Association of insulin sensitivity and glucose tolerance with the c.825C>T variant of the G protein beta-3 subunit gene.

UNLABELLED: The risk of macrovascular complications of diabetes mellitus is greatly enhanced by the presence of high blood pressure. In addition, hypertension and diabetes share insulin resistance as a common pathophysiological mechanism. Despite evidence for a common molecular genetic background of insulin resistance, glucose intolerance, and hypertension, few candidate genes have been shown to influence all of these features simultaneously. We examined the association of insulin sensitivity with the c.825C>T variant of the g-protein beta-3 subunit (GNB3), a candidate gene of hypertension, in families of Mexican-American hypertensive patients. METHODS: One hundred eighty subjects enrolled in a family study of Mexican-American hypertensive patients were recruited from hypertension clinics in Los Angeles. Subjects underwent pretreatment blood pressure recording, an oral glucose tolerance test, euglycemic hyperinsulinemic clamp, and anthropometric measurements. DNA from peripheral blood leukocytes was genotyped by polymerase chain reaction and restriction enzyme digest with BseD1 (GNB). Statistical analysis was performed by transmission disequilibrium testing. RESULTS: In carriers of the T-allele, blood glucose was significantly lower [(mean+S.D.) fasting: 96.7+22.9 vs. 106.7+51.7mg/dl, P=.009; oral glucose tolerance test (oGTT) 120 min: 131.7+48.7 vs. 137.8+64.9 mg/dl, P=.036], and insulin sensitivity was significantly higher (229.0+108.7 vs. 188.5+94.2 mg/kg per minute, P=.037) than in homozygous carriers of the C-allele. Blood pressure did not differ significantly between the phenotypes. CONCLUSION: In a Mexican-American hypertensive population, we found evidence for higher insulin sensitivity in carriers of the T allele of the c.825C>T variant of GNB3.

A genome-wide screen for nicotine dependence susceptibility loci.

Genome-wide model free linkage analysis was conducted for nicotine dependence and tobacco use phenotypes in 607 members of 158 nuclear families consisting of at least two ever smokers (100 or more cigarettes smoked in lifetime). DNA from whole blood was genotyped for 739 autosomal microsatellite polymorphisms with an average inter-marker distance of 4.6 cM. A peak LOD score of 2.7 was observed on chromosome 6 for scores for the Fagerström Test for Nicotine Dependence. Exploratory analyses were conducted to determine whether sequence variation at other loci affected other measures of dependence or tobacco use. Four additional loci with LOD scores of 2.7 or more were associated with alternative measures of nicotine dependence, one with current frequency of use, and one with smoking cessation. Several of the corresponding support intervals were near putative loci reported previously (on chromosomes 6, 7, and 8) while others appear to be novel (on chromosomes 5, 16, and 19).

Support for previously identified alcoholism susceptibility Loci in a cohort selected for smoking behavior.

BACKGROUND: Alcohol consumption and alcoholism are heritable traits. Previous linkage analyses for alcoholism and related traits have identified several putative susceptibility loci. In this paper we use, for the first time, linkage analysis to search for alcoholism-related phenotypes in a family sample selected for smoking behavior. METHODS: Genome-wide model free linkage analysis was conducted for a variety of phenotypes related to alcohol consumption in 158 nuclear families ascertained for having at least two first-degree relatives who smoked 100 or more cigarettes in their lifetime. The phenotypes included dichotomous, ordinal, and continuous traits. Because the traits were typically not normally distributed the QTL score statistic as implemented in Merlin was employed to deal with deviations from normality. Simulation analysis determined that the QTL score statistic is robust to deviations from normality. RESULTS: Linkage analysis detected three loci, one on chromosome 2 and two on chromosome 4, with nominal significance (LOD score > 2.7). These loci appear to be in close proximity to loci reported in other studies. CONCLUSIONS: While these findings did not reach genome-wide significance (LOD >4.0 given multiple comparisons) we have confidence that genes in these regions affect alcohol consumption. Two of the three significant findings in this analysis have been reported previously as alcoholism susceptibility loci. Simulation analysis shows that the most widely replicated finding on chromosome 4 is strongly supported (p=0.01) even with correction for multiple comparisons. These findings suggest that previously reported linkage results are robust to the effects of different approaches to sample ascertainment and definition.

Genetic linkage of prostate cancer risk to the chromosome 3 region bearing FHIT.

We conducted linkage analysis of 80 candidate genes in 201 brother pairs affected with prostatic adenocarcinoma. Markers representing two adjacent candidate genes on chromosome 3p, CDC25A and FHIT, showed suggestive evidence for linkage with single-point identity-by-descent allele-sharing statistics. Fine-structure multipoint linkage analysis yielded a maximum LOD score of 3.17 (P = 0.00007) at D3S1234 within FHIT intron 5. For a subgroup of 38 families in which three or more affected brothers were reported, the LOD score was 3.83 (P = 0.00001). Further analysis reported herein suggested a recessive mode of inheritance. Association testing of 16 single nucleotide polymorphisms (SNP) spanning a 381-kb interval surrounding D3S1234 in 202 cases of European descent with 143 matched, unrelated controls revealed significant evidence for association between case status and the A allele of single nucleotide polymorphism rs760317, located within intron 5 of FHIT (Pearson's chi(2) = 8.54, df = 1, P = 0.0035). Our results strongly suggest involvement of germline variations of FHIT in prostate cancer risk.

Association of CCR5 delta32 deletion with early death in multiple sclerosis.

PURPOSE: The interaction between chemokines and their receptors is extremely important in controlling T cell migration into sites of CNS inflammation. Because trafficking of inflammatory T cells into the central nervous system (CNS) is a key player in the pathogenesis of multiple sclerosis (MS), we investigated the possible association of CCR5 delta32 deletion in this disorder. METHODS: DNA isolated from postmortem brain tissue samples of 132 patients with MS and from blood tissue samples of 163 gender and ethnicity-matched healthy controls was used to screen for the CCR5 delta32 deletion allele. RESULTS: An increased frequency of 32-bp deletion allele was found to be associated with early death (P = 0.00005) and with a progressive reduction in the years of survival (onset to death). The death hazard ratio of CCR5 with deletion versus no deletion was 2.12, suggesting that MS patients with the 32-bp deletion have twice the mortality rate of patients with the normal genotype. This effect was more significant in females (hazard ratio 3.58). CONCLUSION: A strong association of the CCR5delta32 deletion with early death could serve as a prognostic marker for MS.

Genetic determinants of osteoporosis susceptibility in a female Ashkenazi Jewish population.

PURPOSE: To determine the heritability of low bone mineral density (BMD) at the hip in Ashkenazi Jewish families. METHODS: BMD at hip was accessed by dual x-ray absorptiometry (DEXA) in 166 female subjects from 61 families. Variance component analysis was used to estimate genetic contributions. RESULTS: We observed significant genetic contributions to age-adjusted BMD at the femoral neck as measured by heritability 0.67 (P < 0.0001). CONCLUSION: There is significant genetic determination in decreased BMD at the femoral neck in an Ashkenazi Jewish female population. These results warrant further gene mapping studies in this population to identify osteoporosis susceptibility loci.

Environmental and genetic determinants of tobacco use: methodology for a multidisciplinary, longitudinal family-based investigation.

This article describes the ongoing collaborative effort of six research teams to operationalize and execute an integrative approach to the study of gene x environment interactions in the development of tobacco dependence. At the core of the project is a longitudinal investigation of social and behavioral risk factors for tobacco use in individuals who were, on average, 13 years of age at intake and for whom smoking outcomes extending from early adolescence to young adulthood have been characterized previously (current average age of the cohort is 29 years). The conceptual framework for the integrative approach and the longitudinal investigation on which the study is based is presented. A description is also provided of the methods used to: (a) recruit participants and families to provide DNA samples and information on tobacco use; (b) assess participants for relevant tobacco-related phenotypes including smoking history, current use of tobacco, and nicotine metabolism; (c) assess the quality of the DNA samples collected from participants for genome-wide scanning and candidate gene analysis; (d) examine several research questions concerning the role of genetic and environmental factors in the onset and maintenance of tobacco use; and (e) ensure adherence to local and federal guidelines for ethical and legal investigations of genotypic associations with tobacco-related phenotypes in families. This investigation is unique among ongoing studies of the genetics of tobacco dependence in the extent to which equal importance has been assigned to both phenotypic and genotypic measurements.

A "line item" approach to the identification of genes involved in polygenic behavioral disorders: the adrenergic alpha2A (ADRA2A) gene.

The usual approach for using single base pair polymorphisms (SNPs) for the investigation of the genetics of behavioral disorders is to examine a single diagnostic syndrome or personality trait based on variables relating to a cluster of behavioral symptoms. However, since some of these variables may address behaviors that are associated with one allele while others are associated with the other allele, the overall association may be non-significant and significant sub-syndromal associations may be missed. Thus, we have reversed the process in a technique we term a "line item" approach. As a test of the technique we have examined the association between genotypes of a C- > G-1291 Msp I promotor SNP of the ADRA2A gene and 390 individual symptoms from a structured review of DSM-IV criteria for twelve different groups of symptoms. We examined 334 individuals consisting of controls and subjects with Tourette syndrome (TS). Based on the mean scores for each genotype, those symptoms that were individually significant at alpha < or = 0.05 fell into three major groups by mode of inheritance: allele 1 codominant (11 > 12 > 22), allele 2 codominant (22 > 12 > 11), and negative heterosis (12 < 11, 22). Within each mode of inheritance group, the number of symptoms that were significant for the twelve symptom clusters was compared by chi-square analysis. This showed that symptoms were drawn from the diagnostic groups in a significantly non-random fashion. Thus, the allele 1 codominant symptoms came from the anxiety, affective, schizoid, and somatization diagnostic groups (internalizing symptoms) (chi(2) = 80.0, d.f. = 11, P < or = 0.0000001), while the allele 2 codominant symptoms came from the ADHD and oppositional defiant/conduct disorder diagnostic groups (externalizing symptoms) (chi(2) = 81.0, d.f. = 11, P < or = 0.0000001). The questions that fell in the negative heterosis type of inheritance were not significantly associated with specific diagnostic groups (P = 0.87). These results showed that the ADRA2A gene was associated with symptoms of autonomic, sympathetic dysfunction from different diagnostic groups. The advantages of the "line item" approach include (a) the identification of the symptoms associated with each allele, (b) the identification of symptom clusters independent of DSM diagnoses, (c) the elucidation of heterosis and other mode of inheritance effects, (d) the distinction between an association with a primary disorder versus a comorbid disorder, (e) the identification of associations with sub-syndromal symptom clusters that do meet full DSM-IV criteria, and (f) the identification of symptom clusters across databases.