Three common intronic variants in the maternal and fetal thiamine pyrophosphokinase gene (TPK1) are associated with birth weight.

Extreme variations in birth weight increase immediate postnatal mortality and morbidity, and are also associated with the predisposition to metabolic diseases in late adulthood. Birth weight in humans is influenced by yet unknown genetic factors. Since the 7q34-q35 region showed linkage with birth weight in a recent human genome scan (p = 8.10(-5)), this study investigated the TPK1 (thiamine pyrophosphokinase) gene locus, located in 7q34-36. Having found no coding variants in the TPK1 gene, we genotyped 43 non coding SNPs spanning a region of 420kb, and used the QTDT method to test their association with birth weight in 964 individuals from 220 families of European ancestry. Family-based tests detected association of 8 SNPs with birth weight (p<0.008), but after correction for multiple tests only rs228581 C/T (p = 0.03), rs228582 A/G (p = 0.04) and rs228584 C/T (p = 0.03) were still associated with birth weight, as well as their T-A-T haplotype (p = 0.03). In addition, we found an association between maternal rs228584 genotype and offspring birth weight (p = 0.027). These observations suggest that genomic variations in the fetal and maternal TPK1 gene could contribute to the variability of birth weight in normal humans.