Objective. Significant variation in interleukin-1␤ (IL-1␤) protein secretion between subjects has been observed when using a lipopolysaccharide (LPS)/ATPmediated ex vivo blood stimulation assay. To explore the potential relationships between genetic polymorphisms in the IL1B cytokine gene and cellular responses to inflammatory stimuli such as LPS, we investigated the hypothesis that polymorphisms within the promoter and exon 5 of the IL1B gene contribute to the observed differences in IL-1␤ protein secretion.Methods. The IL1B gene polymorphisms C؊511T, T؊31C, and C3954T were tested for association with LPS-induced secretion of IL-1␤ protein as measured by an ex vivo blood stimulation assay. Samples from 2 independent study populations (n ‫؍‬ 31 and n ‫؍‬ 25) were available for use in the ex vivo assay after consent was obtained to analyze the DNA.Results. A specific haplotype, composed of the T allele at ؊511 and the C allele at ؊31, was significantly associated with a 2-3-fold increase in LPS-induced IL-1␤ protein secretion. This association was observed in both of the independent study populations (P ‫؍‬ 0.0084 and P ‫؍‬ 0.0017).Conclusion. These data suggest that polymorphisms within the promoter region of the IL1B gene contribute to observed differences in LPS-induced IL-1␤ protein secretion.

These results suggest that genetic variation in the serotonin transporter gene effects the response time to sertraline and provides complementing evidence to previous reports that this polymorphism affects response time to other SSRIs.

No abstract

Association studies are used to identify genetic determinants of complex human traits of medical interest. With the large number of validated single nucleotide polymorphisms (SNPs) currently available, two limiting factors in association studies are genotyping capability and costs. Pooled DNA genotyping has been proposed as an efficient means of screening SNPs for allele frequency differences in case-control studies and for prioritising them for subsequent individual genotyping analysis. Here, we apply quantitative pooled genotyping followed by individual genotyping and replication to identify associations with human serum high-density lipoprotein (HDL) cholesterol levels. The DNA from individuals with low and high HDL cholesterol levels was pooled separately, each pool was amplified by polymerase chain reaction in triplicate and each amplified product was separately hybridised to a high-density oligonucleotide array. Allele frequency differences between case and control groups with low and high HDL cholesterol levels were estimated for 7,283 SNPs distributed across 71 candidate gene regions spanning a total of 17.1 megabases. A novel method was developed to take advantage of independently derived haplotype map information to improve the pooled estimates of allele frequency differences. A subset of SNPs with the largest estimated allele frequency differences between low and high HDL cholesterol groups was chosen for individual genotyping in the study population, as well as in a separate replication population. Four SNPs in a single haplotype block within the cholesteryl ester transfer protein (CETP) gene interval were significantly associated with HDL cholesterol levels in both populations. Our study is among the first to demonstrate the application of pooled genotyping followed by confirmation with individual genotyping to identify genetic determinants of a complex trait.

In this paper, we address some of the statistical issues concerning false-positive rates that arise when the whole genome, or a portion thereof, is scanned in distantly related individuals, to search for a disease locus. We derive a method for correcting false-positive probabilities for the large number of comparisons that are performed when scanning a large portion of the genome. We consider both the idealized situation of a dense set of fully informative markers and the more realistic data-collection strategy of an initial scan at low resolution to identify promising areas, which then are typed with markers at high resolution. We also examine the accuracy of false-positive rates approximated using a conservative estimate of the separation distance between affected individuals in the current generation and the common ancestral couple. Calculation of false-positive rates when inbreeding is present in the pedigree also is considered.