Coeliac disease has a very strong genetic component: the ratio of the risk of first degree relatives (13%)33,34
to the population risk (0.5%)35
is 26. The CD concordance rate in twins has long been cited as proof of the “genetic load” of the disease. However, concordance rates were based only on case series that rarely included DZ twins.
We have conducted the first population based study in a large area—that is, the south of Italy, which constitutes 40% of the Italian population. To verify that there was no ascertainment bias in the study, we compared the “recruited” twinning rate (1:104) with the expected rate (1:103)20
and also the MZ:DZ of the same sex:DZ of the opposite sex ratio (1.3:1.0:0.8) with the expected ratio (1:1:1). The close agreement between the observed and expected ratios suggests that this study was not affected by a reporting and/or selection bias.
Unlike earlier screening methods, the anti-tTG test was very efficient in identifying silent CD cases.25,26
In fact, anti-tTG screening revealed five clinically silent concordant pairs. However, this test does not predict who may become positive in the future. Therefore, data for individuals less than 20 years of age should be regarded with caution as some of these discordant pairs may change status in the future.
Three of the five MZ discordant pairs were children. One adult MZ pair was discordant at both screening and biopsy. In the other adult discordant pair, the non-index twin was negative for the tTG screening test but refused biopsy. We must await the results of follow up examinations to establish the definitive rate of concordance.2
Our MZ concordance rate of 75.0% probably errs on the low side, and is likely to increase during the follow up of discordant twins. Identification of three asymptomatic cases improved the estimate of concordance, which is quite high for a multifactorial disease. In fact, the concordance rate in MZ twin pairs is 13% for insulin dependent diabetes mellitus,36
12.3% for rheumatoid arthritis,37
26.7% for multiple sclerosis,38
11.1% for systemic lupus erythematosus,39
16% for ulcerative colitis,40
and 20% for Crohn's disease.40
The conclusion of this study does not differ greatly from that of earlier non-population based studies. The MZ versus DZ concordance rate provides a reliable estimate of the size of the genetic component in a disease whereas the DZ twins versus ordinary siblings concordance rate gives an estimate of the effect of a shared environment.41
In the case of CD, the DZ twins:siblings ratio appeared to be close to 1 as the incidence of the disease in siblings was above 11.1% which is very close to that observed in DZ twin pairs (11%). Therefore, our data may suggest that a shared environment (gluten antigen aside) has little or no effect on the concordance of DZ twins reared together.
As expected, the risk of being concordant increased with age and with female sex of the non-index twin. Interestingly, all of the MZ pairs not presenting DQA1*0501/DQB1*0201 or DQA1*0301/DQB1*0302 had a DRB1*07 allele. The pairs in this group were: DRB1*07/07 (CD concordant), DRB1*07/08 (CD concordant), and DRB1*07/07 (CD discordant).
The concordance rate did not differ significantly between DZ twins with the same HLA pattern and DZ twins with different HLA patterns but with the at risk HLA haplotype. Therefore, it is not inconceivable that the HLA molecules that trigger the immune reaction to gliadin peptides do not differ in relation to the CD associated HLA genotype.
These data suggest that environmental factors, apart from gluten, have little or no effect on the pathogenesis of CD. It is generally agreed that HLA contributes to the onset of CD. However, the MZ/DZ concordance rate ratio (0.857/0.20=4.28) and the logistic regression analysis showing that, after adjustment for the HLA at risk haplotype the risk of MZ pairs to be concordant was 17, suggest that other genes are involved in the pathogenesis of the disease. A long term follow up may reveal that the discordance of MZ twins is due to epigenetic factors.
Although genes other than HLA may be implicated in CD, large genome screening studies have failed to identify a gene that exerts a major effect. Consequently, it is likely that the large genetic load of CD identified in this study may not be produced by a missing or “altered” gene but by a series of genetic characteristics which individually exert little effect but which collectively characterise a large gluten intolerant tribe that is spread throughout the gluten consuming world.42