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 first Danish case of Aarskog syndrome is reported. The child had attended several specialized out-patient clinics before the diagnosis was suggested. This underlines the need for dysmorphology in paediatrics.
Genetic diversity, including single nucleotide polymorphisms, contributes to both disease susceptibility and variability in drug response. Since most genes contain multiple single nucleotide polymorphisms, identifying those that are most relevant with respect to disease or drug response is important and may uncover variants that are predictive of either disease susceptibility or therapeutic response to drugs, both with respect to efficacy and toxic side effects. The candidate gene approach has been widely used to search for the genetic basis of pharmacogenomic traits. Although a few successful examples have emerged from this approach, notably trastuzumab (Herceptin; Genentech), imatinib mesylate (Gleevec (USA), Glivec; Novartis) and certain drugs that demonstrate variable efficacy or adverse effects that are attributed to metabolizing enzymes, for most drugs, the genetic variations that determine their clinical response remain uncovered. Genome-wide linkage approach presents an alternative to the candidate gene approach. The powerful combination of linkage when coupled to ultra-high-throughput genotyping, gene array and proteomics technology, together with innovative bioinformatic resources, provides a focused integrative strategy for pinpointing disease-causing genes that may generate validated drug targets and genes that are responsible for differential drug response. Thus, it is anticipated that genetic research will soon generate new information that can be used to develop novel therapeutic strategies and diagnostic tests that will ultimately lead to safer and more efficacious drugs for all patients. This review addresses recent advances in the development of genetic markers that can be used to diagnose disease or drug response.
Numerous asthma and atopy loci have been reported in studies demonstrating associations of the asthma-related phenotypes atopy, elevated IgE levels, and bronchial hyperresponsiveness with alleles of microsatellite markers and single-nucleotide polymorphisms (SNPs) within specific cytokine/chemokine and IgE-regulating genes. Although the studies reporting these observations are compelling, most of them lack statistical power. We assessed the nature, pattern, and frequency of SNPs in 24 candidate genes in Iceland and looked for associations with asthma and atopy. We identified 42 SNPs with an average minor allele frequency of 20.3% (asthma) and 20.7% (control). Twenty SNPs (48%) were within coding sequences and 90% of those led to a predicted change in protein sequence. No differences were detected in the allelic frequencies of SNPs in any of these candidate genes between control subjects and the patients with atopic asthma. Moreover, linkage analysis that included 269 patients with atopic asthma uncovered no evidence of linkage to markers associated with these genes. We conclude that this study has failed to produce evidence in support of the notion that variations within these 24 candidate atopy and asthma genes significantly influence the expression of the atopic asthmatic phenotype or contribute to the susceptibility of atopic asthma.
Comment In: Am J Respir Crit Care Med. 2001 Dec 1;164(11):2014-511739127
AIM: The aim of the present investigation is to study the epidemiology of Alport syndrome in southern Sweden, to search for mutations in the COL4A5 gene and to estimate the mutation frequency. PATIENTS AND METHODS: Patients with suspected Alport syndrome were identified in an area with a population of 1.45 million. Clinical criteria were used to establish the diagnosis and samples for mutation analysis were collected. Mutation analyses were performed with Single-Stranded Conformation Polymorphism analysis (SSCP) of PCR-amplified genomic DNA. RESULTS: Altogether 25 families with hereditary nephritis were identified. Alport syndrome with X-linked transmission was evident in 14 families, with juvenile ( or = 31 years) in four families. CONCLUSION: The frequency of males with X-linked disease was calculated to one in 17,000 male births (95% confidence interval (CI) 1/10,500-1/28,600), and the prevalence to one in 40,000. A total of seven females with ESRF were identified, with a median age at ESRF of 45 years. The male to female ratio of cases with ESRF was 4.9 to 1. The risk of developing ESRF among females was from the expected incidence roughly estimated to 12%. Patients with X-linked disease constituted 1.8% of patients with ESRF in the examined area. A mutation was identified positive in 10 of 14 families with X-linked disease, but never in families not fulfilling the clinical criteria for Alport syndrome. In families with juvenile phenotype and positive mutation analysis, the mutation frequency was calculated to between 1/78,000 and 1/198,000 (95% CI 1/42,000-1/177,000) if the effective fertility was estimated to be between 0 and 0.2.
The mode of inheritance and the clinical manifestations of amelogenesis imperfecta (AI) were studied in 51 families from the county of Västerbotten, northern Sweden. Autosomal dominant (AD) was the most probable mode of inheritance in 33 families, but X-linked dominant (XD) inheritance was a possible alternative in one family. Autosomal recessive (AR) inheritance was found likely in 6 and X-linked recessive inheritance in 2 families. Ten probands were sporadic cases. In the families with AD inheritance, a sex difference was observed between affected and non-affected cases, with an excess of females in the affected group (p less than 0.05). In addition to the 78 index cases, 107 new cases were diagnosed. The clinical manifestations of AI observed could be divided into 2 forms, the hypoplastic form in 72% and the hypomineralization form in 28% of the individuals. AD inheritance was seen in 89% of the cases with the hypoplastic form, and in 44% of the cases with the hypomineralization form. In most families with AD or AR inheritance, each family displayed a characteristic manifestation of either hypoplastic or hypomineralization defects. In 3 families, both hypoplastic and hypomineralization forms of AI were seen. In families with X-linked inheritance, the clinical manifestation differed between females and males with males more seriously affected.
The clinical manifestations of amelogenesis imperfecta (AI) were described in 165 individuals from 51 families. The inheritance pattern for AI in these families had previously been investigated, and it was hypothesized that AI probably is solely an autosomal dominant (AD) or X-linked trait. To test this hypothesis the connection between clinical manifestation and inheritance pattern was studied. Eight different variants of AI were seen. In 33/51 families all affected individuals could be assigned to the same clinical variant. In 8/51 families those affected were assigned to different clinical variants. In the two families where an X-linked recessive (XR) inheritance pattern was found probable, the clinical manifestation differed between women and men. Except for one variant only seen as an AD trait, and the manifestation in women in families with an X-linked recessive inheritance pattern, no connection was found between a specific inheritance pattern and a specific clinical manifestation. Accordingly it seems likely that AI is solely an AD or X-linked trait. The different clinical variants observed should be regarded as a varying expressivity of the gene and in the families with X-linked inheritance probably due to lyonization. In the remaining families the modifying mechanisms are not known.
The proinflammatory cytokine interferon (IFN)-gamma has been shown to influence the course of multiple sclerosis (MS). The IFN-gamma (IFNG) contains a multiallelic dinucleotide repeat in intron 1. To investigate whether alleles at this locus influence susceptibility to MS, we performed linkage and familial association analyses on 100 sibling pairs from four Nordic countries, and case-control association analysis on 220 intermediately disabled sporadic MS patients and 266 controls. To determine the effect of the polymorphism on disease outcome, we compared genotype frequencies in the most and least disabled octiles of a total cohort of 913 cases. We also measured IFN-gamma mRNA levels in unstimulated peripheral blood mononuclear cells from 46 MS patients and 27 controls grouped according to IFNG intron 1 genotype. Both nonparametric linkage analysis and transmission disequilibrium testing of the 100 sibling pairs produced negative results. Genotype frequencies for intermediate-MS patients did not differ significantly from those for controls; nor did genotype frequencies in the benign-MS octile differ significantly from those in the severe-MS octle. Comparison of IFN-gamma mRNA levels in genotype-conditioned subgroups revealed no significant differences. Thus, alleles at the IFNG intron 1 dinucleotide repeat appear to affect neither MS susceptibility and severity nor IFN-gamma mRNA expression in vivo.
Putative prostate cancer susceptibility loci have recently been identified by genetic linkage analysis on chromosomes 1q24-25 (HPC1). 1q44.243 (PCaP), and Xq27-28 (HPCX). In order to estimate the genetic linkage in Icelandic prostate cancer families, we genotyped 241 samples from 87 families with eleven markers in the HPC1 region, six markers at PCaP, and eight at HPCX. Concurrently, we assessed allelic imbalance at the HPC1 and PCaP loci in selected tumors from the patients. For each of the candidate regions, the combined parametric and non-parametric LOD scores were strongly negative. Evidence for linkage allowing for genetic heterogeneity was also insignificant for all the regions. The results were negative irrespective of whether calculations were performed for the whole material or for a selected set of early age at onset families. The prevalence of allelic imbalance was relatively low in both the HPC1 (0%-9%) and PCaP (5%-20%) regions and was not elevated in tumors from positively linked families. Our studies indicate that the putative cancer susceptibility genes at chromosomes 1q24-25, 1q44.2-43, and Xq27-28 are unlikely to contribute significantly to hereditary prostate cancer in Iceland and that selective loss of the HPC1 and PCaP loci is a relatively rare somatic event in prostate cancers.
Alterations in monoamine oxidase A (MAOA) expression and enzyme activity may be associated with alcoholism and impulsive behavior. Therefore, functional polymorphisms in the MAOA gene would be good candidates to consider in the interindividual differences that exist in the susceptibility to alcoholism. One variant that has been considered as a candidate in alcoholism is a repeat polymorphism in the MAOA gene promoter. We analyzed a cohort of Finnish males with either type 1 or type 2 alcoholism, as well as controls, for differences in the distribution of MAOA promoter alleles. Based on other studies, we postulated that type 2 alcoholism, which is associated with antisocial behavior, but not type 1 alcoholism, would be correlated with the inheritance of the low promoter activity allele. However, we failed to find a difference in allele distribution in type 1 and type 2 alcoholics. In addition, there was no difference in the allele distribution when each group of alcoholics was compared with controls. However, when both groups of alcoholics were pooled and compared with controls, the difference in allele distribution reached a trend towards significance. Our results suggest a minimal association between the MAOA low activity promoter alleles and alcoholism, regardless of the presence or absence of antisocial behavior. Interestingly, approximately 3% of type 2 alcoholics were found to be heterozygous for the MAOA promoter polymorphism. Since MAOA is X-linked, the heterozygotes are probable cases of Klinefelter's syndrome (47,XXY) suggesting that X-chromosome aneuploidy may increase the risk for developing type 2 alcoholism.