To identify specific genes affecting vulnerability or resistance, we performed a whole-autosomal genome scan for genetic linkage to alcohol dependence in a Southwestern American Indian tribe. ...Genotypes at 517 autosomal microsatellite loci and clinical evaluations were available for 152 subjects belonging to extended pedigrees and forming 172 sib-pairs. Highly suggestive evidence for linkage emerged for two genomic regions using two- and multipoint sib-pair regression methods; both regions harbored neurogenetic candidate genes. The best evidence is seen with D11S1984 (nominal P = 0.00007, lod approximately equal to 3.1) on chromosome 11p, in close proximity to the DRD4 dopamine receptor and tyrosine hydroxylase (TH) genes. Good evidence is seen with D4S3242 (nominal P = 0.0002, lod approximately equal to 2.8) on chromosome 4p, near the beta1 GABA receptor gene. Interestingly, three loci in the alcohol dehydrogenase gene cluster on chromosome 4q showed evidence for linkage with two-point analyses, but not multipoint analysis.
Context: The high incidence of insulin resistance, type 2 diabetes, and metabolic syndrome in Western societies and their impact on quality of life emphasize the importance of identifying underlying ...susceptibility loci for metabolic diseases. The polycystic ovary syndrome (PCOS) susceptibility locus D19S884 allele 8 (A8) is associated with measures of insulin resistance, β-cell dysfunction, and other metabolic phenotypes in PCOS families. We now investigate the role of D19S884 A8 in pregnancy.
Objective: Using the multiethnic Hyperglycemia and Adverse Pregnancy Outcome cohort, we assessed the associations of D19S884 A8 with measures of maternal glycemia and fetal size.
Design: We tested for association of maternal D19S884 A8 with maternal outcomes (fasting, 1-h, and 2-h plasma glucose, and fasting and 1-h C-peptide from an oral glucose tolerance test) and fetal and maternal D19S884 A8 with fetal outcomes (birth weight, length, head circumference, sum of skin folds, fat mass, cord C-peptide, and 2-h neonatal plasma glucose).
Subjects: We analyzed 4424 Caucasian mothers and 3347 offspring of northern European ancestry, 1957 Thai mothers and 2089 offspring from Bangkok, 1208 Afro-Caribbean mothers and 1209 offspring from Barbados, and 774 Hispanic mothers and 762 offspring from Bellflower, California.
Results: After adjusting for confounding variables and multiple testing, neither maternal nor fetal D19S884 A8 showed significant evidence for association with any of the outcomes tested.
Conclusions: The PCOS susceptibility locus, D19S884 A8, is not a major factor contributing to glycemia during pregnancy or fetal size in a general obstetric population.
The PCOS susceptibility locus D19S884 A8 is not associated with maternal glycemia or fetal size in the Hyperglycemia and Adverse Pregnancy Outcome cohort.
Two cohorts of women with PCOS (400 probands and affected sisters in 365 families and a case-control group including 395 women with PCOS and 171 healthy women with regular menstrual cycles) were ...studied to determine whether SNPs identified as susceptibility loci in genome-wide association studies of type 2 diabetes are also associated with PCOS. None of the 18 allelic variants in ten genes previously shown to be associated with type 2 diabetes were found to be associated with PCOS, but some were associated with indices of beta cell function.
Hereditary predisposition to develop neuroblastoma (Online Mendelian Inheritance in Man 256700), a pediatric cancer of the sympathetic nervous system, segregates as an autosomal dominant Mendelian ...trait. We performed linkage analysis on seven families with two or more first-degree relatives affected with neuroblastoma to localize a hereditary neuroblastoma predisposition gene. A single interval at chromosome bands 16p12-13 was the only genomic region consistent with linkage (LOD(MAX) = 3.30 at D16S764). Identification of informative recombination events in linked families defined a 28.0-cM region between D16S748 and D16S769 that cosegregated with the disease in each pedigree. Loss of heterozygosity was identified in 5 of 11 familial neuroblastomas and 68 of 336 nonfamilial neuroblastomas (20.2%) at multiple 16p polymorphic loci. A 14.5-cM smallest region of overlap of somatic deletions was identified within the interval defined by linkage analysis (tel-D16S500-D16S412-cen). Taken together, these data suggest that a hereditary neuroblastoma predisposition gene (HNB1) is located at 16p12-13 and that disruption of this gene may contribute to the pathogenesis of nonfamilial neuroblastomas.
In the sex hormone binding globulin (SHBG) gene, a pentanucleotide-repeat polymorphism (TAAAA)n and a single nucleotide polymorphism (D327N) have been associated with circulating SHBG concentrations ...in women. Only one study, limited to Scandinavians, has examined these associations in men. Using data from the Coronary Artery Risk Development in Young Adults (CARDIA) Male Hormone Study, the authors assessed associations of SHBG polymorphisms with serum SHBG levels in 511 Black men and 698 White men who had SHBG measured in multiple serum samples collected over an 8-year period from 1987 to 1996 and were aged 20–34 years at the time of the first SHBG measurement. Multivariable repeated-measures analyses were used to assess associations of (TAAAA)n and D327N polymorphisms with SHBG concentrations. Results showed statistically significant differences in mean SHBG concentrations for White men with genotypes of (TAAAA) 6/6 (35.1 nmol/liter), 6/x (30.8 nmol/liter), and x/x (29.6 nmol/liter), where x represents a repeat length greater than 6 (p = 0.001). For Black men, the pattern of association was similar, albeit not statistically significant (p = 0.35). There was no relation between D327N genotype and SHBG levels. These results suggest that the (TAAAA)n repeat length in the SHBG gene, but not the D327N variant, might contribute to the interindividual variability in serum SHBG levels.
Hyperglyceima and adverse pregnancy outcome Freathy, Rachel M; Hayes, M. Geoffrey; Urbanek, Margrit ...
Diabetes (New York, N.Y.),
10/2010, Letnik:
59, Številka:
10
Journal Article
Recenzirano
OBJECTIVE--Common genetic variants in GCK and TCF7L2 are associated with higher fasting glucose and type 2 diabetes in nonpregnant populations. However, their associations with glucose levels from ...oral glucose tolerance tests (OGTTs) in pregnancy have not been assessed in a large sample. We hypothesized that these variants are associated with quantitative measures of glycemia in pregnancy. RESEARCH DESIGN AND METHODS--We analyzed the associations between variants rs1799884 (GCK) and rs7903146 (TCF7L2) and OGTT outcomes at 24-32 weeks' gestation in 3,811 mothers of European (U.K. and Australia) and 1,706 mothers of Asian (Thailand) ancestry from the HAPO cohort. We also tested associations with offspring birth anthropometrics. RESULTS--The maternal GCK variant was associated with higher fasting glucose in Europeans (P = 0.001) and Thais (P < 0.0001), 1-h glucose in Europeans (P = 0.001), and 2-h glucose in Thais (P = 0.005). It was also associated with higher European offspring birth weight, fat mass, and skinfold thicknesses (P < 0.05). The TCFTL2 variant was associated with all three maternal glucose outcomes (P = 0.03, P < 0.0001, and P < 0.0001 for fasting and 1-h and 2-h glucose, respectively) in the Europeans but not in the Thais (P > 0.05). In both populations, both variants were associated with higher odds of gestational diabetes mellitus according to the new International Association of Diabetes and Pregnancy Study Groups recommendations (P = 0.001-0.08). CONCLUSIONS--Maternal GCK and TCF7L2 variants are associated with glucose levels known to carry an increased risk of adverse pregnancy outcome in women without overt diabetes. Further studies will be important to determine the variance in maternal glucose explained by all known genetic variants. Diabetes 59:2682-2689, 2010
OBJECTIVE--Common genetic variants in GCK and TCF7L2 are associated with higher fasting glucose and type 2 diabetes in nonpregnant populations. However, their associations with glucose levels from ...oral glucose tolerance tests (OGTTs) in pregnancy have not been assessed in a large sample. We hypothesized that these variants are associated with quantitative measures of glycemia in pregnancy. RESEARCH DESIGN AND METHODS--We analyzed the associations between variants rs1799884 (GCK) and rs7903146 (TCF7L2) and OGTT outcomes at 24-32 weeks' gestation in 3,811 mothers of European (U.K. and Australia) and 1,706 mothers of Asian (Thailand) ancestry from the HAPO cohort. We also tested associations with offspring birth anthropometrics. RESULTS--The maternal GCK variant was associated with higher fasting glucose in Europeans (P = 0.001) and Thais (P < 0.0001), 1-h glucose in Europeans (P = 0.001), and 2-h glucose in Thais (P = 0.005). It was also associated with higher European offspring birth weight, fat mass, and skinfold thicknesses (P < 0.05). The TCFTL2 variant was associated with all three maternal glucose outcomes (P = 0.03, P < 0.0001, and P < 0.0001 for fasting and 1-h and 2-h glucose, respectively) in the Europeans but not in the Thais (P > 0.05). In both populations, both variants were associated with higher odds of gestational diabetes mellitus according to the new International Association of Diabetes and Pregnancy Study Groups recommendations (P = 0.001-0.08). CONCLUSIONS--Maternal GCK and TCF7L2 variants are associated with glucose levels known to carry an increased risk of adverse pregnancy outcome in women without overt diabetes. Further studies will be important to determine the variance in maternal glucose explained by all known genetic variants. Diabetes 59:2682-2689, 2010
In an earlier study of 37 candidate genes for polycystic ovary syndrome (PCOS), the strongest evidence for genetic linkage was found with the region of the follistatin gene. We have now carried out ...studies to detect variation in the follistatin gene and assess its relevance to PCOS. By sequencing the gene in 85 members of 19 families of PCOS patients, we found sequence variants at 17 sites. Of these, 16 sites have variants that are too rare to make a major contribution to susceptibility; the only common variant is a single base pair change in the last exon at a site that is not translated. In our sample of 249 families, the evidence for linkage between PCOS and this variant is weak. We also examined the expression of the follistatin gene; messenger RNA levels in cultured fibroblasts from PCOS and control women did not differ appreciably. We conclude that contributions to the etiology of PCOS from the follistatin gene, if any, are likely to be small.
Polycystic ovary syndrome (PCOS), the commonest endocrine disorder affecting women of reproductive age, is associated with metabolic abnormalities including insulin resistance and an increased risk ...of diabetes. Heritability studies suggest that there is a strong genetic susceptibility to PCOS, and the investigators have mapped a PCOS susceptibility locus to chromosome 19p13.2 near the dinucleotide repeat marker D19S884.This study was an attempt to localize the susceptibility site and determine its effect—if any —on the metabolic features of PCOS. Resequencing and family-based association testing were used to examine the effect of sequence variation within 100 kb of D19S884 on the reproductive and metabolic phenotypes of PCOS. Genetic analysis was carried out on DNA from 1723 persons in 412 index families with the same number of index cases, and also in 43 affected sisters of predominantly European origin. Genotype/phenotype associations were evaluated in 601 women with PCOS and 168 brothers of affected women.Of the 53 variants tested, D19S884 allele 8 (A8) within intron 55 of the fibrillin-3 (FBN3) gene was most strongly associated with PCOS. A8 was associated with higher levels of fasting insulin and insulin resistance in women with PCOS, and with higher fasting levels of proinsulin and the proinsulin/insulin ratio in brothers of women having PCOS. A8 was not associated with any particular metabolic profile in unaffected sisters. Patients who were A8-positive did not differ substantially from those who were A8-negative with respect to age, body mass index, waist circumference, or blood pressure.These findings strongly support the view that A8 of D19S884 is the chromosome 19p13.2 PCOS susceptibility locus, and it seems likely that the same variant contributes to the reproductive and metabolic abnormalities of PCOS in affected women and their brothers.
PDF
