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PubMed2004

Experimental studies on cervical and lumbar ribs in mouse embryos.

In humans, the presence of cervical and lumbar ribs is of particular clinical significance. However, the relevance of their occurrence in the offspring of experimental animals in reproductive toxicologic studies is poorly understood. Maternal toxicity has been implicated in the etiology but conclusive evidence is lacking. The present study was undertaken to determine the incidence of supernumerary ribs (SNR) in mouse fetuses prenatally exposed to valproic acid (VPA) and retinoic acid (RA), and to compare their differential developmental susceptibility and morphological association with other axial skeletal anomalies. Single doses of valproic acid (VPA) or retinoic acid (RA) were administered to groups of mice on one of gestation days (GD) 7-12. Fetuses were collected on GD 18 and their skeletons examined for SNR. VPA treatment on GD 7 and GD 8 resulted in a high incidence of cervical and lumbar ribs, respectively. Cervical neural arch anomalies in the GD 7 group, and eight pairs of sternal ribs and seven sternebrae in the GD 8 group were observed in excess of the background SNR suggesting a direct effect of VPA on the developing mouse skeletal system. In the RA groups, GD 8-12 were susceptible for lumbar rib induction but increased incidence of cervical ribs was observed only from GD 9-12. Peak incidence of cervical ribs was found in the GD 10 and 11 groups and that of the lumbar ribs in the GD 8 and 11 groups. Although SNR incidence generally increased with increasing dose of RA, a strict dose-response relationship was lacking. Cervical arch anomalies were observed in as many embryos as those with cervical ribs, but eight pairs of sternal ribs and seven sternebrae did not correlate well with the lumbar ribs in the peak day groups. Interrupted cervical neural arches correlated well with lumbar ribs. The reduction in the frequency of presacral vertebrae from 26 to 25 in the VPA groups was limited to GD 7 (30%) and 8 (18%) groups. RA-induced reduction in presacral vertebral number extended to GD 9 and was greater in the GD 8 than in the GD 9 groups. Sternal anomalies occurred both in VPA and RA experiments and did not strictly correlate with the frequency of SNR. VPA had a narrow window of susceptibility, whereas RA effects on sternum extended from GD 9-12. The incidence of sternal anomalies generally increased with increasing dose and advancing developmental stage at which RA exposure occurred. These developmental susceptibility windows and associated malformations, when considered in the context of the ability of these drugs to induce alterations in gene expression in mouse embryos suggest that SNR are polygenic in origin and greatly influenced by environmental toxicants.

Abnormalities, Drug-Induced↗
PubMed2004

The genetic epidemiology of alopecia areata in China.

BACKGROUND: Alopecia areata (AA) is hypothesized to be an organ-specific autoimmune disease with genetic predisposition and an environmental trigger. There are few clinical data in Asians. OBJECTIVES: To describe the genetic epidemiological features of AA patients in China and to determine the possible genetic model for AA. METHODS: Data for 1032 patients with AA were obtained by questionnaire in the Institute of Dermatology of Anhui Medical University in China from 2001 to 2003. Complex segregation analysis and heritability analysis were performed using Falconer's method, EPI INFO 6.0 and SAGE-REGTL programs. RESULTS: In total, 1032 AA patients (male/female ratio 1.1 : 1) were enrolled, representing 0.94% of the total number of cases seen in our outpatient clinic during that time. The mean +/- SD age of onset was 28.98 +/- 13.43 years. The difference between the mean age of onset in males and females was not significant. Most patients (82.6%) experienced their first episode of AA within the first four decades of life. A positive family history of AA was obtained in 87 patients (8.4%). The prevalence of AA in first-, second- and third-degree relatives of the proband with AA was 1.6%, 0.19% and 0.03%, respectively. These figures were higher than those in controls. A greater severity and longer duration of AA were seen in the early onset group than in the late-onset group. The early onset group also had more affected first- and second-degree relatives. The heritability of AA in first-, second- and third-degree relatives was 47.16%, 42.53% and 22.29%, respectively. Based on the REGTL results, the best model was a polygenic additive model for AA. CONCLUSIONS: The effect of genetic factors is strong in AA, but environmental factors such as infection and psychological stress may still play an important role. Our findings on the genetics of AA are consistent with a polygenic additive mode of inheritance.

Adolescent↗
PubMed2025

Investigating the interplay between prematurity and genetic variation in the context of rare developmental disorders.

BACKGROUND: Rare damaging genetic variation accounts for a substantial proportion of the risk of rare developmental disorders (DDs), but common genetic variants as well as environmental factors, including prematurity, also contribute. Little is known about the interplay between prematurity and genetic variation in influencing phenotypic outcomes in DDs, nor about how genetic factors may contribute to risk of preterm birth in DDs. METHODS: We leveraged phenotypic and genetic data from 21,712 patients with DDs recruited for clinical sequencing, 16% of whom were born prematurely. Using multivariable regression models, we compared phenotypic features and the prevalence of diagnostic genetic variation in specific genes between preterm and term individuals with DDs. We tested whether the fraction of cases attributable to de novo mutations differed between term and preterm probands. Additionally, we assessed whether associations between common variant contributions to education-related traits and prematurity are explained by direct genetic effects. RESULTS: Prematurity was associated with more severe clinical phenotypes among these DD patients, including more affected organ systems and more delayed developmental milestones. Prematurity and the presence of a monogenic diagnosis contributed additively to severity. We found that genes associated with fetal anomalies were enriched for diagnostic mutations among preterm individuals (p = 7.83 × 10-5). We also demonstrated an exome-wide enrichment of de novo mutations (DNMs) in both term and preterm probands; the fraction of cases explained by DNMs in known DD-associated genes was higher in term than preterm cases (25% versus 20%) but DNMs in as-yet-undiscovered genes likely contribute approximately equally to both groups (14% versus 13%). Finally, we showed that the positive association between polygenic predisposition to education-related traits and gestational duration is likely to be the result of genetically influenced parental traits or confounders, rather than direct genetic effects in the child, and that a monogenic diagnosis modifies this association. CONCLUSIONS: Our findings emphasise the importance of considering environmental factors like prematurity in understanding outcomes in DDs suspected to have a genetic component, and motivate further exploration of the role that genetic variation plays in influencing prematurity.

Humans↗
PubMed1996

Evidence for genetic basis of multiple sclerosis. The Canadian Collaborative Study Group.

BACKGROUND Increased familial risks in multiple sclerosis (MS) range from 300-fold for monozygotic twins to 20-40-fold for biological first-degree relatives, suggesting a genetic influence. Yet if one identical twin has MS the other usually will not. One way of sorting out the contributions of genes and environment is to study half-sibs. METHODS In a Canadian population-based sample of 16 000 MS cases seen at 14 regional MS clinics one half-sib (or more) was reported by 939 index cases. By interview we elicited information on family structure and an illness in half-sibs and any full brothers or sisters. FINDINGS The age-adjusted MS rate in the 1839 half-sibs of these index cases was 1.32 percent compared with 3.46 percent for the 1395 full sibs of the same cases (p<0.001; likelihood ratio test). There were no significant differences in risk for maternal versus paternal half-sibs (1.42 percent vs 1.19 percent) or for those raised together versus those raised apart from the index case (1.17 percent vs 1.47 percent). INTERPRETATION Besides demonstrating the power and the feasibility of using half-sib studies to throw light on the aetiology of complex disorders, our findings show that a shared environment does not account for familial risk in MS and that maternal effects (such as intrauterine and perinatal factors, breastfeeding, and genomic imprinting) have no demonstrable effect on familial risk. Halving the number of potentially contributory genes (by comparing full-sib and half-sib rates) lowers the risk of MS by a factor of 2.62, an observation consistent with a polygenic hypothesis.

Canada↗
PubMedDate not supplied

Familial correlation and segregation analysis of forced expiratory volume in one second (FEV1), with and without smoking adjustments, in a Tucson population.

BACKGROUND: Previous researchers have found significant familial aggregation but no evidence of Mendelian inheritance of forced expiratory volume in one second (FEV1) in general population studies. However, the influence of cigarette smoking on familial aggregation of FEV1 has been difficult to assess in these studies. OBJECTIVES: The main objective of our study was to attempt to discern the effects of smoking on familial correlation and segregation models of FEV1. SUBJECTS AND METHODS: In a randomly selected sample of white, non-Mexican American families in Tucson, Arizona, we performed two separate familial correlation and segregation analyses of FEV1, one adjusted for cigarette smoking and one unadjusted for smoking. In both, initial survey measures of FEV1 for 1329 females and 1291 males in 746 families were standardized for gender, age, height and height-squared using piecewise linear regression models. In the smoking-adjusted model, total number of pack-years smoked, current and ex-smoking status, and the interaction between total pack-years and current smoking status were also included. RESULTS: FEV1 was significantly correlated among sibling pairs and parent-offspring pairs (both p < 0.001), regardless of smoking adjustment, but sibling correlation was significantly higher than parent-offspring correlation (p < 0.05), suggesting additional effects beyond common parentage. Spousal correlations were not significant even when both spouses smoked. We found no evidence of major gene segregation of FEV1, with or without smoking adjustment, and all of the segregation models were significantly different from the unrestricted model. CONCLUSIONS: The best-fitting model was an environmental model with three distinct distributions of FEV1 and significant residual familial effects. A significant familial component suggests the presence of polygenic factors and/or effects due to a shared environment (multifactorial). That familial correlations of smoking-adjusted and smoking-unadjusted residuals were not appreciably different suggests that current smoking status and number of pack-years smoked do not account for the observed familial aggregation of FEV1.

Adolescent↗
PubMed2004

A common sequence variation of the CLCNKB gene strongly activates ClC-Kb chloride channel activity.

BACKGROUND: Tubular transepithelial reabsorption of chloride along the nephron is a major determinant of body salt and water homeostasis and blood pressure regulation. About 40% of the glomerulary filtered sodium chloride are reabsorbed in the distal nephrons. Vectorial transepithelial sodium chloride transport is critically dependent on the function of basolateral ClC-K type chloride channels there. Modulation of ClC-Kb chloride channel activity by polymorphic variations of the CLCNKB gene, thus, could form a molecular basis for salt sensitivity of blood pressure regulation. In this study we tested the effect of several polymorphic variants on ClC-Kb chloride channel activity. METHODS: After heterologous expression in Xenopus oocytes, ClC-Kb channel activity and surface expression in presence of the ClC-K beta subunit barttin were determined by two-electrode voltage-clamp analysis, immunofluorescence, and ClC-Kb surface enzyme-linked immunosorbent assay (ELISA). RESULTS: Chloride currents induced by the ClC-Kb variants L27R, G214A, I419V, T562M, and E578K were not significantly different from wild-type currents. The ClC-KbT481S variation, however, which showed a frequency of 20% in our control population, dramatically activated chloride conductance by a factor of 20. Activation of chloride currents was also observed after introducing homologous mutations in ClC-Ka and ClC-K1, but not in ClC-2 and ClC-5 chloride channels. ClC-Kb activation by the T481S mutation did not change intrinsic ion channel pore properties and did not require increased surface expression of ClC-KbT481S. CONCLUSION: Genetic heterogeneity of ClC-Kb chloride channels correlates with functional heterogeneity, which assigns ClC-Kb to a set of genes potentially relevant for polygenic salt-sensitivity of blood pressure regulation.

Animals↗
PubMed2000

Heritability of intracerebral hemorrhagic lesions and cerebral aneurysms in the rat.

BACKGROUND AND PURPOSE: Under certain conditions, the Brown Norway (BN) rat is susceptible to intracerebral hemorrhagic vascular (ICV) lesions within the cerebral cortex, whereas the Long-Evans (LE) rat is prone to develop aneurysms in the circle of Willis. The incidence of these 2 pathological phenotypes was studied in progeny of different BNXLE crosses to determine their heritability in these new rat models. In addition, a possible link between ICV lesion occurrence and either the susceptibility to spontaneous rupture of the arterial internal elastic lamina (IEL) or basal plasma angiotensin-converting enzyme (ACE) activity was also studied in back-cross (BC) F1XBN rats, the only second-generation group with a high incidence of ICV lesions. METHODS: To induce cerebrovascular lesions, rats were submitted to experimental hypertension associated with ligation of 1 carotid artery. After death, the brain was examined for cerebral lesions. Numbers of arterial IEL ruptures were determined microscopically with the use of en face preparations. Plasma ACE activity was determined before the induction of hypertension. RESULTS: In general, groups that developed ICV lesions presented a low incidence of aneurysms. ICV lesion incidence was similar in F1 hybrids and BC(F1XBN) and greatly decreased in F2 and BC(F1XLE) rats compared with BN rats. No cerebral aneurysms developed in F1 rats. Aneurysmal incidence was 24% (20% ruptured) in LE, 42% (59% ruptured) in F2, and 50% (75% ruptured) in BC(F1XLE) rats. In BC(F1XBN) rats, neither the incidence of IEL rupture nor the plasma ACE activity was higher in the rats with ICV lesions. However, the mean blood pressure level was higher in these rats, and peak blood pressure was higher in rats with the most severe grades of ICV lesions. CONCLUSIONS: These data suggest a polygenic and dominant mode of inheritance of ICV pathology. The formation of aneurysms in the circle of Willis tended to be favored, and their rupture was clearly increased by the presence of BN rat alleles within the LE rat genome. These data may provide the basis for future studies to determine, in new rat models, which genes are involved in these pathologies.

Animals↗
PubMed1998

Development of an I-Ag7-expressing antigen-presenting cell line: intrinsic molecular defect in compact I-Ag7 dimer generation.

Insulin-dependent diabetes mellitus (IDDM) results from chronic, T-cell dependent, autoimmune destruction of the insulin-producing beta-cells in the Langerhans' islets of the pancreas. Non-obese diabetic (NOD) mice spontaneously develop IDDM that resembles human type I diabetes. The susceptibility to diabetes in the NOD strain is a complex polygenic trait that determines a phenotype of immune alterations. The unique MHC class II molecule expressed by NOD mice (I-Ag7) plays a major role in the development of disease. Recently, it has been reported that I-Ag7 molecules generate a lower proportion of compact alphabeta heterodimers, compared to other haplotypes. However, it is not clear whether this reflects an intrinsic defect of this molecule to bind peptide stably or is the result of abnormal processing and/or peptide loading into the I-Ag7 molecule. Our aim was to develop and characterize a suitable antigen-presenting cell (APC) that expressed I-Ag7 in the context of a non-diabetes-prone antigen processing and presentation machinery. Here, we report the generation of a mouse DAP.3 fibroblast cell line (DAP.3Ag7) that constitutively expresses high levels of I-Ag7. Using DAP.3 cells transfected with I-Ag7 or I-Ak, we show that the expression of compact dimers in the same cell type is proportionally less for I-Ag7 molecules than for I-Ak molecules, implying an intrinsic defect of the I-Ag7 molecule as the cause for the low generation of compact dimers. However, DAP.3Ag7 cells are able to process and present antigen, as indicated by I-Ag7-dependent IL-2 production by a GAD67-specific NDO T-cell hybridoma after stimulation with GAD and live, but not fixed, DAP.3Ag7 cells. The IL-2 response to GAD when presented by DAP.3Ag7 was significantly higher than the response to GAD presented by NOD splenocytes. Based on these data, we conclude that the low generations of compact dimers is an intrinsic feature of I-Ag7 molecules and not affected by other genes in the NOD background. The DAP.3Ag7 cell line should be a valuable tool with which to dissect the role of the I-Ag7 molecule in antigen presentation and T-cell activation in NOD mice, which clearly contributes to the development of IDDM.

Animals↗
PubMed2000

Incidence of RET mutations in patients with Hirschsprung's disease.

BACKGROUND: RET mutations have been reported variously to affect 7% to 41% of Hirschsprung's disease (HSCR) patients depending on familial or sporadic occurrence of the disease, length of aganglionosis and possible association with other disease phenotypes. The authors report a study of the incidence of RET mutations in unselected HSCR patients from two regional centers and correlate their genotypes and phenotypes. METHODS: The records of HSCR patients treated in 2 regional centers with a combined population of 5 million were reviewed, and blood samples were obtained from 57 patients. During the same period, 39 patients with similar demographic data refused or provided insufficient blood for study. DNA was extracted, and the 21 exons of the RET protooncogene were screened for mutations using denaturing gradient gel electrophoresis (DGGE). RESULTS: Of 57 patients, 48 were sporadic, and 9 were familial. Lengths of aganglionosis were total colonic, 4; long, 11; short, 39; ultrashort, 1; unclassified, 2. Associated anomalies were present in 20. Causative mutations were identified in 4 (7%): missense or "silent" in 3 (exons 5, 11, 13) and deletion in 1. The silent mutation of exon 11 recently has been shown to have effects on correct RET mRNA splicing. One mutation occurred in total colonic aganglionosis (25%), 1 in long segment dysganglionosis (9%), and 2 in short segment aganglionosis (5%). Surprisingly, all these mutations occurred in sporadic cases (10%). Five patients (9%) had rare polymorphic alleles at exon 14 (n = 1) and exon 18 (n = 4). Fifty patients (88%) showed common polymorphic alleles (sequence variants) in 1 or more exons (> 4, n = 5). CONCLUSIONS: RET mutation as a primary cause for Hirschsprung's disease in the general surgical population is less frequent than previously thought. This observation is compatible with the hypothesis that HSCR could be a polygenic disease caused by additive subclinical effects of more than one gene, including RET.

Drosophila Proteins↗
PubMed2006

Combining information from common type 2 diabetes risk polymorphisms improves disease prediction.

BACKGROUND: A limited number of studies have assessed the risk of common diseases when combining information from several predisposing polymorphisms. In most cases, individual polymorphisms only moderately increase risk (approximately 20%), and they are thought to be unhelpful in assessing individuals' risk clinically. The value of analyzing multiple alleles simultaneously is not well studied. This is often because, for any given disease, very few common risk alleles have been confirmed. METHODS AND FINDINGS: Three common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to predispose to type 2 diabetes mellitus across many large studies. Risk allele frequencies ranged from 0.30 to 0.88 in controls. To assess the combined effect of multiple susceptibility alleles, we genotyped these variants in a large case-control study (3,668 controls versus 2,409 cases). Individual allele odds ratios (ORs) ranged from 1.14 (95% confidence interval [CI], 1.05 to 1.23) to 1.48 (95% CI, 1.36 to 1.60). We found no evidence of gene-gene interaction, and the risks of multiple alleles were consistent with a multiplicative model. Each additional risk allele increased the odds of type 2 diabetes by 1.28 (95% CI, 1.21 to 1.35) times. Participants with all six risk alleles had an OR of 5.71 (95% CI, 1.15 to 28.3) compared to those with no risk alleles. The 8.1% of participants that were double-homozygous for the risk alleles at TCF7L2 and Pro12Ala had an OR of 3.16 (95% CI, 2.22 to 4.50), compared to 4.3% with no TCF7L2 risk alleles and either no or one Glu23Lys or Pro12Ala risk alleles. CONCLUSIONS: Combining information from several known common risk polymorphisms allows the identification of population subgroups with markedly differing risks of developing type 2 diabetes compared to those obtained using single polymorphisms. This approach may have a role in future preventative measures for common, polygenic diseases.

Adult↗
PubMed2004

Interaction between gene polymorphisms of nitric oxide synthase and renin-angiotensin system in the progression of membranous glomerulonephritis.

BACKGROUND: The renin-angiotensin system (RAS) and nitric oxide synthase (NOS) play a key role in the progression of primary glomerulonephritis (GN). Although previous studies have examined genetic risk associated with single gene variations, experiments assessing risk conferred by multiple gene variations are still scanty. METHODS: The effect of combination of variant alleles of four genes encoding for three components of the RAS [angiotensin converting enzyme insertion/deletion (ACE I/D), angiotensin II receptor 1 (AT1R 1166A/C), angiotensinogen (AGT M235T)] and for NOS (ecNOS4b/a) on the development and progression of membranous GN (MGN) were evaluated in a longitudinal study comparing 117 patients with serum creatinine (s-Cr) <1.5 mg/dl at renal biopsy and follow-up > or = 5 years (Kaplan-Meier and Cox multivariate analysis). The control group consisted of DNA from 171 organ donors. RESULTS: We found no relationship between single or combined variations of the four gene polymorphisms and development of MGN. Among single gene variations, there were no independent genetic risk factors for the progression of renal disease, after adjustment for age, sex, hypertension, proteinuria, s-Cr, chronicity and activity index. However, double variation coincidences such as the combination of the allele a of ecNOS4b/a and both the allele D of ACE I/D (chi(2) =4.80, P = 0.028; HR = 1.97, 95% CI 0.98-3.96) and the allele T of AGT (M235T) (chi(2) = 5.09, P = 0.024; HR = 2.84, 95% CI 1.39-5.82) exerted an additional effect that was higher than that of the single gene variations. CONCLUSION: This study is the first to demonstrate a role for an interaction between simultaneous variations of genes encoding for NOS and components of RAS in the progression of MGN. Interactions between various polymorphisms may explain conflicting results obtained in previous studies that examined single gene variations, since the effect of a single locus variation may be influenced by the simultaneous presence of other variant alleles in polygenic diseases such as primary GN. However, the small sample sizes and possible multiple interactions limited the interpretation of the current findings, which may represent true biological interaction or simply statistical interactions or spurious results due to the small sample sizes.

Adult↗
PubMed2001

LEPR gene polymorphisms: associations with overweight, fat mass and response to diet in women.

BACKGROUND: In humans, a mutation of the leptin receptor gene (LEPR) leads to a rare obese syndrome of mendelian inheritance. However, obesity in humans results from interactions between genes and environment, mainly nutritional factors. Variations at the LEPR locus could be involved in the regulation of body weight. DESIGN: Genetic variations at the LEPR locus were screened in a selection of 30 French overweight subjects by Single Strand Conformation Polymorphism (SSCP) analysis, then an association study between genotypes and obesity phenotypes was performed in 179 French overweight patients recruited from the Nutrition Department of Bichat Hospital in Paris who were prescribed a low calorie diet and in 387 unrelated volunteers (98 overweight, 289 normal weight) drawn from the Stanislas Family Study in Nancy. RESULTS: Two new genetic variants were found: T + 70-->C (exon 1) and Asp (A) 96 Asp (G) (exon 4). In Nancy, the T + 70-->C polymorphism was associated with fat mass adjusted for BMI in women (P = 0.025). The genotype and allele frequencies of the Ser (T) 343 Ser (C) polymorphism (exon 9) were significantly different between normal and overweight women, with the T allele being more frequent in the overweight group (T frequency in Nancy, 0.82; in Nancy + Paris, 0.79) than in the normal weight group (0.69; P = 0.017 vs. Nancy overweight, P = 0.003 vs. Nancy + Paris overweight). In women from Nancy, fat mass adjusted for BMI was significantly associated with this polymorphism (P = 0.01). The overweight women carrying the C allele of this polymorphism lost more weight in response to low calorie diet than the non carriers (P = 0.006). CONCLUSIONS: In women, genetic variations at the LEPR gene level are associated with overweight and fat mass in a cross sectional study and with response to low calorie diet in an intervention study. These results indicate that variations at the leptin receptor locus are associated with common obesity phenotypes and are a part of the polygenic influences on the response to nutritional environment.

Adipose Tissue↗
PubMed2000

An X-linked gene involved in androgenetic alopecia: a lesson to be learned from adrenoleukodystrophy.

BACKGROUND: Adrenoleukodystrophy (ALD), including its adult variant adrenomyeloneuropathy (AMN), is an X-linked recessive trait characterized by progressive demyelinization of the nervous system. The gene defect involves a peroxisomal transporter protein, resulting in accumulation of very-long-chain fatty acids in the brain and other organs such as the adrenal glands. Affected men show various endocrine disorders. Moreover, disturbances of hair growth are frequently mentioned in reports on ALD/AMN. OBJECTIVE: This study was performed to delineate further the hair status and type of hair loss in men with AMN. METHODS: We examined and documented the status of hair growth in 16 men suffering from AMN. A meticulous history with particular regard to hair changes was taken from all patients and their family members. RESULTS: The age of the patients varied between 27 and 62 years, their mean age was 39.8 years. Twelve men showed male-pattern androgenetic alopecia (AGA), Hamilton grades IV-VIII, 3 men had a female-pattern AGA (Ludwig grade I or II). Ten of the patients with male-pattern AGA had reached Hamilton stage VII or VIII. The remaining scalp hair was unusually scarce and thin in 11 cases, regardless of the grade of AGA. Moreover, in 10 of 16 patients the eyelids showed pronounced madarosis. The remaining body hair was found to be normal. If present, endocrine manifestations had started prior to the onset of alopecia, and in 11 of 12 patients hair loss was apparent before neurological symptoms were noted. CONCLUSION: ALD/AMN gives rise to two different types of hair loss. Firstly, affected men show diffuse hair loss involving the entire scalp and the eyelashes. Secondly, they tend to develop AGA more frequently and earlier and in a severer form. Paradoxically, pronounced AGA is present although the patients may simultaneously show some degree of hypogonadism. Hence, the X-linked ALD mutation can be taken as a well-defined gene within the polygenic spectrum of genes responsible for AGA. This may be of theoretical importance for the elucidation of the pathogenetic pathways of AGA.

Adrenoleukodystrophy↗
PubMed2004

Lack of major involvement of human uroplakin genes in vesicoureteral reflux: implications for disease heterogeneity.

BACKGROUND: Primary vesicoureteral reflux (VUR) is a hereditary disorder characterized by the retrograde flow of urine into the ureters and kidneys. It affects about 1% of the young children and is thus one of the most common hereditary diseases. Its associated nephropathy is an important cause of end-stage renal failure in children and adults. Recent studies indicate that genetic ablation of mouse uroplakin (UP) III gene, which encodes a 47 kD urothelial-specific integral membrane protein forming urothelial plaques, causes VUR and hydronephrosis. METHODS: To begin to determine whether mutations in UP genes might play a role in human VUR, we genotyped all four UP genes in 76 patients with radiologically proven primary VUR by polymerase chain reaction (PCR) amplification and sequencing of all their exons plus 50 to 150 bp of flanking intronic sequences. RESULTS: Eighteen single nucleotide polymorphisms (SNPs) were identified, seven of which were missense, with no truncation or frame shift mutations. Since healthy relatives of the VUR probands are not reliable negative controls for VUR, we used a population of 90 race-matched, healthy individuals, unrelated to the VUR patients, as controls to perform an association study. Most of the SNPs were not found to be significantly associated with VUR. However, SNP1 of UP Ia gene affecting a C to T conversion and an Ala7Val change, and SNP7 of UP III affecting a C to G conversion and a Pro154Ala change, were marginally associated with VUR (both P= 0.08). Studies of additional cases yielded a second set of data that, in combination with the first set, confirmed a weak association of UP III SNP7 in VUR (P= 0.036 adjusted for both subsets of cases vs. controls). CONCLUSION: Such a weak association and the lack of families with simple dominant Mendelian inheritance suggest that missense changes of uroplakin genes cannot play a dominant role in causing VUR in humans, although they may be weak risk factors contributing to a complex polygenic disease. The fact that no truncation or frame shift mutations have been found in any of the VUR patients, coupled with our recent finding that some breeding pairs of UP III knockout mice yield litters that show not only VUR, but also severe hydronephrosis and neonatal death, raises the possibility that major uroplakin mutations could be embryonically or postnatally lethal in humans.

Alanine↗
PubMed2000

Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease.

BACKGROUND & AIMS: The detection of phenotype-determining genes as opposed to disease susceptibility genes requires precise phenotypic characterization of patients. Peripheral arthropathies in inflammatory bowel disease (IBD) are well recognized and are classified with the HLA-B*27-related spondyloarthropathies by the European Spondyloarthropathy Study Group. However, previous HLA studies in IBD have only shown this association with axial disease rather than peripheral arthropathy. We recently reported a clinical classification that describes 2 types of peripheral arthropathy, distinguished by their natural history and articular distribution. We now report the results of immunogenetic studies in these patients and compare them with other spondyloarthropathies. METHODS: IBD patients with type 1 (n = 57) and type 2 (n = 45) peripheral arthropathy were identified by case note review and questionnaire. Patients and 603 controls from Oxfordshire were assigned HLA-A, -B, -C, -DR, and -DQ genotypes by sequence-specific primer polymerase chain reaction. Patient results were compared with controls (corrected for multiple comparisons), then with each other in light of existing hypotheses. The results were compared with those of a cohort of 30 patients with postenteric reactive arthritis (ReA) and 16 patients with IBD-associated ankylosing spondylitis (IBD-AS). RESULTS: Type 1 arthropathy was associated with HLA-DRB1*0103 (DR103; a rare subtype of DR1) in 33% (P < 0.0001; relative risk [RR], 12.1), B*35 in 30% (P = 0.01; RR, 2.2), and B*27 in 26% (P = 0. 001; RR, 4.0). In contrast, type 2 was associated with HLA-B*44 in 62% (P = 0.01; RR, 2.1). Similar significant associations to type 1 arthropathy were found in ReA, except that the HLA-B*27 association was significantly stronger and an association was found with DRB1*0101 (DR1) in 43% (P = 0.001; RR, 2.2). IBD-AS was associated only with HLA-B*27 and DRB1*0101. CONCLUSIONS: These data suggest that the clinical classification into type 1 and type 2 arthropathies describes immunogenetically distinct entities and establish that in polygenic disorders, genes may determine clinical phenotype without conferring overall disease susceptibility (in this case, HLA genes). Type 1 arthropathy is clinically and immunogenetically similar to the spondyloarthropathies, but different HLA associations may define phenotypically distinct groups. Type 2 arthropathy has different HLA associations and may have a different etiology. Further studies are now required to confirm these associations and to elucidate the different pathogenetic mechanisms.

Colitis, Ulcerative↗
PubMed2001

Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways.

BACKGROUND: Ethnicity, when it is used to mean shared genetic inheritance within a group, has become one of the most important factors in determining prostate carcinoma risk. Genetic polymorphisms were hypothesized to be the probable explanation for differences in risk among ethnic groups. The authors evaluated the association between polymorphisms in genes involved in the androgen biosynthesis and metabolism pathway and the risk of prostate carcinoma. METHODS: Two hundred twenty-six patients with the pathologic diagnosis of sporadic prostate tumor and 156 healthy matched (age, ethnic group) male controls from a large epidemiologic cohort were genotyped for previously described polymorphisms in the androgen receptor (AR), 5alpha-reductase type II (SRD5A2), p450c17 (CYP17), and aromatase (CYP19) genes. The different polymorphisms in prostate carcinoma patients also were analyzed according to age of onset, preoperative prostate-specific antigen level, tumor stage, and tumor grade. RESULTS: The distribution of the tetranucleotide simple tandem repeat polymorphism (STRP) in intron 4 of CYP19 was significantly different in control and cancer patients (P = 0.012). The 171 allele and the 187 allele were associated with prostate carcinoma risk (P = 0.05 and P = 0.045, respectively). Conversely, no association was observed between prostate carcinoma risk and the other polymorphisms studied as follow: the CAG repeat in exon 1 of AR, the (TA)n dinucleotide repeat polymorphism in the 3' untranslated region, and the A49T or V89L substitutions in SDR5A2, the single base pair (bp) (a T to C transition) polymorphism that creates an additional Sp1-type (CCACC box) promoter site in CYP17. In prostate carcinoma patients, CAG repeats of AR, and TA repeats of SDR5A2 are associated with age of onset (P = 0.05 and P < 0.001, respectively). CONCLUSIONS: The association between the 171-bp allele of CYP19 and prostate carcinoma risk suggests that aromatase could be used as a new indicator for prostate carcinoma prevention in men of White French ethnogeographic origin. Conversely, it is possible that an individual carries both a high- and a low-risk marker (e.g., CYP17 A2 allele and V89L in SRD5A2) resulting in no overall difference in risk observed across the population. For these reasons, the development of a polygenic model, incorporating multiple loci from the individual genes may maximize the chance of identifying individuals with high-risk genotypes.

Aged↗
PubMed1999

Cigarette smoking as a triggering factor of hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa is a chronic inflammatory skin disease involving the axillary, inguinal and anogenital regions and sometimes, in addition, the submammary or sacral areas. The etiology of this condition is unknown. OBJECTIVE: A matched-pair case-control study was performed to evaluate the influence of smoking habits on the manifestation of this disease. METHODS: Patients who had received surgical treatment for hidradenitis suppurativa in two dermatological centers completed a questionnaire dealing with family history, course of the disease and smoking habits. To form a randomized matched-pair control group, an equal number of patients admitted for various other skin diseases such as atopic dermatitis, varicose veins, skin tattoos, alopecia areata or melanoma was matched for sex and age and evaluated for smoking habits. Statistical analysis was performed by use of several chi2 tests in a cross-table setting. Moreover, a comparison to the expected smoking prevalence in Germany based on national statistics was performed. RESULTS: Out of 84 patients treated for hidradenitis suppurativa, 63 subjects (27 men, 36 women) completed the questionnaire. The rate of active cigarette smokers was 88.9% (56 patients), whereas 4 subjects (6.4%) had never smoked. 3 patients (4.8%) stated to be ex-smokers, but 2 of these had quit smoking only recently and after onset of the disease. The rate of smokers in the matched-pair control group was 46%. The significantly higher proportion of active smokers among patients with hidradenitis suppurativa can be expressed by an odds ratio of 9.4, the calculated 95% confidence interval was 3.7-23.7 (p < 0.001). The expected smoking prevalence in Germany was 26.7% according to national statistics. 73% of our patients had no family history of hidradenitis suppurativa whereas 27% reported at least one affected first-degree relative. CONCLUSION: From the exceedingly high rate of smokers among patients with this condition we conclude that cigarette smoking is a major triggering factor of hidradenitis suppurativa. Remarkably, the disease can be categorized as a smoking sequel that is neither of vascular nor neoplastic nature. Because familial occurrence was rather rarely reported, and because an environmental factor in the form of cigarette smoking appears to be of crucial importance to trigger the disease, we assume that the genetic basis of hidradenitis suppurativa is polygenic rather than mendelian. Smoking cessation should be encouraged particularly in patients with hidradenitis suppurativa although it is unknown whether this improves the course of the disease.

Adolescent↗
PubMed2026

Maternal genetic variants associated with aneuploid conception: a narrative review.

BACKGROUND: Human aneuploid conception, a leading cause of infertility, pregnancy loss, and congenital disorders (e.g. Down's syndrome), arises from errors in chromosome segregation during oocyte meiosis or embryonic mitosis. While advanced maternal age is a well-established risk factor, significant inter-individual variation exists among younger women, suggesting a substantial role for maternal genetic determinants. OBJECTIVE AND RATIONALE: This review summarizes the identified maternal genetic variants associated with aneuploid conceptions and highlights directions for future research. SEARCH METHODS: We systematically searched PubMed, Embase, and the Cochrane Library (up to 12 January 2026), using key terms related to maternal genetics, genetic variants, aneuploidy, and pregnancy. Inclusion criteria were human studies, genetic confirmation of aneuploidy (in oocytes/embryos/products of conception/fetal cells), maternal variants (rare single-nucleotide variations, single-nucleotide polymorphisms, and small indels [&#x2264;50&#x2009;bp]), and English-language publications. Exclusion criteria were non-human studies, structural/non-aneuploid numerical abnormalities, paternal factors, and conference abstracts. Extracted data items included study identifiers, population characteristics, variant details, detection methods, clinical phenotypes, type and origin of aneuploidy, pathogenicity or effect assessment, and gene inclusion in currently commercially available infertility next-generation sequencing (NGS) panels. Rare variants were classified per American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, whereas common variants were evaluated based on effect estimates and functional validation. Study quality was appraised using a modified Newcastle-Ottawa Scale. Supplementary searches explored associations between the identified genes and a broader range of reproductive phenotypes. OUTCOMES: From 28 studies covering the broad clinical spectrum of aneuploid pregnancies (including embryo arrest, implantation failure, pregnancy loss, hydatidiform mole, and fetal aneuploidy), we identified maternal variants associated with aneuploid conceptions. These were functionally categorized into meiotic recombination, spindle dynamics, checkpoint enforcement, and the maternal-to-zygotic transition. Among them, variants in several genes are supported by higher-quality evidence, including likely pathogenic rare variants in KIF18A, ELL3, and CEP120, as well as common variants in PLK4 and CCDC66. Although some identified genes (HFM1, MCM9, MEI1, BUB1B, NLRP2, NLRP7, and TLE6) are included in commercial infertility NGS panels, their direct association with aneuploidy requires further validation. WIDER IMPLICATIONS: This review proposes that 'aneuploidy predisposition' constitutes a critical, mechanism-driven dimension for the genetic diagnosis of infertility, complementing phenotype-based frameworks. This approach would best serve women with unexplained infertility and a normal karyotype who have either a history of recurrent aneuploidy or heterogeneous reproductive phenotypes across different cycles. Adopting this perspective refines clinical genetic testing paradigms and underscores the need to prioritize artificial intelligence-enhanced clinico-genomic association studies and develop polygenic risk models integrated with clinical factors. PROSPERO REGISTRATION NUMBER: CRD42025636217.

Humans↗