Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease.

Associations have been reported between vitamin D receptor (VDR) gene polymorphisms, type 1 diabetes, insulin secretion, and the insulin resistance syndrome. As VDR polymorphisms have no known functional significance, these findings may implicate a variant of the VDR gene or a locus in linkage disequilibrium with the VDR. We have examined VDR mRNA and VDR protein levels in relation to VDR polymorphisms (41 Bangladeshi subjects) and analyzed insulin secretory capacity (143 Bangladeshi subjects), allowing for other known determinants. Peripheral blood mononuclear cells (PBMCs) from subjects who had been genotyped for BsmI, ApaI, TaqI, and FokI VDR restriction fragment length polymorphisms were used for both total VDR mRNA quantitation (using TaqMan) and measurement of VDR protein levels (using a specific microimmunoassay). Stepwise multiple regression analyses were used (to P < 0.05) to analyze the data. For the insulin secretion index, the best-fit model (n ‫؍‬ 143, P < 0.0001) gave age (P ‫؍‬ 0.002), TaqI (P < 0.0001), and BMI (P ‫؍‬ 0.001) as independent determinants; with the inclusion of VDR mRNA and VDR protein levels, VDR mRNA was the sole independent determinant (n ‫؍‬ 41, P ‫؍‬ 0.024). However, the best-fit model for VDR mRNA (P ‫؍‬ 0.004) gave FokI (P ‫؍‬ 0.044) and TaqI (P ‫؍‬ 0.04) genotypes and insulin secretory capacity (P ‫؍‬ 0.042) as independent determinants. For VDR protein levels, the best-fit model (P ‫؍‬ 0.006) gave TaqI genotype (P ‫؍‬ 0.005) and circulating 1,25-dihydroxyvitamin-D levels (P ‫؍‬ 0.03) as independent determinants. In conclusion, these studies confirm an association between VDR polymorphisms and insulin secretory capacity and demonstrate the VDR genotype to be a significant determinant of VDR mRNA and VDR protein levels in PBMCs, providing functional support to previously described genetic associations with the VDR gene. Furthermore, VDR expression has been shown to be a determinant of insulin secretory capacity. Because the VDR is expressed in a large number of tissues, it is not surprising that ligand-activated VDR modulates the expression of many genes. The VDR gene, located on chromosome 12q, has 14 exons, 6 of which are in the 5Ј untranslated region (1a-1f). At least 22 unique nonfunctional VDR variants have been described, most of which lead to rare syndromes associated with vitamin D-resistant rickets (4). A number of common chronic disorders of inflammatory, infective, and autoimmune etiologies, including both type 1 and type 2 diabetes and colorectal adenoma, have been shown to be associated with specific polymorphisms of the vitamin D receptor gene, although not all such associ-

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ObjectivesFamine exposure in utero can ‘programme’ an individual towards type 2 diabetes and obesity in later life. We sought to identify, (1) whether Bangladeshis exposed to famine during developmental life are programmed towards diabetes and obesity, (2) whether this programming was specific to gestational or postnatal exposure windows and (3) whether epigenetic differences were associated with famine exposure.DesignA historical cohort study was performed as part of a wider cross-sectional survey. Exposure to famine was defined through birth date and historical records and participants were selected according to: (A) exposure to famine in postnatal life, (B) exposure to famine during gestation and (C) unexposed.SettingMatlab, a rural area in the Chittagong division of Bangladesh.ParticipantsYoung adult men and women (n=190) recruited to a historical cohort study with a randomised subsample included in an epigenetic study (n=143).Outcome measuresPrimary outcome measures of weight, body mass index and oral glucose tolerance tests (0 and 120 min glucose). Secondary outcome measures included DNA methylation using genome-wide and targeted analysis of metastable epialleles sensitive to maternal nutrition.ResultsMore young adults exposed to famine in gestation were underweight than those postnatally exposed or unexposed. In contrast, more young adults exposed to famine postnatally were overweight compared to those gestationally exposed or unexposed. Underweight adults exposed to famine in gestation in utero were hyperglycaemic following a glucose tolerance test, and those exposed postnatally had elevated fasting glucose, compared to those unexposed. Significant differences in DNA methylation at seven metastable epialleles (VTRNA2-1, PAX8, PRDM-9, near ZFP57, near BOLA, EXD3) known to vary with gestational famine exposure were identified.ConclusionsFamine exposure in developmental life programmed Bangladeshi offspring towards diabetes and obesity in adulthood but gestational and postnatal windows of exposure had variable effects on phenotype. DNA methylation differences were replicated at previously identified metastable epialleles sensitive to periconceptual famine exposure.