Meta-analysis of the IPF1 D76N polymorphism in a worldwide type 2 diabetes population.
OBJECTIVE
Mutations in the IPF1 gene cause MODY4; IPF1 D76N is a polymorphism, which inhibits the insulin promoter and decreases insulin-secretion. We planned to estimate the odds ratio (OR) between D76N genotype and type 2 diabetes (T2D) in Italian, European and worldwide cohorts.


METHODS
We recruited 90 unrelated late-onset T2D subjects and 50 unrelated control subjects from Italy. We screened the subjects for IPF1 mutations. We sequenced the control subjects' DNA to determine D76N presence/absence and tested for association in the Italian dataset. We estimated the OR for a T2D cohort of D76N carriers by performing a meta-analysis of published data from multiple populations. We performed the association by pooling ORs and we tested for heterogeneity between the different population samples. We analyzed separately total, late-onset and early-onset T2D subjects using both European and worldwide data. The statistical power for each data set was defined.


RESULTS
In the Italian cohort, we identified one late-onset T2D subject and his affected sibling as D76N carriers and one late-onset T2D subject as a carrier of a silent mutation (P244P). Our meta-analysis shows only a trend toward association in the early-onset European population. Given the observed rarity of the putative susceptibility genotype, power to detect a significant association between D76N and T2D for OR < 1.59 was less than 0.8 in all samples.


CONCLUSIONS
So far, this is the largest association study regarding the effect of D76N IPF1 on T2D. We conclude that D76N IPF1 is not contributing to T2D in early-onset or late-onset cohorts in the currently present worldwide dataset.
Gragnoli
C
C
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Claudia.Gragnoli@gmail.com
Cronsell
J
J
D000328:Adult; D016009:Chi-Square Distribution; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005060:Europe; D014943:Global Health; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007558:Italy; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D015534:Trans-Activators / Q000235:genetics*
D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein