Maternal testosterone levels are associated with C-peptide levels in the Mexican American subset of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study cohort.

Altered sex hormone levels are thought to play an important role in adult-onset diseases including obesity, cardiovascular disease, and diabetes. They contribute to these complex diseases through changes in their availability, which is influenced, in part, by binding proteins. Insulin resistance, which is characteristic of these diseases, along with increased insulin secretion, is a physiologic change that occurs normally during pregnancy. To determine the relationship between insulin resistance and sex hormone levels, we examined the associations of sex hormone-binding globulin (SHBG) and testosterone with measures of glycemia and insulinemia in a healthy pregnant population. We measured fasting serum SHBG and testosterone levels in 215 Hispanic mothers of Mexican ancestry from the HAPO Study cohort and tested for associations between SHBG and testosterone levels and maternal plasma glucose and C-peptide. After adjusting for confounding variables, serum total testosterone (TT) was positively associated with fasting C-peptide (0.18 µg/l higher for TT higher by 1 SD, p=0.001) and 1-h C-peptide (0.79 µg/l higher for TT higher by 1 SD, p<0.001). Free testosterone (FT) was also positively associated with fasting C-peptide (0.19 µg/l higher for FT higher by 1 SD, p<0.001), and 1-h C-peptide (0.83 µg/l higher for FT higher by 1 SD, p<0.001). Although these findings are from a single cohort, this study provides evidence for an association between testosterone and C-peptide during pregnancy in a nondiabetic Hispanic obstetric population.

Paraoxonase-1 (PON1) status in pancreatic cancer: relation to clinical parameters.

Human paraoxonase 1 (PON1) has been shown to decrease the level of systemic oxidative stress, which is thought to contribute to cancer development. The aim of this study was to examine the interrelationships between PON1 status and some clinical characteristics in patients with pancreatic cancer (PC). A group of 73 consecutive patients with PC (stage II-IV) and 73 control subjects were examined. Laboratory studies included five polymorphisms of the PON1 gene (L55M, Q192R, -108C/T, -126C/T, and -162A/G), PON1 arylesterase (PON1-A) and lactonase (PON1-L) activities, as well as some markers of protein metabolism, insulin resistance, and oxidative stress. In comparison with the control group, no difference in the distribution of the PON1 polymorphisms was found in cancer patients, both arylesterase and lactonase activities being significantly lower (-33, -47 %, respectively, both P < 0.001). There was neither statistically significant association of PON1 polymorphisms with tumour stages nor with diabetes mellitus connected with PC. The genotype distribution of L55M and ­108C/T differed only in a subgroup of patients presenting clinically relevant malnutrition (χ² = 6.50, 6.25, respectively, both P < 0.05). In the PC group, PON1-A and PON1-L activities correlated with Nutritional Risk Index (r = 0.351, 0.409, respectively, both P < 0.01), PON1-L with mid-arm muscle circumference (r = 0.328, P < 0.05), and PON1-A and PON1-L with serum albumin (r = 0.352, 0.391 respectively, both < 0.01). Our results suggest that PON1 plays an important role in PC, especially in cancer-associated malnutrition.

First assessment of menstrual cycle function and reproductive endocrine status in Samoan women.

BACKGROUND: American Samoa and Samoa are now characterized by one of the world's highest levels of adult overweight and obesity. Our objective was to investigate patterns of menstrual cyclicity reported by Samoan women and examine the relationship to adiposity and select hormone levels. METHODS: A cross-sectional analysis was performed among Samoan women, aged 18-39 years (n = 322), using anthropometric and biomarker measures of adiposity and reproductive health, including insulin, adiponectin, testosterone, sex hormone-binding globulin, free androgen index (FAI) and mullerian-inhibiting substance (MIS). Menstrual regularity was assessed from self-reported responses. Multivariable models were estimated to adjust for potential confounding of the associations between menstrual patterns and other measures. RESULTS: A high proportion of the women (13.7%) reported oligomenorrhea or amenorrhea (OM/AM). More than three-quarters, 80.7%, of women were either overweight or obese, using Polynesian-specific criteria, and OM/AM was significantly associated with higher BMI. Abdominal circumference and insulin levels were significantly higher, and adiponectin levels were lower, in those who reported OM/AM versus regular menstruation. The FAI was higher in women with increased BMI. MIS levels declined with age, more slowly in those reporting OM/AM. CONCLUSIONS: Self-reported OM/AM was associated with an elevated BMI, abdominal adiposity and serum insulin, and with reduced adiponectin levels. These findings support a high rate of metabolic syndrome, and perhaps PCOS and reproductive dysfunction, among Samoan women.

Focused ion beam fabrication of spintronic nanostructures: an optimization of the milling process.

Focused ion beam (FIB) milling has been used to fabricate magnetic nanostructures (wires, squares, discs) from single magnetic layers (Co, permalloy) and spin-valve (permalloy/Cu/Co) multilayers (thicknesses 5-50 nm) prepared by ion beam sputtering deposition. Milled surfaces of metallic thin films typically exhibit residual roughness, which is also transferred onto the edges of the milled patterns. This can lead to domain wall pinning and influence the magnetization behaviour of the nanostructures. We have investigated the milling process and the influence of the FIB parameters (incidence angle, dwell time, overlap and ion beam current) on the roughness of the milled surface. It has been found that the main reasons for increased roughness are different sputter yields for various crystallographic orientations of the grains in polycrystalline magnetic thin films. We have found that the oblique ion beam angle, long dwell time and overlap < 1 are favourable parameters for suppression of this intrinsic roughness. Finally, we have shown how to determine the ion dose necessary to mill through the whole thin film up to the silicon substrate from scanning electron microscopy (SEM) images only.

Mn3Ge-based tetragonal Heusler alloy thin films with addition of Ni, Pt, and Pd.

We have investigated substitution effects of Ni, Pt, and Pd on phase formation and magnetic properties of D022-Mn3Ge thin films. We prepared (Mn1-x M x )3Ge thin films (M = Ni, Pt, Pd) at 650 °C by magnetron sputtering on MgO(0 0 1) substrates with x varying from 0.03 to 0.6. For improving the film quality, a Cr(0 0 1) seed layer was employed. The D022 structure formed only for the lowest concentrations of Ni and Pt. Nevertheless, the doped samples showed strong perpendicular magnetic anisotropy up to x = 0.1. For high Ni concentrations, we observed the formation of a soft ferromagnetic Mn x Ni y Ge phase with a Curie temperature of about 230 K, while in samples with high Pt content the antiferromagnet L10-MnPt phase is formed along with GePt. In contrast, for Pd substitution, the D022 structure is preserved up to x = 0.2, exhibiting strong perpendicular magnetic anisotropy and low saturation magnetization. Interestingly, the coexistence of the D022-Mn3Ge and a novel D022-(Mn1-x Pd x )3Ge phase was revealed, which might have been facilitated by the low lattice mismatch to the Cr(0 0 1) seed layer. With further increase of the Pd concentration, the D022 structure vanishes and mainly the GePd and GePd2 phases are present. Overall within the investigated sample series, the saturation magnetization strongly decreases with increasing dopant concentration, offering the possibility to adjust the saturation magnetization in the range between 20 and 100 emu cm-3, while still preserving strong perpendicular magnetic anisotropy, which is important for spintronic applications.

Gender and neurogenin3 influence the pathogenesis of ketosis-prone diabetes.

Ketosis-prone diabetes (KPD) is a phenotypically defined form of diabetes characterized by male predominance and severe insulin deficiency. Neurogenin3 (NGN3) is a proendocrine gene, which is essential for the fate of pancreatic beta cells. Mice lacking ngn3 develop early insulin-deficient diabetes. Thus, we hypothesized that gender and variants in NGN3 could predispose to KPD. We have studied clinical and metabolic parameters according to gender in patients with KPD (n = 152) and common type 2 diabetes (T2DM) (n = 167). We have sequenced NGN3 in KPD patients and screened gene variants in T2DM and controls (n = 232). In KPD, male gender was associated with a more pronounced decrease in beta-cell insulin secretory reserve, assessed by fasting C-peptide [mean (ng/ml) +/- s.d., M: 1.1 +/- 0.6, F: 1.5 +/- 0.9; p = 0.02] and glucagon-stimulated C-peptide [mean (ng/ml) +/- s.d., M: 2.2 +/- 1.1, F: 3.1 +/- 1.7; p = 0.03]. The rare affected females were in an anovulatory state. We found two new variants in the promoter [-3812T/C (af: 2%) and -3642T/C (af: 1%)], two new coding variants [S171T (af: 1%) and A185S (af: 1%)] and the variant already described [S199F (af: 69%)]. These variants were not associated with diabetes. Clinical investigation revealed an association between 199F and hyperglycaemia assessed by glycated haemoglobin [HbA1c (%, +/-s.d.) S199: 12.6 +/- 1.6, S199F: 12.4 +/- 1.4 and 199F: 14.1 +/- 2.2; p = 0.01]. In vitro, the P171T, A185S and S199F variants did not reveal major functional alteration in the activation of NGN3 target genes. In conclusion, male gender, anovulatory state in females and NGN3 variations may influence the pathogenesis of KPD in West Africans. This has therapeutic implications for potential tailored pharmacological intervention in this population.

Characterization and histologic localization of human growth hormone-variant gene expression in the placenta.

The human growth hormone-variant (hGH-V) gene is one of five highly similar growth hormone-related genes clustered on the short arm of chromosome 17. Although the pattern of expression of the adjacent normal growth hormone (hGH-N) and chorionic somatomammotropin (hCS) genes in this cluster are well characterized, the expression of the hGH-V gene remains to be defined. In previous studies, we have demonstrated that the hGH-V gene is transcribed in the term placenta and expressed as two alternatively spliced mRNAs: one is predicted to encode a 22-kD hormone (hGH-V), the other retains intron 4 in its sequence resulting in the predicted synthesis of a novel 26-kD hGH-V-related protein (hGH-V2). In the present report, we document the expression of both of these hGH-V mRNA species in the villi of the term placenta, demonstrate an increase in their concentrations during gestation, and directly sublocalize hGH-V gene expression to the syncytiotrophoblastic epithelium of the term placenta by in situ cDNA-mRNA histohybridization. The demonstrated similarity in the developmental and tissue-specific expression of the hGH-V gene with that of the related hCS gene suggests that these two genes may share common regulatory elements.

Fine mapping of genetic susceptibility to polycystic ovary syndrome on chromosome 19p13.2 and tests for regulatory activity.

CONTEXT: Little is known about genes that contribute to polycystic ovary syndrome (PCOS). We previously found linkage and association of PCOS with the dinucleotide marker D19S884 in two independent sets of families; allele 8 of D19S884 confers increased risk. OBJECTIVE/DESIGN: The objectives of the study were: 1) use the transmission/disequilibrium test (TDT) to assess linkage and association between PCOS and D19S884 (and nearby markers) in a third set of families; and 2) test D19S884 and surrounding DNA sequence for in vitro regulatory activity in lymphoblastoid cell lines (LCLs) and granulosa cells. SETTING/SUBJECTS: We studied 98 new families with a PCOS proband, father, mother, and other available offspring. We analyzed data from these families separately and in combination with data obtained previously. INTERVENTIONS: Interventions were venipuncture. MAIN OUTCOME MEASURES: Measures were transmission frequencies and in vitro functional studies. RESULTS: The first result we found was that in the 98 new families, the TDT was significant for allele 8 of D19S884 (P = 0.043). In the total collection of 465 families, the TDT evidence is very strong (nominal P < 7 x 10(-5)). Results for all other genetic markers near D19S884 were nonsignificant after correction for multiple testing. The second result was that an approximately 800-bp fragment containing various alleles of D19S884 showed modest but reproducible promoter activity in LCLs. However, no allelic differences were detected. No activity of this fragment was detected in granulosa cells. CONCLUSIONS: This is the second independent confirmation of linkage and association of D19S884 with PCOS. We found in addition that some sequence in the region of D19S884 confers in vitro promoter activity in LCLs.

Nephrotoxic potential of cis-diamminedichloroplatinum and four analogs in male Fischer 344 rats.

Cis-diamminedichloroplatinum [cis-DDP; NSC-119875] and four analogs (NSC-241240, NSC-271674, NSC-263158, and NSC-268252) were evaluated for their acute nephrotoxic potential in male F344 rats following iv administration. Indices of nephrotoxicity included blood urea nitrogen, serum creatinine, kidney weights, and microscopic examination. Results indicated that renal function, organ weights, and histology are important criteria for assessing the nephrotoxic potential of cis-DDP analogs, although alterations in these parameters may have been influenced by severe body weight loss. cis-DDP appeared to be the most nephrotoxic compound studied, and NSC-241240 demonstrated minimal renal damage. Ranking of compounds in order of their nephrotoxic potential (most to least) was cis-DDP, NSC-263158, NSC-268252, NSC-271674, and NSC-241240.

Candidate gene region for polycystic ovary syndrome on chromosome 19p13.2.

CONTEXT: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is believed to have a genetic basis. However, no specific susceptibility gene or region has been conclusively identified. OBJECTIVE: The objective of this study was to duplicate a previous study that localized a PCOS susceptibility region to chromosome 19p13.2 and to narrow the susceptibility region. DESIGN: This study was designed to test for genetic linkage and association between PCOS and short tandem repeat polymorphisms in 367 families, by analysis of linkage and family-based association. SETTING: The study was conducted at academic medical centers. PATIENTS OR OTHER PARTICIPANTS: We studied 367 families of predominantly European origin with at least one PCOS patient. Families included 107 affected sibling (sister) pairs (ASPs) in 83 families, and 390 trios with both parents and an affected daughter. The data set comprises two independent groups. Set 1 consists of 44 ASPs and 163 trios. Set 2 consists of 63 ASPs and 227 trios. INTERVENTION(S): The intervention was the drawing of blood for DNA extraction. MAIN OUTCOME MEASURE: We employed measures of evidence for linkage and association between PCOS and 19 STRs. RESULTS: Linkage with PCOS was observed over a broad region of chromosome 19p13.2. The strongest evidence for association was observed with D19S884 (chi2 = 11.85; nominal P < 0.0006; permutation P = 0.034) and duplicated our earlier findings. CONCLUSIONS: The present analysis suggests that a PCOS susceptibility locus maps very close to D19S884. Additional studies that systematically characterize DNA sequence variation in the immediate area of D19S884 are required to identify the PCOS susceptibility variant.

Expression of a human growth hormone (hGH) receptor isoform is predicted by tissue-specific alternative splicing of exon 3 of the hGH receptor gene transcript.

Four members of the GH gene family, human (h) GH-V, human chorionic somatomammotropin-A (hCS-A), hCS-B, and hCS-L, are expressed in the human placenta. In attempting to define the role of these hormones in placental development, we have structurally characterized the human placental GH receptor (GHR) mRNA. Human GHR cDNAs were cloned from a human placental cDNA library. Clone pGHR-P1 encompasses the entire hGHR-coding region and is identical to the previously reported liver hGHR cDNA, except for a precise deletion of the sequences corresponding to exon 3. This mRNA with an exon 3 deletion is the sole form of the hGHR mRNAs in the placental villi. A reverse transcription/polymerase chain reaction assay was used to further characterize GHR mRNA expression. Human GHR mRNA was detected in all placental tissues as well as in a wide spectrum of other tissues and cell lines. The distribution of the exon 3-retaining and exon 3-excluding isoforms of the hGHR mRNA shows distinct tissue specificity. Some tissues and cell lines contain only one of the two forms, and some contain a mixed population. Since exon 3 encodes a segment in the extracellular domain of the receptor, its alternative inclusion or exclusion may mediate critical alterations in hormone binding and physiological function.

Allelic variants of the follistatin gene in polycystic ovary syndrome.

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.

Polymorphism and genetic mapping of the human oxytocin receptor gene on chromosome 3.

Centrally administered oxytocin has been reported to facilitate affiliative and social behaviours, in functional harmony with its well-known peripheral effects on uterine contraction and milk ejection. The biological effects of oxytocin could be perturbed by mutations occurring in the sequence of the oxytocin receptor gene, and it would be of interest to establish the position of this gene on the human linkage map. Therefore we identified a polymorphism at the human oxytocin receptor gene. A portion of the 3' untranslated region containing a 30 bp CA repeat was amplified by polymerase chain reaction (PCR), revealing a polymorphism with two alleles occurring with frequencies of 0.77 and 0.23 in a sample of Caucasian CEPH parents (n = 70). The CA repeat polymorphism we detected was used to map the the human oxytocin receptor to chromosome 3p25-3p26, in a region which contains several important genes, including loci for Von Hippel-Lindau disease (VHL) and renal cell carcinoma.

Linkage and association of a functional DRD2 variant [Ser311Cys] and DRD2 markers to alcoholism, substance abuse and schizophrenia in Southwestern American Indians.

Alcoholism is one of a group of common psychiatric diseases which are well-defined clinically and strongly influenced genetically, but which are likely to be highly heterogeneous in causation, genetically and otherwise. Dopamine is a key neurotransmitter in drug-mediated reinforcement. Based on association studies with the Taq1A downstream marker, the D2 dopamine receptor has been proposed to be the "Reward Deficiency Syndrome Gene." Ser311Cys, a naturally occurring variant which largely inactivates transduction after D2 receptor activation, was abundant (0.16) in a Southwestern American Indian population we studied. Therefore, we were able to provide a critical test of the D2 hypothesis of vulnerability to alcoholism by evaluating Ser311Cys and also the intron-2 STR and Taq1A markers at this locus in a total of 459 subjects, including 373 sib pairs, from large families. The result is that neither alcoholism, substance use disorders nor schizophrenia show a relationship to Ser311Cys genotype, even when the 15 Cys311/Cys311 homozygous individuals are compared to others. Furthermore, sib pair analysis incorporating information across all three sib pair categories: concordant affected, discordant and concordant unaffected revealed no effect of DRD2 genotype or haplotype on alcoholism or substance use disorder.

Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosome-wide scan in an American Indian population.

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.

Clinical significance of ventricular late potentials in patients with obstructive sleep apnoea.

Patients with obstructive sleep apnoea (OSA) have an increased cardiovascular mortality and probably also an increased incidence of sudden cardiac death. Thus the question arises whether ventricular late potentials can constitute markers for an increased electric vulnerability in these patients. Signal-averaged electrocardiograms were recorded in 64 patients (6 female, 58 male; mean age 53.2 y) with OSA (mean apnoea-hypopnoea index (AHI) 41.7 h-1 +/- 24.3 h-1). Furthermore, a continuous ambulatory electrocardiogram and gated radionuclide ventriculography were performed. Ventricular late potentials were recorded in 5 men out of 64 patients. Two of them had coronary artery disease (1 patient post-myocardial infarction), 2 hypertension, and 1 nocturnal hypertension. No correlation could be traced between left ventricular ejection fraction, severity and extent of ventricular premature beats, or severity of OSA and occurrence of ventricular late potentials. It was noticeable, however, that the patients with ventricular late potentials had severe OSA (mean AHI 50.2/h vs. 40.9/h). Although OSA may lead to structural myocardial changes that could be the basis for re-entrant circuits, ventricular late potentials were found in only 7.8% of these patients. The results of this study demonstrate that at present ventricular late potentials and signal-averaged electrocardiograms do not prove useful as screening methods for risk stratification of patients with OSA.

Determination of bopindolol in pharmaceuticals by capillary isotachophoresis.

Capillary isotachophoresis (ITP) with conductimetric detection has been used for separating and determining bopindolol (I) in commercial mass-produced pharmaceutical preparations. The optimised operational electrolyte system consisted of 5 mM potassium picolinate and 5 mM picolinic acid (leading electrolyte, LE; pH 5.37) and 10 mM formic acid as the terminating electrolyte (TE). The driving and detection currents were 50 microA (for 350 s) and 10 microA, respectively. The single analysis took about 12 min. Under such conditions the effective mobility of I was determined as 16.73 10(-9)m(2) V(-1) s(-1) (with tetraethylammonium as the mobility standard). The calibration graph relating the ITP zone length to the concentration of I was rectilinear (r=0.99990) in the range 10-100 mg l(-1). The relative standard deviation (R.S.D.) was 0.90% (n=6) when determining 50 mg l(-1) of I in pure test solution. Sample pre-treatment of the tablets involved ice-cooled extraction of I with methanol. The method was suitable for determining I in Sandonorm tablets with R.S.D. value 1.45% (n=6). According to the validation procedure based on the standard addition method the recovery was 97.3%.

Capillary isotachophoretic determination of flufenamic, mefenamic, niflumic and tolfenamic acid in pharmaceuticals.

Anionic capillary isotachophoresis (ITP) with conductimetric detection has been used for determining selected non-steroid anti-inflammatory and analgesic drugs of the phenamate group, namely tolfenamic (I), flufenamic (II), mefenamic (III) and niflumic (IV) acid. Initially the pKa values (proton lost) of I-IV were determined as 5.11, 4.91, 5.39 and 4.31, respectively, by the UV spectrophotometry in aqueous 50% (w/w) methanol. The optimised ITP electrolyte system consisted of 10 mM HCl + 20 mM imidazole (pH 7.1) as the leading electrolyte and 10 mM 5,5'-diethylbarbituric acid (pH 7.5) as the terminating electrolyte. The driving and detection currents were 100 microA (for 450 s) and 30 microA, respectively (a single analysis took about 20 min). Under such conditions the effective mobilities of I-IV varied between 23.6 and 24.6 m2 V(-1) s(-1) (evaluated with orotic acid as the mobility standard). The calibration graphs relating the ITP zone length to the concentration of the analytes were rectilinear (r = 0.9987-0.9999) in the range 10-100 mg l(-1) of the drug standard. The R.S.D.s were 0.96-1.55% (n = 6) when determining 50 mg l(-1) of the analytes in pure test solutions. The method has been applied to the assay of the phenamates in six commercial mass-produced pharmaceutical preparations (Mobilisin gel and ointment, Lysalgo capsules, Nifluril cream, Niflugel gel, and Clotam capsules). According to the validation procedure based on the standard addition technique the recoveries were 98.4-104.3% of the drug and the R.S.D. values were 1.25-3.32% (n = 6).

A functionally deficient DRD2 variant [Ser311Cys] is not linked to alcoholism and substance abuse.

Association studies with the DRD2 Taq1A marker have been variable in implicating DRD2 as a "Reward Deficiency Syndrome Gene" for alcoholism and substance abuse. Given that the Taq1A marker is not functionally significant, second-generation studies on the DRD2 receptor to identify functional variants and evaluate their effect on the phenotype are the logical step towards confirming and extending the DRD2 hypothesis. This article discusses the implications and process of progress made in these directions. The new findings are the description of structural variants in the D2 receptor, the demonstration that one of these, Ser311Cys, largely prevents signal transduction following receptor activation and the use of Ser311Cys in a large association and sib-pair linkage anlysis in an American Indian isolate. In this particular population, the Cys311 variant is far more abundant (0.16) than in Caucasians (0.03). Genotyping of Ser311Cys, the DRD2 intron 2 STR, and the Taq1A marker in 459 subjects, including 373 sib-pairs and 15 Cys311/Cys311 homozygous individuals, revealed no association to alcoholism, substance use disorders, or schizophrenia. The implication is that a DRD2 variant that dramatically impairs receptor function was not sufficient to significantly alter alcoholism vulnerability in a relatively large and also genetically and environmentally homogeneous sample.

Searching for the polycystic ovary syndrome genes.

PCOS is a common disorder of unknown etiology. Studies of first-degree relatives of women diagnosed with PCOS suggest familial clustering of the disease. A prospective study of first-degree female relatives of women with PCOS conducted by NCPIR found that 46% of ascertainable sisters of women with PCOS were hyperandrogenemic. NCPIR has conducted linkage and association studies using affected sibling-pair analysis and the transmission/disequilibrium test to explore candidate PCOS genes. These studies point a finger at a region 1 MB centromeric to the insulin receptor gene on chromosome 19.