Homozygotes Odds Ratio Research Articles

A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample

The dopamine (DA) transporter DAT1 is a major target bound by cocaine in brain. We examined the influence of functional genetic variants in DAT1 on cocaine addiction. Repeat polymorphisms, including a 30-bp variable-number tandem repeat (VNTR) in intron 8 (Int8 VNTR) with two common alleles, were genotyped in cocaine-dependent abusers (n = 699) and in controls with no past history of drug abuse (n = 866) from São Paulo, Brazil. Positive association was observed with allele 3 of the Int8 VNTR and cocaine abuse (allele odds ratio = 1.2, 95% confidence interval = 1.01-1.37, P = 0.036; 3/3 homozygote odds ratio = 1.45, 95% confidence interval = 1.18-1.78, P = 0.0008). Population stratification was assessed and did not affect the results. Haplotypic analyses using additional polymorphisms indicated that the Int8 VNTR is responsible for the observed association. Functional analyses in reporter-gene constructs, demonstrated that allele 3 mediates significant (P < 0.05) but small reduced expression compared with the "protective" allele 2. This difference increased when 1 and 10 muM cocaine was added to the cell culture ( approximately 40% reduction of the 3 allele expression versus the 2 allele). The 3 allele also demonstrated approximately 3-fold-increased expression over the 2 allele in response to KCl plus forskolin challenge. We demonstrate a robust association between cocaine dependence and a VNTR allele in SLC6A3, conferring a small but detectable effect, and we show that this VNTR may be functional. This study suggests that DAT1 gene variation may play a role in cocaine dependence etiology.

A CXCL2 tandem repeat promoter polymorphism is associated with susceptibility to severe sepsis in the Spanish population

Sepsis describes a complex clinical syndrome resulting from a systemic inflammatory response to bacteria. Functional studies in animal models of sepsis have catalogued CXCL2 as a candidate gene for the development of the disease. We hypothesized that CXCL2 polymorphisms may confer susceptibility to sepsis and performed an association study using 178 severe sepsis patients and 357 population-based controls. We selected two polymorphisms from the promoter of the gene (-437A/G and -665(AC)n), and analyzed whether haplotypes or single loci were associated with disease susceptibility. An overall test of differentiation showed that haplotype distribution was not different between cases and controls (P=0.407). Likewise, -437A/G was not associated with disease susceptibility (heterozygote odds ratio (OR) 0.68 (0.47-1.03), and homozygote OR 0.86 (0.56-1.32); P=0.706). However, for the -665(AC)n, we found that the 24+/-1 repeat alleles were associated with susceptibility (heterozygote OR 2.82 (1.10-7.24), and homozygote OR 3.65 (1.41-9.43); P=0.0006). This association remained significant when using a multiple logistic regression analysis (OR 2.23; 95% confidence intervals (95% CI) 1.22-4.03; P=0.008) and after a genomic control adjustment (P=0.017). Although replicate studies and functional assays are needed, these results suggest that CXCL2 gene variants may contribute to the development of severe sepsis.

Functional polymorphisms in the promoter region of macrophage migration inhibitory factor and atopy.

Macrophage migration inhibitory factor (MIF) is a pleiotrophic lymphocyte and macrophage cytokine; it is likely to play an important role in innate immunity. Genome-wide search for atopy susceptibility genes recently identified human chromosome 22q11, where the gene encoding MIF resides, as a region of interest for atopic traits. Both the -173G/C and -794 [CATT]5-8 repeat polymorphisms in the MIF promoter region are associated with altered levels of MIF gene transcription in vitro. We, therefore, hypothesized that these potentially functional polymorphisms may influence susceptibility to atopy and asthma. A case-control analysis examined the genetic influence of these promoter polymorphisms on the development of atopy and asthma in a Japanese population (n = 584). Evidence for significant association between the -173G/C and -794 [CATT]5-8 repeat polymorphisms and atopy was found; odds ratio for homozygotes of -173C allele was 3.67 (compared with homozygotes of -173G allele, 95% confidence interval = 1.43-9.46, p < 0.01), and odds ratio for noncarriers of the -794 [5-CATT] allele was 3.51 (compared with 5-CATT repeat homozygotes, 95% confidence interval = 1.82-6.78, p < 0.0005). No associations with asthma were detected. These results indicate that promoter polymorphisms in the MIF promoter region are risk factors for atopy and implicate MIF in the pathogenesis of atopy in a Japanese population.

Risk of Alzheimer disease with the epsilon4 allele for apolipoprotein E in a population-based study of men aged 62-73 years.

The epsilon4 allele at APOE, the polymorphic locus for apolipoprotein E, increases the risk of Alzheimer disease (AD), especially among those with the homozygous epsilon4/epsilon4 genotype. In family studies, epsilon4 homozygotes typically develop AD at 55-75 years, an age range when AD is otherwise relatively infrequent. Population-based studies of the AD risk associated with allele epsilon4 (and especially with genotype epsilon4/epsilon4) are limited in number, and most such studies have included few AD cases between the ages of 55 and 75 years. In a large population-based twin registry, the screening of 12,709 men who were 62-73 years old yielded 38 prevalent cases of AD whose onset age ranged from 54 to 73. Genotype at APOE was determined for 37 of these cases and independently, for a similarly aged probability sample of 344 men from the same registry. The epsilon4 allele frequencies among the AD cases and the population samples were 0.39 and 0.15, respectively. The odds ratios (ORs) for AD were 17.7 for genotype epsilon4/epsilon4 versus epsilon3/epsilon3 and 13.8 for epsilon4/epsilon4 versus all remaining genotypes. By contrast, the ORs with heterozygous epsilon4/epsilon3 were only 2.76 versus epsilon3/epsilon3 and 2.01 versus all genotypes other than epsilon4/epsilon3 (p for homozygote vs. heterozygote ORs=0.002). The estimated etiologic fraction for AD with homozygous epsilon4 among men in their mid-50s to mid 70s is therefore 0.20; for the much more common heterozygous genotype epsilon4/epsilon3, the fraction is 0.18. In combination with other studies that have adjusted statistically for age, these results suggest that the effect of the epsilon4 allele dose is neither linear nor homogeneous for age. Homozygous epsilon4/epsilon4 appears to confer an extreme risk of AD at the age when onset with this genotype is most likely. These results are consistent with the view that individual genotypes modify risk by predisposing to substantially different distributions of AD onsets.