1. Dmo1 (Diabetes Mellitus OLETF type I) is a major quantitative trait locus for dyslipidaemia, obesity and diabetes phenotypes of male Otsuka Long Evans Tokushima Fatty (OLETF) rats. 2. Our congenic lines, produced by transferring Dmo1 chromosomal segments from the non-diabetic Brown Norway (BN) rat into the OLETF strain, have confirmed the strong, wide-range therapeutic effects of Dmo1 on dyslipidaemia, obesity and diabetes in the fourth (BC4) and fifth (BC5) generations of congenic animals. Analysis of a relatively small number of BC5 rats (n = 71) suggested that the critical Dmo1 interval lies within a
Calcium urolithiasis is often associated with increased intestinal absorption and urine excretion of calcium, and has been suggested to result from increased vitamin D production. The role of the enzyme 1 alpha-hydroxylase, the rate-limiting step in active vitamin D production, was evaluated in 36 families, including 28 sibships with at least a pair of affected sibs, using qualitative and quantitative trait linkage analyses. Sibs with a verified calcium urolithiasis passage (n = 117) had higher 24-h calciuria (P = 0.03), oxaluria (P = 0.02), fasting and postcalcium loading urine calcium/creatinine (Ca/cr) ratios (P = 0.008 and P = 0.002, respectively), and serum 1,25(OH)2 vitamin D levels (P = 0.02) compared with nonstone-forming sibs (n = 120). Markers from a 9-centiMorgan interval encompassing the VDD1 locus on chromosome 12q13-14 (putative 1 alpha-hydroxylase) were analyzed in 28 sibships (146 sib pairs) of single and recurrent stone formers and in 14 sibships (65 sib pairs) with recurrent-only (> or = 3 episodes) stone-forming sibs. Two-point and multipoint analyses did not reveal excess in alleles shared among affected sibs at the VDD1 locus. Linkage of stone formation to the VDD1 locus could be excluded, respectively, with a lambda d of 2.0 (single and recurrent stone formers) and 3.25 (recurrent stone formers). Quantitative trait analyses revealed no evidence for linkage to 24-h calciuria and oxaluria, serum 1,25(OH)2 vitamin D levels, and Ca/cr ratios. This study shows absence of linkage of the putative 1 alpha-hydroxylase locus to calcium stone formation or to quantitative traits associated with idiopathic hypercalciuria. In addition, there is coaggregation of calciuric and oxaluric phenotypes with stone formation.
Over 45 years ago, Montreal Platelet Syndrome was first described as a rare inherited platelet disorder characterised by macrothrombocytopenia with spontaneous platelet clumping, abnormal platelet shape change upon stimulation and a defect in platelet calpain. This syndrome has now been reclassified as type 2B von Willebrand disease with the V1316M VWF mutation in the only kindred ever reported. We herein revisit the historical platelet characteristics originally described in Montreal Platelet Syndrome in light of the new diagnosis. This paper will review the 45-year saga of Montreal Platelet Syndrome, a story that highlights the value of revisiting a rare diagnosis to look for a more common explanation.
The role of 5-aminosalicylic acid (5-ASA) in Crohn's disease is unclear. The outcome of the first course of 5-ASA monotherapy with emphasis on 5-ASA dependency was retrospectively assessed in consecutive cohort of 537 Crohn's disease patients diagnosed 1953-2007.
Following outcome definitions were used: Immediate outcome (30 days after 5-ASA start) defined as complete/partial response (total regression/improvement of symptoms) and no response (no regression of symptoms with a need of corticosteroids, immunomodulator or surgery). Long-term outcome defined as prolonged response (still in complete/partial response 1 year after induction of response); 5-ASA dependency (relapse on stable/reduced dose of 5-ASA requiring dose escalation to regain response or relapse =1 year after 5-ASA cessation regaining response after 5-ASA re-introduction).
One hundred sixty-five (31%) patients had monotherapy with 5-ASA. In 50% 5-ASA monotherapy was initiated =1 year after diagnosis (range 0-49 years). Complete/partial response was obtained in 75% and no response in 25% of patients. Thirty-six percent had prolonged response, 23% developed 5-ASA dependency and 38% were non-responders in long-term outcome. Female gender had higher probability to develop prolonged response or 5-ASA dependency (OR 2.89, 95%CI: 1.08-7.75, p=0.04). The median duration (range) of 5-ASA monotherapy was 34 months (1-304) in prolonged responders, 63 (6-336) in 5-ASA dependent and 2 (0-10) in non-responders.
A selected phenotype of Crohn's disease patients may profit from 5-ASA. Fifty-nine percent of patients obtained long-term benefit with 23% becoming 5-ASA dependent. Prospective studies are warranted to assess the role of 5-ASA in Crohn's disease.
Several copy number variants have been associated with neuropsychiatric disorders and these variants have been shown to also influence cognitive abilities in carriers unaffected by psychiatric disorders. Previously, we associated the 15q11.2(BP1-BP2) deletion with specific learning disabilities and a larger corpus callosum. Here we investigate, in a much larger sample, the effect of the 15q11.2(BP1-BP2) deletion on cognitive, structural and functional correlates of dyslexia and dyscalculia. We report that the deletion confers greatest risk of the combined phenotype of dyslexia and dyscalculia. We also show that the deletion associates with a smaller left fusiform gyrus. Moreover, tailored functional magnetic resonance imaging experiments using phonological lexical decision and multiplication verification tasks demonstrate altered activation in the left fusiform and the left angular gyri in carriers. Thus, by using convergent evidence from neuropsychological testing, and structural and functional neuroimaging, we show that the 15q11.2(BP1-BP2) deletion affects cognitive, structural and functional correlates of both dyslexia and dyscalculia.
Bladder exstrophy is a congenital malformation of the bladder and urethra. The genetic basis of this malformation is unknown however it is well known that chromosomal aberrations can lead to defects in organ development. A few bladder exstrophy patients have been described to carry chromosomal aberrations. Chromosomal rearrangements of 22q11.2 are implicated in several genomic disorders i.e. DiGeorge/velocardiofacial- and cat-eye syndrome. Deletions within this chromosomal region are relatively common while duplications of 22q11.2 are much less frequently observed. An increasing number of reports of microduplications of this region describe a highly variable phenotype. We have performed array-CGH analysis of 36 Swedish bladder exstrophy patients. The analysis revealed a similar and approximately 3 Mb duplication, consistent with the recently described 22q11.2 microduplication syndrome, in two unrelated cases with bladder exstrophy and hearing impairment. This finding was confirmed by multiplex ligation-dependent probe amplification (MLPA) and FISH analysis. Subsequent MLPA analysis of this chromosomal region in 33 bladder exstrophy patients did not reveal any deletion/duplication within this region. MLPA analysis of 171 anonymous control individuals revealed one individual carrying this microduplication. This is the first report of 22q11.2 microduplication associated with bladder exstrophy and hearing impairment. Furthermore the finding of one carrier among a cohort of normal controls further highlights the variable phenotype linked to this microduplication syndrome.
Numerous linkage studies have indicated chromosome 18q21-22 as a locus of importance for blood pressure regulation. This locus harbors the neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) gene, which is instrumental for the regulation of the amiloride-sensitive epithelial sodium channel (ENaC). In a linkage study of 16 markers (including two single nucleotide polymorphism markers located within the NEDD4L gene) on chromosome 18 between 70-104 cM and ambulatory blood pressure (ABP), in 118 families, the strongest evidence of linkage was found for 24 h and day-time systolic ABP at the NEDD4L locus (82.25 cM) (P=0.0014). In a large population sample (n=4001), we subsequently showed that a NEDD4L gene variant (rs4149601), which by alternative splicing leads to varying expression of a functionally crucial C2 domain, was associated with diastolic blood pressure (DBP) (P=0.03) and DBP progression over time (P=0.04). A genotype combination of the rs4149601 and an intronic NEDD4L marker (rs2288774) was associated with systolic blood pressure (SBP) (P=0.01), DBP (P=0.04), and progression of both SBP (P=0.03) and DBP (P=0.05) over time. A quantitative transmission disequilibrium test in the family material of the rs4149601 supported this NEDD4L variant as being at least partially causative of the linkage result. In conclusion, our findings suggest that the chromosome 18 linkage peak at 82.25 cM is explained by genetic NEDD4L variation affecting cross-sectional and longitudinal blood pressure, possibly as a consequence of altered NEDD4L interaction with ENaC.
The objective was to test the hypothesis that a described association between homozygosity for a 50bp deletion in the SOD1 promoter 1684bp upstream of the SOD1 ATG and an increased age of onset in SALS can be replicated in additional SALS and control sample sets from other populations. Our second objective was to examine whether this deletion attenuates expression of the SOD1 gene. Genomic DNA from more than 1200 SALS cases from Ireland, Scotland, Quebec and the USA was genotyped for the 50bp SOD1 promoter deletion. Reporter gene expression analysis, electrophoretic mobility shift assays and chromatin immunoprecipitation studies were utilized to examine the functional effects of the deletion. The genetic association for homozygosity for the promoter deletion with an increased age of symptom onset was confirmed overall in this further study (p=0.032), although it was only statistically significant in the Irish subset, and remained highly significant in the combined set of all cohorts (p=0.001). Functional studies demonstrated that this polymorphism reduces the activity of the SOD1 promoter by approximately 50%. In addition we revealed that the transcription factor SP1 binds within the 50bp deletion region in vitro and in vivo. Our findings suggest the hypothesis that this deletion reduces expression of the SOD1 gene and that levels of the SOD1 protein may modify the phenotype of SALS within selected populations.
The rise of ancient genomics has revolutionised our understanding of human prehistory but this work depends on the availability of suitable samples. Here we present a complete ancient human genome and oral microbiome sequenced from a 5700 year-old piece of chewed birch pitch from Denmark. We sequence the human genome to an average depth of 2.3× and find that the individual who chewed the pitch was female and that she was genetically more closely related to western hunter-gatherers from mainland Europe than hunter-gatherers from central Scandinavia. We also find that she likely had dark skin, dark brown hair and blue eyes. In addition, we identify DNA fragments from several bacterial and viral taxa, including Epstein-Barr virus, as well as animal and plant DNA, which may have derived from a recent meal. The results highlight the potential of chewed birch pitch as a source of ancient DNA.
To investigate, at a population level, whether a family history of abdominal aortic aneurysm (AAA) is independently related to increased aortic diameter and prevalence of AAA in men, and to elucidate whether the mean aortic diameter and the prevalence of AAA are different between participants with male and female relatives with AAA.
18,614 male participants screened for AAA in the VIVA-trial 2008-2011 with information on both family history of AAA and maximal aortic diameter.
Standardized ultrasound scan measurement of maximum antero-posterior aortic diameter. Family history obtained by questionnaire. Multivariate regression analysis was used to test for confounders: age, sex, smoking, comorbidity and medication.
From the screened cohort, 569 participants had at least one first degree relative diagnosed with AAA, and 38 had AAA. Participants with a family history of AAA (+FH) had a significantly larger mean maximum aortic diameter (20.50 mm) compared with participants without family history of AAA (-FH) (19.07 mm, p