No abstract

The Wright (Wr) blood group antigens, Wra and Wrb, have been suggested to be determined by alleles of the same gene. The Wrb antigen appears to involve both red blood cell (RBC) band 3 and glycophorin A (GPA). We have examined the cDNA sequences of the band 3 and GPA of one of the two known Wr(a+b-) individuals. We show that this individual is homozygous for the mutation Glu658--<Lys in band 3, but has normal GPA. Putative heterozygotes with Wr(a+b+) RBCs have both Glu and Lys at residue 658 of band 3, whereas the common Wr(a-b+) RBC phenotype only have band 3 with Glu658. The Wra and Wrb antigens are determined by the amino acid at residue 658 of band 3 and are antithetical. Examination of the amino acid sequence and Wrb antigen expression of GPA-related hybrid glycophorins suggests that Arg61 of GPA interacts with Glu658 of band 3 to form the Wrb antigen. We suggest that the interaction is stabilized by the presence of anti-Wrb antibodies and that this site of association between GPA and band 3 may be responsible for the previously reported ability of anti-GPA antibodies to decrease the deformability of RBCs.

Aims/hypothesisInsulin-like growth factor-1 is a major childhood growth factor and promotes pancreatic islet cell survival and growth in vitro. We hypothesised that genetic variation in IGF1 might be associated with childhood growth, glucose metabolism and type 1 diabetes risk. We therefore examined the association between common genetic variation in IGF1 and predisposition to type 1 diabetes, childhood growth and metabolism.Materials and methodsVariants in IGF1 were identified by direct resequencing of the exons, exon–intron boundaries and 5′ and 3′ regions in 32 unrelated type 1 diabetes patients. A tagging subset of these variants was genotyped in a collection of type 1 diabetes families (3,121 parent–child trios). We also genotyped a previously reported CA repeat in the region 5′ to IGF1. A subset of seven tag single nucleotide polymorphism (SNPs) that captured variants with minor allele frequency (MAF) ≥0.05 was genotyped in 902 children from the Avon Longitudinal Study of Parents And Children with data on growth, IGF-1 concentrations, insulin secretion and insulin action.ResultsResequencing detected 27 SNPs in IGF1, of which 11 had a MAF > 0.05 and were novel. Variants with MAF ≥ 0.10 were captured by a set of four tag-SNPs. These SNPs showed no association with type 1 diabetes. In children, global variation in IGF1 was weakly associated with IGF-1 concentrations, but not with other phenotypes. The CA repeat in the region 5′ to IGF1 showed no association with any phenotype.Conclusions/interpretationCommon genetic variation in IGF1 alters IGF-1 concentrations but is not associated with growth, glucose metabolism or type 1 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-008-0970-7) contains supplementary material, which is available to authorised users.

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Here, we analyse 1000-Genome reference panel imputed genotype data on up to ~370,000 women and identify 389 independent signals (all P<5×10 -8 ) for age at menarche, a notable milestone in female pubertal development. In Icelandic data from deCODE, these signals explain ~7.4% of the population variance in age at menarche, corresponding to one quarter of the estimated heritability. We implicate over 250 genes via coding variation or associated gene expression, and demonstrate enrichment across genes active in neural tissues. We identify multiple rare variants near the imprinted genes MKRN3 and DLK1 that exhibit large effects on menarche only when paternally inherited. Disproportionate effects of variants on early or late puberty timing are observed: single variant and heritability estimates are larger for early than late puberty timing in females. The opposite pattern is seen in males, with larger estimates for late than early puberty timing. Mendelian randomization analyses indicate causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women, and prostate cancer in men. In aggregate, our findings reveal new complexity in the genetic regulation of puberty timing and support new causal links with adult cancer risks.

BackgroundStatistical models (known as epigenetic clocks) that use an individual’s DNA methylation to predict their age have recently been developed, with 96% correlation found between predicted and chronological age. Departures of predictions from actual age, called age acceleration residuals, can be used as a measure of biological ageing. We aimed to investigate whether age acceleration was associated with development during childhood and adolescence using repeated measures data from a large birth cohort in the UK.MethodsWe obtained DNA methylation at three clinics (birth, age 7 and 17) in 1018 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We used the epigenetic clock algorithm to obtain DNA methylation age for each child at each clinic. Age acceleration residuals were obtained for each sample as a measure of the difference between predicted and actual age. We then investigated whether age acceleration was associated with repeated measures of height, weight, BMI, bone mineral density, bone mass, fat mass or lean mass. Multilevel models were used to account for both between- and within-individual correlation in the birth cohort, and spline terms were used to account for nonlinear trajectories over time.ResultsIn ALSPAC, the epigenetic clock predicted actual age with a correlation of 96% and an average absolute difference between predicted and actual age of 2.9 years. Positive age acceleration at birth was associated with higher average height (0.65 cm per year of age acceleration, 95% CI 0.02 cm–1.29 cm; p = 0.044) and fat mass (1.39 kg per year of age acceleration, 95% CI 0.54–2.34 kg; p = 0.002) during childhood and adolescence (i.e., from age 0–17).DiscussionThe epigenetic clock represents a useful application of DNA methylation data, with a correlation of 96% between chronological and predicted age. We have found evidence that being ahead of one’s epigenetic clock at birth is associated with increased height and fat mass. This demonstrates the potential of using age acceleration as a measure of development in future research. Our analysis was limited in having data available until 17 rather than into adulthood, but our strengths include  repeated measurements of both developmental responses and DNA methylation.