Association between polymorphisms at the GREM1 locus and the risk of nonsyndromic cleft lip with or without cleft palate in the Polish population.

BACKGROUND

The locus on chromosome 15q13.3 containing GREM1 is correlated with the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P). The aim of the present study was to find the GREM1 functional variants implicated in the aetiology of this common developmental anomaly in the Polish population.

METHODS

Eight polymorphisms were genotyped in 334 NSCL/P patients and 955 controls. In addition, the GREM1 protein-coding region was sequenced in 96 NSCL/P patients.

RESULTS

Significant association with a risk of oral clefts was found for 5 tested polymorphisms. The lowest p(trend) values were identified for rs16969681, rs16969816, and rs1258763 (p(trend) 4.09E-05, 3.35E-05, and 0.0002, respectively). The putative functional variant rs16969681, located in a region that has enhancer activity, was associated with a 2.6-fold lower risk for NSCL/P (odds ratio [OR] = 0.38; 95% confidence interval [CI], 0.24-0.61, p = 2.37E-05). The previously reported association of rs1258763 with NSCL/P was replicated (OR = 0.57; 95% CI, 0.44-0.73; p = 1.10E-05). For all tested GREM1 variants, no significant sex-by-genotype interaction effects were observed. The sequencing analysis did not detect any rare variants implicated in the development of oral clefts.

CONCLUSION

Our results might suggest that variants influencing GREM1 expression levels, rather than variants affecting the function of the encoded protein, are significant factors in NSCL/P etiology.