Homozygosity or mixed heterozygosity for mutations in the adenine phosphoribosyltransferase gene cause enzyme deficiency directing adenine through an alternative metabolic pathway. This results in the production of 2,8-dihydroxyadenine, which is actively secreted into the urine. 2,8-dihydroxyadenine is insoluble at physiological urinary pH but as marked supersaturation is possible the manifestations differ: there may be minimal consequences, there may be infiltration of the tubulointerstitial tissue with acute or chronic damage or there may be stone formation in the urinary tract. Effective treatment can be offered and therefore the prognosis depends upon the renal function at diagnosis. Treatment consists of adequate fluid intake, a low-purine diet and administration of allopurinol. Urinary 2,8-dihydroxyadenine crystals are easily recognized under a microscope. The diagnosis of 2,8-dihydroxyadeninuria can be confirmed by estimation of adenine phosphoribosyltransferase activity in erythrocyte lysates. More than 300 cases of 2,8-dihydroxyadeninuria have been diagnosed worldwide, most of them in Japan, France and Iceland. One case has been reported in Finland but there have been no reports from the Scandinavian peninsula or from Denmark. The relevant mutations may be very rare in these countries but underdiagnosis is also possible.
Prostate cancer is a significant cause of death in Western countries and is under the strong influence of androgens. The steroid 5alpha-reductase 2 catalyzes the metabolism of testosterone into the more potent androgen dihydrotestosterone in the prostate gland. The enzyme is a target in pharmacological treatment of benign prostatic hyperplasia using specific inhibitors such as finasteride. Makridakis et al. have characterized the V89L and A49T polymorphisms in recombinant expression systems. The L allelic variant has a lower Vmax/Km ratio than the V variant. In the A49T polymorphism, the T variant has an increased Vmax/Km ratio. We performed a population-based case-control study of the impact of the SRD5A2 V89L and A49T polymorphisms on the risk of prostate cancer. We also studied the relation between the genotypes and age at diagnosis, tumor, node, metastasis stage, differentiation grade, prostate specific antigen and heredity. The study included 175 prostate cancer patients and 159 healthy controls that were matched for age. There was an association with SRD5A2 V89L LL genotype and metastases at the time of diagnosis, OR 5.67 (95% CI 1.44-22.30) when adjusted for age, differentiation grade, T-stage and prostate specific antigen. Heterozygous prostate cancer cases that carried the SRD5A2 A49T AT genotype were significantly younger than cases that carried the AA genotype, (mean age 66 years vs 71, P = 0.038). The SRD5A2 V89L and A49T polymorphisms were, however, not associated with altered prostate cancer risk. Further studies of the V89L polymorphism may lead to better understanding of the etiology of prostate cancer metastases.
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.
Since beta2-adrenergic receptors are important regulators of blood pressure, genetic variation in this receptor could explain risk of elevated blood pressure in selected individuals. We tested the hypothesis that Gly16Arg, Gln27Glu, and Thr164Ile in the beta2-adrenergic receptor gene associated with elevated blood pressure.
We genotyped 9185 individuals from the adult Danish general population.
Allele frequencies of 16Arg, 27Glu, and 164Ile were 0.38, 0.44, and 0.01, respectively. Among women never treated with antihypertensive medication those heterozygous for Thr164Ile versus non-carriers had increased diastolic blood pressure (P=0.02). Women heterozygous for Thr164Ile versus non-carriers had an odds ratio for elevated blood pressure of 1.93 (95% CI: 1.30-2.86). Finally, women double heterozygous for Thr164Ile and Gln27Glu or Gly16Arg versus non-carriers at all 3 loci had an odds ratio for elevated blood pressure of 2.49 (1.28-4.85) or 3.19 (1.46-6.97). In men, blood pressure was not influenced by this genetic variation.
In women Thr164Ile heterozygosity is associated with increased diastolic blood pressure, and represent a risk factor for elevated blood pressure in women in the general population. This was most pronounced in those women also heterozygous for Gln27Glu or Gly16Arg.
The -250G>A promoter variant in hepatic lipase associates with elevated fasting serum high-density lipoprotein cholesterol modulated by interaction with physical activity in a study of 16,156 Danish subjects.
CONTEXT: Hepatic lipase plays a pivotal role in the metabolism of high-density lipoprotein (HDL) and low-density lipoprotein by involvement in reverse cholesterol transport and the formation of atherogenic small dense low-density lipoprotein. OBJECTIVES: The objective was to investigate the impact of variants in LIPC on metabolic traits and type 2 diabetes in a large sample of Danes. Because behavioral factors influence hepatic lipase activity, we furthermore examined possible gene-environment interactions in the population-based Inter99 study. DESIGN: The LIPC -250G>A (rs2070895) variant was genotyped in the Inter99 study (n = 6070), the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care Denmark screening cohort of individuals with risk factors for undiagnosed type 2 diabetes (n = 8662), and in additional type 2 diabetic patients (n = 1,064) and glucose-tolerant control subjects (n = 360). RESULTS: In the Inter99 study, the A allele of rs2070895 associated with a 0.057 mmol/liter [95% confidence interval (CI) 0.039-0.075] increase in fasting serum HDL-cholesterol (HDL-c) (P = 8 x 10(-10)) supported by association in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care study [0.038 mmol/liter per allele (95% CI 0.024-0.053); P = 2 x 10(-7)). The allelic effect on HDL-c was modulated by interaction with self-reported physical activity (P(interaction) = 0.002) because vigorous physically active homozygous A-allele carriers had a 0.30 mmol/liter (95% CI 0.22-0.37) increase in HDL-c compared with homozygous G-allele carriers. CONCLUSIONS: We validate the association of LIPC promoter variation with fasting serum HDL-c and present data supporting an interaction with physical activity implying an increased effect on HDL-c in vigorous physically active subjects carrying the -250 A allele. This interaction may have potential implications for public health and disease prevention.
Nijmegen breakage syndrome (NBS, OMIM 251260) is a rare hereditary disease, characterized by immune deficiency, microcephaly, and an extremely high incidence of lymphoid tissue malignancies. The gene mutated in NBS, NBS1, was recently cloned from its location on chromosome 8q21. The encoded protein, nibrin (p95), together with hMre11 and hRad50, is involved in the double-strand DNA break repair system. We screened two Russian cohorts for the 657del5 NBS1 mutation and found no carriers in 548 controls and two carriers in 68 patients with lymphoid malignancies: one with acute lymphoblastic leukemia (ALL) and one with non-Hodgkin lymphoma (NHL). Several relatives of the second patient, who were carriers of the same mutation, had cancer (ALL, breast cancer, GI cancers). These preliminary data suggest that NBS1 mutation carriers can be predisposed to malignant disorders.
To evaluate C to T substitution at nucleotide 677 of N(5), N(10)-methylenetetrahydrofolate reductase gene in women with prior preeclamptic or normotensive pregnancies.
Methylenetetrahydrofolate reductase genotypes were determined in 113 Finnish women with preeclamptic first pregnancies and 103 controls with one or more normotensive pregnancies, using polymerase chain reaction and restriction enzyme analysis. Preeclampsia was defined as severe in 100 women who fulfilled one or more of the subsequent criteria: systolic blood pressure (BP) at least 160 mmHg, diastolic BP at least 110 mmHg, or proteinuria at least 2 g per 24-hour urine collection.
There were no significant differences in prevalences of the methylenetetrahydrofolate reductase genotypes (CC, CT, and TT) between groups (57%, 40%, and 3% in the preeclamptic group and 54%, 39%, and 7%, respectively, in controls). The frequency of the T677 allele was 0.23 in the preeclamptic group and 0.26 in the control group (difference 0.03; 95% confidence interval -0.08, 0.14; P =.51). Our sample had 60% power to detect a difference of the allele frequencies similar to that (0.12) reported previously. The result was similar when analysis was restricted to patients with severe preeclampsia (T677 allele frequency 0.22).
A carrier status for the T677 allele of the methylenetetrahydrofolate reductase gene does not predispose to preeclampsia, at least in the Finnish population.
Inherited retinal dystrophies represent the most important cause of vision impairment in adolescence, affecting approximately 1 out of 3000 individuals. Mutations of the photoreceptor-specific gene ABCA4 (ABCR) are a common cause of retinal dystrophy. A number of mutations have been repeatedly reported for this gene, notably the 2588G>C mutation which is frequent in both patients and controls. Here we ascertained the frequency of the 2588G>C mutation in a total of 2343 unrelated random control individuals from 11 European countries and 241 control individuals from the US, as well as in 614 patients with STGD both from Europe and the US. We found an overall carrier frequency of 1 out of 54 in Europe, compared with 1 out of 121 in the US, confirming that the 2588G>C ABCA4 mutation is one of the most frequent autosomal recessive mutations in the European population. Carrier frequencies show an increasing gradient in Europe from South-West to North-East. The lowest carrier frequency, 0 out of 199 (0%), was found in Portugal; the highest, 11 out of 197 (5.5%), was found in Sweden. Haplotype analysis in 16 families segregating the 2588G>C mutation showed four intragenic polymorphisms invariably present in all 16 disease chromosomes and sharing of the same allele for several markers flanking the ABCA4 locus in most of the disease chromosomes. These results indicate a single origin of the 2588G>C mutation which, to our best estimate, occurred between 2400 and 3000 years ago.
Sudden death due to acute intoxication occurs frequently in patients with opioid addiction (OA). To examine whether certain genotypes were associated with this, we examined the frequencies of 29 SNPs located in candidate genes related to opioid pharmacology: ABCB1, OPRM1, UGT2B7, CYP3A5, CYP2B6, CYP2C19, CYP2D6, COMT, KCNJ6 and SCN9A in 274 deceased patients with OA (DOA), 309 living patients with OA (LOA) and in 394 healthy volunteers (HV). The main hypothesis of the study was that subjects homozygous for the variant 3435T in ABCB1 (rs1045642) occur more frequently in DOA than in LOA and HV because morphine and methadone more readily cross the blood barrier in these subjects due to a lower efflux transporter activity of the ABCB1 (p-glycoprotein) transporter. Our results did not support this hypothesis, because no statistically significant difference (p = 0.506) in the frequency of the TT genotype of rs1045642 was observed between the DOA, LOA and HV cohorts. However, for another ABCB1 variant, rs9282564, we found that the frequencies of the AG and TT genotypes were 13, 21 and 25% in DOA, LOA and HV, respectively, and after correcting for age, sex and multiple testing, the differences between DOA and LOA were statistically significantly different (p = 0.027). The COMT rs4680 AA genotype frequencies were 25%, 35% and 31% in DOA, LOA and HV, respectively, and the difference between DOA and LOA was also statistically significant (p = 0.0028). In conclusion, this study generated two hypotheses suggesting possible associations of a reduced risk of death and carrying, respectively, the ABCB1 rs9282564 AG and TT genotypes and the COMT rs4680 AA genotype among patients with OA. These findings should be confirmed in independent cohorts, and if a causal relationship between these variants and fatal poisoning in OA is confirmed, then it may be possible at least in theory to personalize prevention of sudden death in this patient group.
A transgenic mouse line carrying ornithine decarboxylase cDNA as the transgene under the control of a mouse mammary tumor virus long terminal repeat (MMTV LTR) promoter was generated in order to study whether ornithine decarboxylase transgene expression will have any physiological or pathological effect during the entire life of a transgenic mouse. The high frequency of infertile animals and the loss of pups made the breeding of homozygous mice unsuccessful. However, a colony of heterozygous transgenic mice was followed for 2 years. In adult heterozygous transgenic mice, ornithine decarboxylase activity was significantly increased in the testis, seminal vesicle and preputial gland when compared to non-transgenic controls. In contrast, ornithine decarboxylase activity was decreased in the kidney and prostate of transgenic mice. No significant changes in ornithine decarboxylase activity were found in the ovary and mammary gland and only moderate changes in ornithine decarboxylase activity were detected in the heart, brain, pancreas and lung. The most common abnormalities found in adult animals (12 males and 20 females) of the transgenic line were inflammatory processes, including pancreatitis, hepatitis, sialoadenitis and pyelonephritis. Spontaneous tumors were observed in eight animals, including two benign tumors (one dermatofibroma, one liver hemangioma) and six malignant tumors (one lymphoma, one intestinal and three mammary adenocarcinomas and one adenocarcinoma in the lung). No significant pathological changes were found in 17 nontransgenic controls.