The South Asian genome.

The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.

A novel albumin gene mutation (R222I) in familial dysalbuminemic hyperthyroxinemia.

CONTEXT: Familial dysalbuminemic hyperthyroxinemia, characterized by abnormal circulating albumin with increased T4 affinity, causes artefactual elevation of free T4 concentrations in euthyroid individuals. OBJECTIVE: Four unrelated index cases with discordant thyroid function tests in different assay platforms were investigated. DESIGN AND RESULTS: Laboratory biochemical assessment, radiolabeled T4 binding studies, and ALB sequencing were undertaken. (125)I-T4 binding to both serum and albumin in affected individuals was markedly increased, comparable with known familial dysalbuminemic hyperthyroxinemia cases. Sequencing showed heterozygosity for a novel ALB mutation (arginine to isoleucine at codon 222, R222I) in all four cases and segregation of the genetic defect with abnormal biochemical phenotype in one family. Molecular modeling indicates that arginine 222 is located within a high-affinity T4 binding site in albumin, with substitution by isoleucine, which has a smaller side chain predicted to reduce steric hindrance, thereby facilitating T4 and rT3 binding. When tested in current immunoassays, serum free T4 values from R222I heterozygotes were more measurably abnormal in one-step vs two-step assay architectures. Total rT3 measurements were also abnormally elevated. CONCLUSIONS: A novel mutation (R222I) in the ALB gene mediates dominantly inherited dysalbuminemic hyperthyroxinemia. Susceptibility of current free T4 immunoassays to interference by this mutant albumin suggests likely future identification of individuals with this variant binding protein.

Presence of hepcidin-25 in biological fluids: bile, ascitic and pleural fluids.

AIM: To examine body fluids such as ascitic fluid (AF), saliva, bile and pleural effusions for the presence of hepcidin using a novel radioimmunoassay (RIA). METHODS: Serum samples were collected from 25 healthy volunteers (mean age: 36 +/- 11.9 years, 11 males, 14 females). In addition bile was obtained from 12 patients undergoing endoscopic retrograde cholangiopancreatography (mean age: 66.9 +/- 16.7 years, M:F = 5:7). Saliva was collected from 17 healthy volunteers (mean age: 35 +/- 9.9 years, M:F = 8:9). Pleural and AF were collected from 11 and 16 patients [(mean age: 72 +/- 20.5 years, M:F = 7:4) and (mean age: 67.32 +/- 15.2 years, M:F = 12:4)], respectively. All biological fluid samples (serum, exudative and transudative fluids) were tested for the presence of hepcidin-25 molecule using RIA. RESULTS: Hepcidin-25 was detected in all biological fluids tested. The mean +/- SD hepcidin-25 in serum was 15.68 +/- 15.7 ng/mL, bile 7.37 +/- 7.4 ng/mL, saliva 3.4 +/- 2.8 ng/mL, exudative fluid 65.64 +/- 96.82 ng/mL and transudative fluid 14.1 +/- 17.8 ng/mL. CONCLUSION: We provide clear evidence that hepcidin-25 is present in bile, saliva, pleural and ascitic fluids. Hepcidin is likely to play a role here in innate immunity.

Hepcidin and inflammatory bowel disease: dual role in host defence and iron homoeostasis.

OBJECTIVE: Hepcidin is an endogenous antimicrobial peptide with a key role in iron homoeostasis. Hepcidin is similar to defensin, the deficiency of which is associated with Crohn's disease. To date there has been no validated method to reliably assay serum hepcidin. We studied iron indices in inflammatory bowel disease (IBD) including hepcidin. DESIGN: We assessed serum hepcidin concentrations (using a newly developed competitive radioimmunoassay) and ferritin in patients with IBD. Haematinics including serum soluble transferrin receptor, serum iron, serum vitamin B12 and red cell folate levels were also measured. The hepcidin results were compared with a control group of healthy volunteers from the local community. SETTING: This study was based in a hospital. PATIENTS: Sixty-one patients with IBD (51 patients with ulcerative colitis and 10 with Crohn's disease). Their mean hepcidin results were compared with 25 healthy controls. MAIN OUTCOME MEASURE: hepcidin concentration in serum samples in IBD patients compared with normal volunteers. RESULTS: We found significantly low serum hepcidin levels in patients with IBD. The hepcidin levels were low in IBD patients without iron deficiency anaemia as evidenced by normal ferritin and serum iron levels (n=41, mean hepcidin 6.81 ng/ml, SEM 1.2) and in IBD patients with iron deficiency anaemia (n=18, mean hepcidin 4.14 ng/ml, SEM 0.72) compared with healthy controls (n=25, mean hepcidin 15.3 ng/ml, SEM 3.14) (P=0.0045 and P=0.0050 on unpaired t-tests, respectively). We also measured IL-6 (enzyme-linked immunosorbent assay method, Abcam plc) in 21 of the 61 patients with IBD and compared the results with samples from 10 healthy volunteers. The IL-6 level was significantly higher (P=0.0222 on unpaired t-tests) in this group of IBD patients (n=21, IL-6 mean 2.94 pg/ml, SEM 0.64) compared with controls (n=10, IL-6 mean 0.663 pg/ml SEM 0.14). A significant positive correlation (Pearson's correlation coefficient r=0.6331) was present between hepcidin and IL-6, but not between hepcidin and serum soluble transferrin receptor (r=-0.235). CONCLUSION: The low hepcidin results in IBD patients may reflect a causal or perpetuator effect on intestinal inflammation.

Prohepcidin levels in refractory anaemia caused by lead poisoning.

Recent research evidence suggests a central role for hepcidin in iron homeostasis. Hepcidin is a hormone synthesized in the liver. Hepcidin is also thought to play a vital role in the pathogenic mechanism of anaemia in patients with inflammation or chronic disease. A 38-year-old female who presented with recurrent abdominal pain was found to have raised urinary porphyrins and a blood lead level of 779 µg/l. Her haemoglobin level was 8.3 g/dl. Her MCV was normal. Serum ferritin, B12 and folate were normal. Her serum prohepcidin level was 2,489 ng/ml (normal <450 ng/ml). To our knowledge, this is the first report of raised prohepcidin levels in a patient with anaemia of chronic disease resulting from lead poisoning.