Populations Of European Origin Research Articles

Microalbuminuria and Coronary Heart Disease Risk in an Ethnically Diverse UK Population

Microalbuminuria (MA) is a strong risk factor for subsequent chronic disease, both renal and coronary heart disease (CHD), in European origin populations, but CHD risks differ by ethnicity, and it was hypothesized that prevalence of MA and relations with CHD may also differ. Combined analyses of two population-based cohorts started in 1988 and consisted of 1460 Europeans (70% male), 946 South Asians (78% male), and 559 African Caribbeans (51% male) who resided in London and were aged 40 to 69. Baseline fasting blood, overnight urine collection, and clinical measurements were performed. Prevalent CHD was defined by clinical history or major electrocardiogram changes. Age-adjusted albumin excretion rates (AER; geometric means, mug/min) were significantly higher in African Caribbeans (men: 6.1, 95% confidence interval [CI] 5.5 to 6.7; women: 5.7, 95% CI 5.2 to 6.2) than in South Asians (men: 4.3, 95% CI 4.0 to 4.5; women 3.4, 95% CI 3.0 to 3.8) and Europeans (men: 4.5, 95% CI 4.3 to 4.8; women: 3.3, 95% CI 3.1 to 3.6). MA was associated with both prevalent CHD and CHD mortality in South Asian men (hazard ratio 2.5; 95% CI 1.3 to 4.8) and in European women (hazard ratio 13.0; 95% CI 2.6 to 64.2) but not in any other group. Greater AER in African Caribbeans and the absence of association with CHD contrast with lower AER in South Asian men and European women, both strongly associated with CHD prevalence and mortality. These differences suggest that the pathogenesis of kidney disease and its link with CHD differ by ethnicity and gender.

Unique genetic profile of hereditary hemochromatosis in Russians: High frequency of C282Y mutation in population, but not in patients

Hereditary hemochromatosis (HH) is a common cause of primary iron overload induced by genetic impairment of iron metabolism. More than 80% of HH patients in populations of European origin are homozygotes for a single mutation C282Y, or compound heterozygotes for C282Y and H63D mutations in the HFE gene. However, in the majority of Asian, African, Australasian, and Amerindian populations, frequencies of C282Y are close to zero. Data on the prevalence of HFE mutations in Russian population and in Russian patients with HH are very limited. In this work, we determined frequencies of C282Y and H63D in ethnical Russians living in the Central European region of Russia. Furthermore, we tested whether homozygocity for C282Y is the major cause of HH in Russians. We found that, in the Russian population, the frequency of C282Y mutation in the HFE gene is relatively high and corresponds to mean European levels. However, in contrast to the majority of European populations, homozygocity for C282Y is found only in a small proportion (5%) of patients with biochemical and clinical signs of HH. These data suggest that either the penetrance of C282Y in Russia is lower than in Western countries, or that a more frequent non- HFE dependent mechanism of primary iron overload dominates in Russian population.

Conspicuous by Their Absence: French Canadians and the Settlement of the Canadian West

The failure of French Canadians to settle the Canadian west before 1900, when substantial numbers of anglophones and Europeans were migrating, is a long-standing puzzle. Historians have relied mainly on cultural differences to explain it. Using new individual-level data, we demonstrate that anglophones and francophones had very different personal characteristics, so that movement to the west was rarely economically attractive for francophones. However, large-scale migration into New England fitted French Canadians’ demographic and human capital profile. Even if the United States had imposed immigration restrictions by the 1880s, this would not likely have diverted many French Canadians westward. Introduction The almost complete absence of French Canadians among settlers of Western Canada at the end of the nineteenth century is striking. Had there been a substantial flow of francophone internal migrants to the Prairies and the Pacific coast, there would have been a significant francophone presence in 1914, instead of a proportionately shrinking minority in Manitoba, and only scattered pockets of French-speaking settlers elsewhere. This is one of the great mighthave-beens of Canadian history. Without much of a base established by the beginning of the twentieth century, there was little possibility for later chain migration of French Canadians to the West. By contrast, migrants from anglophone Canada, the U.K., the U.S., and parts of continental Europe, had put networks into place by 1900. At the time of Confederation (1867), virtually all of Canada’s population was located between the Atlantic Ocean and Lake Erie. By the early 1870s, control of all British territory west to the Pacific Ocean had passed to the new dominion, but the European-origin population 1 Norrie, “Rate of Settlement”. 2 Probably less than 20 percent of the population in western Canada in 1871 was of European origin (Urquhart and Buckley, Historical Statistics, p. 4). Population data from series A2-14. 3 Manitoba became a province in 1870, British Columbia in 1871. 2 remained almost entirely in the east. Western settlement, particularly of the Prairies, was very limited until the mid 1890s, and then accelerated rapidly during the Wheat Boom. In 1871, the total population of western Canada was only about 110,000, by 1891 about 350,000, with those of European origin highly concentrated in Manitoba and British Columbia. The population nearly doubled in the next decade, rising to almost 650,000, and more than doubled (to 1.75 million) between 1901 and 1911. Westerners were less than 3 percent of the total Canadian population in 1871, almost a quarter in 1911. Regional divisions in language and ethnicity have had a tremendous impact on a wide range of Canadian institutions, fuelling bitter disputes over language policies, the appropriate degree of centralization of political decision-making, and at least since 1960, the desirability of Canada remaining as a single nation-state. As total population increased and its regional composition shifted westward, the political weight of Canada’s French Canadian minority diminished. In 1867, Quebec was the only predominantly French-speaking province, but it was one province out of four. From 1905, the year when Alberta and Saskatchewan were separated from the North West Territories, Quebec was still the only predominantly French-speaking province, and it was one province out of nine. Despite the establishment of some French Canadian settlements in Manitoba prior to the 1860s, only about 5 percent of the white population of western Canada in 1901 spoke French as

Technical standards and guidelines: Prenatal screening for Down syndrome: This new section on “Prenatal Screening for Down Syndrome,” together with the new section on “Prenatal Screening for Open Neural Tube Defects,” replaces the previous Section H of the American College of Medical Genetics Standards and Guidelines for Clinical Genetics Laboratories

Technical standards and guidelines: Prenatal screening for Down syndrome: This new section on “Prenatal Screening for Down Syndrome,” together with the new section on “Prenatal Screening for Open Neural Tube Defects,” replaces the previous Section H of the American College of Medical Genetics Standards and Guidelines for Clinical Genetics Laboratories *

The many faces of celiac disease: Clinical presentation of celiac disease in the adult population

The major modes of presentation of patients with celiac disease are the classic diarrhea-predominant form and silent celiac disease. Those with silent celiac disease lack diarrhea, although they may present with manifestations of celiac disease that include an irritable bowel syndrome, anemia, osteoporosis, neurologic diseases, or malignancy. A significant proportion of patients are diagnosed through screening at-risk groups including relatives of patients and insulin-dependant diabetics. Nondiarrheal presentations now are seen more commonly than those with diarrhea. Patients with celiac disease have a greater burden of disease than the general population because of autoimmune diseases and malignancies. There is a need for screening studies of patients with conditions associated with celiac disease to determine whether the large numbers of people with undiagnosed celiac disease currently are seeking health care.

CEPH Individuals are Representative of the European American Population: Implications for Pharmacogenetics

Previous studies have highlighted the use of phenotype generation in immortalized lymphoblastoid cells from the Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees as a powerful means of discovering genes involved in complex biological and pharmacological phenotypes. However, there is no data on how representative CEPH pedigrees are of the general population of European origin for genetic variants of pharmacogenetic significance. A vast amount of data in a population of restricted applicability would be of little value. Genotype and allele frequencies of 28 variants in 15 pharmacogenetically relevant genes were analyzed in germ-line DNA from European- and African-origin blood donors, and CEPH cell lines of European origin. The results demonstrate that allele frequencies for the 28 polymorphisms are highly similar between the CEPH and the European-origin populations. However, genotype frequencies in the CEPH population did not provide a high level of prediction for the African-origin population. These data support the usefulness of the CEPH panel in pharmacogenetic discovery efforts for European-derived populations.

Molecular Diagnosis of the First Ferroportin Mutation (C326Y) in the Far East Causing a Dominant Form of Inherited Iron Overload.

Genetic hemochromatosis (HH) is a common inherited disorder in populations of European origin in which different types of genetic hemochromatosis (type 1–4) have been characterized. Most hemochromatosis-type 1 patients are homozygotes or compound heterozygotes for two HFE mutations C282Y and H63D. Studies of several non-HFE iron overload families led to identification of mutations in hemojuvelin and hepcidin (juvenile form-HFE2A and B), transferrin receptor 2 (HFE3) and ferroportin (HFE4) as a cause of different forms of hemochromatosis. In the Far East, inherited hemochromatosis has rarely been reported and may have been misdiagnosed due to the high prevalence of secondary iron loading from hemoglobin disorders. This report describes, for the first time, non-HFE iron overload in patients from Southeast Asia. The affected Thai family presented with a distinctive clinical phenotype including macrocytosis and elevated transferrin saturation (>95%), increased non-transferrin bound iron (NTBI) as well as raised serum ferritin and marked hepatic hemochromatosis. Our patients tolerated therapeutic phlebotomy well. DNAs from peripheral blood leukocytes were firstly analyzed for three common HFE mutations (C282Y, H63D and IVS5+1 G→A). Subsequently, we screened all coding sequences, promoters and exon/intron boundaries of the HFE, HAMP, TfR2, HJV and SLC40A1 genes using denaturing high performance liquid chromatography (DHPLC). The entire coding region and splice sites of these genes were amplified and directly sequenced. We identified a novel mutation (C326Y) in ferroportin (SLC40A1, IREG-1, MTP-1), a membrane iron transport protein due to a G→A substitution at nucleotide 1281 in exon 7. This mutation was confirmed by restriction fragment length polymorphism (RFLP) analysis using Sfa NI. Six hundred Thai and two hundred Vietnamese chromosomes were analyzed for the C326Y mutation by RFLP analysis and it was not detected in any of the healthy controls studied. This result suggested that the G→A substitution is not a common polymorphism and is likely to be the causative mutation for the phenotype in this family. Previous reported mutations of ferroportin, including A77D and V162del, which lead to type IV hemochromatosis, were characterized by increased serum ferritin despite normal transferrin saturation, in contrast to our patients' phenotype. These autosomal dominant mutants are postulated to lead to disease due to loss of iron exporting function. Preliminary in vivo assay using transient transfection of wild-type and ferroportin mutants in HeLa or 293T cells revealed, as expected, a loss of function and diminished surface membrane localisation in A77D and V162del mutants. Surprisingly, the C326Y mutant was indistinguishable from wt ferroportin in both iron status of the cell and protein localization suggesting different pathophysiology leading to iron overload in our patients.

Ethnic patterns in the phonetics of Montreal English

Most North American cities no longer display strong ethnic differentiation of speech within the European‐origin population. This is not true in the English‐speaking community of Montreal, Canada, where English is a minority language. Differences in the phonetic realization of vowels by Montrealers of Irish, Italian, and Jewish ethnic origin are investigated by means of acoustic analysis. A statistical analysis of ethnic differences in formant frequencies shows that ethnicity has a significant effect on several variables, particularly the phonetic position of /u:/ and /ou/ and the allophonic conditioning of /æ/ and /au/ before nasal consonants. The unusual tenacity of ethnophonetic variation in Montreal English is explained in light of the minority status of English, and the social and residential segregation of ethnic groups in distinct neighborhoods, which limits their exposure to speakers of Standard Canadian English who might otherwise serve as models for assimilation.

Association of leptin levels with obesity and blood pressure: possible common genetic variation

To ascertain the extent to which relationships between obesity (OB) and blood pressure (BP) can be explained by an individual's leptin plasma levels. Pedigree-based cross-sectional study in an apparently healthy population of European origin. The study sample is comprised of 90 nuclear and more complex families totaling 210 male and 213 female subjects aged 18-75 y, randomly recruited in Bashkorstan Autonomic region, Russia. Various fatness and fat distribution traits (including nine circumferences (CRCs), and eight skinfolds (CKFs) by anthropometry), blood pressure, and plasma leptin levels (by ELISA kits). Adjustment for circulating leptin led to attenuation of the magnitude of correlations between OB and BP, regardless of trait pair and sex cohort. Some of these correlations became statistically nonsignificant. All familial effects were gone, and heritability estimates became virtually zero after adjustment of each of the OB traits and systolic blood pressure (SBP) in offspring for leptin values in parents. BP and OB covariation is substantially mediated by circulating leptin levels. As a result, body fat has only a weak independent effect on BP variation after adjustment for leptin levels. Our findings also strongly suggest that genetic variation in body mass index, SKFs, and even body CRCs, as well as of SBP is due to genetic variation of leptin. Genetic variation of diastolic blood pressure in the present sample, however, shared very little with that of leptin.

Indications of Linkage and Association of Gilles de la Tourette Syndrome in Two Independent Family Samples: 17q25 Is a Putative Susceptibility Region

Gilles de la Tourette syndrome (GTS) is characterized by multiple motor and phonic tics and high comorbidity rates with other neurobehavioral disorders. It is hypothesized that frontal-subcortical pathways and a complex genetic background are involved in the etiopathogenesis of the disorder. The genetic basis of GTS remains elusive. However, several genomic regions have been implicated. Among them, 17q25 appears to be of special interest, as suggested by various independent investigators. In the present study, we explored the possibility that 17q25 contributes to the genetic component of GTS. The initial scan of chromosome 17 performed on two large pedigrees provided a nonparametric LOD score of 2.41 near D17S928. Fine mapping with 17 additional microsatellite markers increased the peak to 2.61 (P=.002). The original families, as well as two additional pedigrees, were genotyped for 25 single-nucleotide polymorphisms (SNPs), with a focus on three genes in the indicated region that could play a role in the development of GTS, on the basis of their function and expression profile. Multiple three-marker haplotypes spanning all three genes studied provided highly significant association results (P<.001). An independent sample of 96 small families with one or two children affected with GTS was also studied. Of the 25 SNPs, 3 were associated with GTS at a statistically significant level. The transmission/disequilibrium test for a three-site haplotype moving window again provided multiple positive results. The background linkage disequilibrium (LD) of the region was studied in eight populations of European origin. A complicated pattern was revealed, with the pairwise tests producing unexpectedly high LD values at the telomeric TBCD gene. In conclusion, our findings warrant the further investigation of 17q25 as a candidate susceptibility region for GTS.

Ethnicity, infection and sudden infant death syndrome

Epidemiological studies found the incidence of SIDS among Indigenous groups such as Aboriginal Australians, New Zealand Maoris and Native Americans were significantly higher than those for non-Indigenous groups within the same countries. Among other groups such as Asian families in Britain, the incidence of SIDS has been lower than among groups of European origin. Cultural and childrearing practices as well as socio-economic factors have been proposed to explain the greater risk of SIDS among Indigenous peoples; however, there are no definitive data to account for the differences observed. We addressed the differences among ethnic groups in relation to susceptibility to infection because there is evidence from studies of populations of European origin that infectious agents, particularly toxigenic bacteria might trigger the events leading to SIDS. The risk factors for SIDS parallel those for susceptibility to infections in infants, particularly respiratory tract infections which are also major health problems among Indigenous groups. Many of the risk factors identified in epidemiological studies of SIDS could affect three stages in the infectious process: (1) frequency or density of colonisation by the toxigenic species implicated in SIDS; (2) induction of temperature-sensitive toxins; (3) modulation of the inflammatory responses to infection or toxins. In this review we compare genetic, developmental and environmental risk factors for SIDS in ethnic groups with different incidences of SIDS: low (Asians in Britain); moderate (European/Caucasian); high (Aboriginal Australian). Our findings indicate: (1) the major difference was high levels of exposure to cigarette smoke among infants in the high risk groups; (2) cigarette smoke significantly reduced the anti-inflammatory cytokine interleukin-10 responses which control pro-inflammatory responses implicated in SIDS; (3) the most significant effect of cigarette smoke on reduction of IL-10 responses was observed for donors with a single nucleotide polymorphism for the IL-10 gene that is predominant among both Asian and Aboriginal populations. If genetic makeup were a major factor for susceptibility to SIDS, the incidence of these deaths should be similar for both populations. They are, however, significantly different and most likely reflect differences in maternal smoking which could affect frequency and density of colonisation of infants by potentially pathogenic bacteria and induction and control of inflammatory responses.

P0355 AUTOIMMUNE HEPATITIS IN MALAYSIAN CHILDREN

Introduction: Autoimmune hepatitis (AIH) is a recognized cause of chronic childhood hepatitis. It is more commonly described in population of northern European Caucasoid origin. We described the clinical features and outcome of 8 Malaysian children with AIH. Methods: Children with abnormal liver enzymes and/or deranged liver function from 2000 onwards were included. AIH was diagnosed based on the criteria according to Alvarez et al, after known viral, drugs-related and metabolic causes of hepatitis were excluded. They were classified as AIH type 1 (positive SMA and/or ANA), AIH type 2 (positive LKM1 antibody), or AIH / primary sclerosing cholangitis overlap syndrome (AIH/PSC) if features suggestive of primary sclerosing cholangitis were present as well. Results: 8 children (5 girls, 3 boys; 5 Chinese, 2 Malays, 1 Indian; median age at referral: 6.5 years, range 2–12 years) fulfilled the diagnostic criteria. Six had AIH type 1, one had AIH type 2, and one had AIH/PSC overlap syndrome. The father of one child who has AIH type 1 has AIH type 1 himself, while another child (with AIH type 1 and thyrotoxicosis) had family history of thyrotoxicosis. Of the 7 children with AIH, 5 presented with jaundice and hepatomegaly, one had vague constitutional symptoms, abdominal pain and enlarged liver, while another child had abnormal liver enzymes on routine screening. All had raised liver cell enzymes. One child with AIH type 1 developed grade 1 hepatic encephalopathy during the course of illness. The girl with AIH/PSC had prolonged jaundice, steatorrhoea, and enlarged liver. Magnetic resonance cholangiography showed irregularity and attenuation of hepatic ducts. Liver histology ranged from mild hepatitis, chronic active hepatitis to cirrhosis. All children with AIH alone responded to prednisolone +/− azathioprine, with resolution of jaundice within one month and normalization of liver enzymes two months after therapy. All are in remission. The child with AIH/PSC had resolution of jaundice with a course of prednisolone, but the liver enzymes remained persistently elevated. Conclusion: AIH is a known cause of acute liver dysfunction in children from Asian population. It should be excluded in any children who have recent onset of jaundice, or constitutional symptoms with hepatomegaly.

A rare event of insertion polymorphism of a HERV-K LTR in the human genome

Human endogenous retroviruses (HERVs), which constitute a significant part of the human genome, might have a serious impact on primate evolution. Over a hundred insertions of HERV-K(HML-2) family members distinguish the human genome from other primate genomes. However, only three cases of insertion polymorphisms have been reported so far, all for endogenous HERV-K proviruses. This suggests that some retroviral integrations occurred rather recently in human genome evolution. In this report, we describe a very rare case of true insertion polymorphism of a solitary HERV-K LTR in the human genome. Distribution of the LTR-containing allele was tested in 5 Africans and 83 individuals from three Russian populations. The allele frequency appeared to be relatively high in populations of both European and Asian origin. The detected polymorphic LTR could be a useful molecular genetic marker of the corresponding genomic region.

Ancestral proportions and their association with skin pigmentation and bone mineral density in Puerto Rican women from New York city.

Hispanic and African American populations exhibit an increased risk of obesity compared with populations of European origin, a feature that may be related to inherited risk alleles from Native American and West African parental populations. However, a relationship between West African ancestry and obesity-related traits, such as body mass index (BMI), fat mass (FM), and fat-free mass (FFM), and with bone mineral density (BMD) in African American women has only recently been reported. In order to evaluate further the influence of ancestry on body composition phenotypes, we studied a Hispanic population with substantial European, West African, and Native American admixture. We ascertained a sample of Puerto Rican women living in New York ( n=64), for whom we measured BMI and body composition variables, such as FM, FFM, percent body fat, and BMD. Additionally, skin pigmentation was measured as the melanin index by reflectance spectroscopy. We genotyped 35 autosomal ancestry informative markers and estimated population and individual ancestral proportions in terms of European, West African, and Native American contributions to this population. The ancestry proportions corresponding to the three parental populations are: 53.3+/-2.8% European, 29.1+/-2.3% West African, and 17.6+/-2.4% Native American. We detected significant genetic structure in this population with a number of different tests. A highly significant correlation was found between skin pigmentation and individual ancestry ( R(2)=0.597, P<0.001) that was not attributable to differences in socioeconomic status. A significant association was also found between BMD and European admixture ( R(2)=0.065, P=0.042), but no such correlation was evident with BMI or the remaining body composition measurements. We discuss the implications of our findings for the potential use of this Hispanic population for admixture mapping.

Multiple sclerosis in its European matrix: some aspects of history, mechanisms and treatment.

Susceptibility to multiple sclerosis is influenced by several genes which are relatively common in populations of European origin. Their precise identification is currently being intensively investigated. The pathophysiology of the main clinical features is better understood. Relapse results from abnormalities of conduction to which both demyelination and inflammation contribute. At the membrane level, remission depends on the formation of new sodium channels which restore conduction even in persistently demyelinated axons. Remyelination presumably contributes and synaptic reorganisation may also do so. Axonal degeneration contributes to irrecoverable deficit and progression of disability. These observations suggest new therapeutic strategies. The management of multiple sclerosis needs to be improved. Progress requires an ethically based partnership between patients, whose needs are paramount, the research and caring communities and the pharmaceutical industry.

The most common mutation inFKRP causing limb girdle muscular dystrophy type 2I (LGMD2I) may have occurred only once and is present in Hutterites and other populations

Limb girdle muscular dystrophy (LGMD) is common in the Hutterite population of North America. We previously identified a mutation in the TRIM32 gene in chromosome region 9q32, causing LGMD2H in approximately two-thirds of the 60 Hutterite LGMD patients studied to date. A genomewide scan was undertaken in five families who did not show linkage to the LGMD2H locus on chromosome 9. A second LGMD locus, LGMD2I, was identified in chromosome region 19q13.3, and the causative mutation was identified as c.826C>A (L276I), a missense mutation in the FKRP gene. A comparison of the clinical characteristics of the two LGMD patient groups in this population reveals some differences. LGMD2I patients generally have an earlier age at diagnosis, a more severe course, and higher serum creatine kinase (CK) levels. In addition, some of these patients show calf hypertrophy, cardiac symptoms, and severe reactions to general anesthesia. None of these features are present among LGMD2H patients. A single common haplotype surrounding the FKRP gene was identified in the Hutterite LGMD2I patients. An identical core haplotype was also identified in 19 other non-Hutterite LGMD2I patients from Europe, Canada, and Brazil. The occurrence of this mutation on a common core haplotype suggests that L276I is a founder mutation that is dispersed among populations of European origin.

HFE mutations in the elderly

Most individuals diagnosed with hereditary hemochromatosis have mutations in both copies of the HFE gene, with such mutations being common in populations of north European origin. The number of individuals currently diagnosed and treated for hemochromatosis is small relative to the number carrying two HFE mutations. Studies searching for undiagnosed hemochromatosis cases among disease cohorts have generally failed to find the number of cases that would be expected if disease were the commonest outcome for individuals with two C282Y HFE mutations. Our aim was to test the hypothesis that individuals with two HFE mutations would be under-represented in an elderly population because many would have died from disease caused by hemochromatosis before they reached old age. This is a cross-sectional study of elderly patients referred for full blood counts at the Norfolk and Norwich University Hospital. We screened blood samples from 1000 elderly men (aged 85 and over) and women (aged 89 and over) for the C282Y, H63D, and S65C mutations of the HFE gene. We also analyzed any recent laboratory data relevant to signs of hemochromatosis. None of the ten possible genotypes was significantly under- or over-represented compared to the expected frequency calculated from the Hardy-Weinberg equation. Four C282Y homozygotes were found. There were few significant differences in the laboratory findings between the genotypes. Our data suggest that most people with HFE mutations survive to old age and do not suffer from signs of iron overload and hemochromatosis.

Lower risk of Parkinson's disease in an admixed population of European and Indian origins.

We studied whether the occurrence of Parkinson's disease (PD) in the Anglo-Indians, an admixed population of European and Asian Indian origin, differs from Indians living in the same environment. Epidemiological studies show considerably higher prevalence of PD amongst white compared to non-white populations. Normal Indians contain a approximately 40% lower number of melanized nigral neurons compared to Caucasians from the UK. Anglo-Indians are an admixed population of European and Indian origin. We used the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria (steps 1 and 2) to diagnose PD in 84 of 493 residents (Indians, 409; Anglo-Indians, 84) living in elderly homes in Bangalore, India. Of these 84, 80 were Indians (19.5%) and 4 were Anglo-Indians (4.8%). Occurrence of PD is nearly five times higher amongst Indians compared to the Anglo-Indians (odds ratio, 3.9; 95% confidence interval, 1.3-12.9). We conclude that an admixture population of European and Indian origins, rather than averaging, might result in reduced occurrences of PD. Hence, studying an admixed population could provide crucial insights into understanding genetic mechanisms in the etiopathogenesis of PD.

Autosomal recessive polycystic kidney disease: outcomes from a single-center experience.

Autosomal recessive polycystic kidney disease (ARPKD) is a relatively common form of pediatric polycystic kidney disease with an incidence of 1:20,000 live births. Previous reports, primarily from populations of European origin, indicate that the clinical presentation and disease course are quite variable. Using a retrospective study design, we sought to determine whether the clinical course and outcome of our multi-ethnic patient cohort differs from the published literature. A 10-year (1990-2000) retrospective study was conducted in which we reviewed the clinical, histopathological, and imaging records of our 31 ARPKD patients. Patients were diagnosed between 0 and 14 years of age, with 17 (55%) presenting within the 1st month of life. The mean follow-up was 67 months and age at last follow-up ranged from 0.5 to 16 years. Of the 17 patients diagnosed as neonates, 11 (65%) had respiratory insufficiency complicated by pneumothoraces. Two died shortly after birth and 2 died within the 1st year of life due to respiratory failure. Among the 13 neonatal survivors, 7 (54%) developed progressive renal insufficiency, whereas 6 of 14 (43%) of those children who presented beyond 1 month of age developed renal insufficiency. Hypertension was present in 55% of our patients, with nearly all neonatal survivors requiring antihypertensive management. Evidence of portal hypertension was found in 10 (37%) of the 27 patients who survived the 1st year of life. In our multi-ethnic ARPKD cohort, the 1-year survival rate (87%) and the clinical variability are comparable to those previously reported. With the recent identification of the PKHD1 gene, characterization of disease-causing mutations should provide new insights into the molecular basis for this phenotypic variability.

Iron metabolism in mice with partial frataxin deficiency.

Friedreich ataxia (FRDA), the most common autosomal recessive inherited ataxic disorder, is the consequence of deficiency of the mitochondrial protein frataxin, typically caused by homozygous intronic GAA expansions in the corresponding gene. The yeast frataxin homologue (yfh1p) is required for cellular respiration. Yfh1p appears to regulate mitochondrial iron homeostasis and protect from free radical toxicity. Complete loss of frataxin in knockout mice leads to early embryonic lethality, indicating an important role for frataxin during development. Heterozygous littermates with partial frataxin deficiency are apparently healthy and have no obvious phenotype. Here we evaluate iron metabolism and sensitivity to dietary and parenteral iron loading in heterozygote frataxin knockout mice (Fx(+/-)). Iron concentrations in the liver, heart, pancreas and spleen, and cellular iron distribution patterns were compared between wild type and Fx(+/-) mice. Response to parenteral iron challenge was not different between Fx(+/-) mice and wild type littermates, while sporadic iron deposits were observed in the hearts of dietary iron-loaded Fx(+/-) mice. Finally, we evaluated the effect of partial frataxin deficiency on susceptibility to cardiac damage in the mouse model of hereditary hemochromatosis (HH), the Hfe knockout mice. HH, an iron overload disease, is one of the most frequent genetic diseases in populations of European origin. By breeding Hfe(-/-) with Fx(+/-) mice, we obtained compound mutant mice lacking both Hfe and one frataxin allele. Sparse iron deposits in areas of mild to moderate cardiac fibrosis were found in the majority of these mice. However, they did not develop any neurological symptoms. Our studies indicate an association between frataxin deficiency, iron deposits and cardiac fibrosis, but no obvious association between iron accumulation and neurodegeneration similar to FRDA could be detected in our model. In addition, these results suggest that frataxin mutations may have a modifier role in HH, that predisposes to cardiomyopathy.