3):233-41
14501174
Am Heart J. 2007 Dec;154(6):1035-42
18035072
Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R202-9
16987885
Diabetes. 2003 Jan;52(1):102-10
12502499
Diabetes. 2008 Jul;57(7):1983-6
18426861