Genetic association study for RSV bronchiolitis in infancy at the 5q31 cytokine cluster.

BACKGROUND: The pathophysiological basis of severe respiratory syncytial virus (RSV) bronchiolitis in infancy is poorly understood and has hindered vaccine development. Studies implicate the cell-mediated immune response in the pathogenesis of the disease. A recent twin study estimated a heritable contribution of 22% to RSV bronchiolitis. Genetic epidemiology provides a new approach to identifying important immune determinants of disease severity. METHODS: A comprehensive high-density gene-region association study for severe RSV bronchiolitis in infancy at 5q31 across 11 genes including the Th2-cytokine cluster was performed. A haplotype tagging approach was used to analyse genetic variation at 113 single nucleotide polymorphisms (SNPs) in 780 independent cases and 1045 controls. The study had sufficient power to detect small effects, perform extensive haplotype analysis and analyse both a principal phenotype and a refined age-limited phenotype enriched for first-exposure RSV infection. RESULTS: SNP associations were found at IL4 and a highly significant risk haplotype was identified across IL13 CNS-1 and IL4 (odds ratio 1.69, p<0.0001), present in both case-control and family-based analyses. All associations were strongest for a phenotype limited to <6 months of age, implicating this locus in primary RSV disease. The same risk haplotype has previously been shown to be associated with increased IL13 expression. CONCLUSIONS: A haplotype at IL13-1L4, which is associated with increased IL13 production, confers an increased risk of severe primary RSV bronchiolitis in early infancy. This study, together with previous studies implicating the same locus in atopic sensitisation, suggests that primary RSV bronchiolitis and atopy share a genetic contribution at the IL13-IL4 locus.

Interferon regulatory factor-1 polymorphisms are associated with the control of Plasmodium falciparum infection.

We describe the haplotypic structure of the interferon regulatory factor-1 (IRF-1) locus in two West African ethnic groups, Fulani and Mossi, that differ in their susceptibility and immune response to Plasmodium falciparum malaria. Both populations showed significant associations between IRF-1 polymorphisms and carriage of P. falciparum infection, with different patterns of association that may reflect their different haplotypic architecture. Genetic variation at this locus does not therefore account for the Fulani-specific resistance to malaria while it could contribute to parasite clearance's ability in populations living in endemic areas. We then conducted a case-control study of three haplotype-tagging single nucleotide polymorphisms (htSNPs) in 370 hospitalised malaria patients (160 severe and 210 uncomplicated) and 410 healthy population controls, all from the Mossi ethnic group. All three htSNPs showed correlation with blood infection levels in malaria patients, and the rs10065633 polymorphism was associated with severe disease (P=0.02). These findings provide the first evidence of the involvement in malaria susceptibility of a specific locus within the 5q31 region, previously shown to be linked with P. falciparum infection levels.

Population-specific patterns of linkage disequilibrium in the human 5q31 region.

Linkage disequilibrium across the human genome is generally lower in West Africans than Europeans. However in the 5q31 region, which is rich in immune genes, we find significantly more examples of apparent nonrecombination between distant marker pairs in West Africans. Much of this effect is due to SNPs that are absent in Europeans, possibly reflecting recent positive selection in the West African population.

Growth of long-term survivors of liver transplantation.

OBJECTIVE: To assess growth in survivors of liver transplantation. STUDY DESIGN: Growth was studied in 105 children up to seven years after liver transplantation. RESULTS: At transplantation, mean height standard deviation score (zH) was -1.22 but 19% of patients were severely growth retarded (height below 0.4th centile). Growth and pubertal retardation were seen in the first six months after liver transplantation. Significant catch up in growth and puberty continued for more than five years. At five years, mean zH was -0.95 and at seven years -0.84. The mean zH of patients at final height was -0.55. zH at six months was predicted by zH and bilirubin at the time of transplantation and prednisolone dose at six months. At four years, zH was predicted by zH at the time of transplantation and the cumulative prednisolone dose. There was no association between zH and age at transplantation, sex, or diagnosis, although those with biliary atresia and those undergoing transplantation under 2 years of age showed more initial growth delay and subsequent catch up. Average age at menarche was 14.2 years. CONCLUSIONS: The mean height of the group to have reached final height after liver transplantation was on the 27th centile. Those transplanted earlier in childhood are likely to achieve more normal final heights. High steroid dose, poor liver function, and retransplantation are associated with poorer height outcomes. Persisting severe short stature is largely confined to children with severely retarded growth at the time of transplantation. Transient delay in puberty and menarche occur early after transplantation, although appropriate pubertal progress is resumed after two to three years.