Skin pigmentation polymorphisms associated with increased risk of melanoma in a case-control sample from southern Brazil.

BACKGROUND: Melanoma is the most aggressive type of skin cancer and is associated with environmental and genetic risk factors. It originates in melanocytes, the pigment-producing cells. Single nucleotide polymorphisms (SNPs) in pigmentation genes have been described in melanoma risk modulation, but knowledge in the field is still limited. METHODS: In a case-control approach (107 cases and 119 controls), we investigated the effect of four pigmentation gene SNPs (TYR rs1126809, HERC2 rs1129038, SLC24A5 rs1426654, and SLC45A2 rs16891982) on melanoma risk in individuals from southern Brazil using a multivariate logistic regression model and multifactor dimensionality reduction (MDR) analysis. RESULTS: Two SNPs were associated with an increased risk of melanoma in a dominant model: rs1129038AA and rs1426654AA [OR = 2.094 (95% CI: 1.106-3.966), P = 2.3 10- 2 and OR = 7.126 (95% CI: 1.873-27.110), P = 4.0 10- 3, respectively]. SNP rs16891982CC was associated with a lower risk to melanoma development in a log-additive model when the allele C was inherited [OR = 0.081 (95% CI: 0.008-0.782), P = 3 10- 2]. In addition, MDR analysis showed that the combination of the rs1426654AA and rs16891982GG genotypes was associated with a higher risk for melanoma (P = 3 10- 3), with a redundant effect. CONCLUSIONS: These results contribute to the current knowledge and indicate that epistatic interaction of these SNPs, with an additive or correlational effect, may be involved in modulating the risk of melanoma in individuals from a geographic region with a high incidence of the disease.

A tale of agriculturalists and hunter-gatherers: Exploring the thrifty genotype hypothesis in native South Americans.

OBJECTIVES: To determine genetic differences between agriculturalist and hunter-gatherer southern Native American populations for selected metabolism-related markers and to test whether Neel's thrifty genotype hypothesis (TGH) could explain the genetic patterns observed in these populations. MATERIALS AND METHODS: 375 Native South American individuals from 17 populations were genotyped using six markers (APOE rs429358 and rs7412; APOA2 rs5082; CD36 rs3211883; TCF7L2 rs11196205; and IGF2BP2 rs11705701). Additionally, APOE genotypes from 39 individuals were obtained from the literature. AMOVA, main effects, and gene-gene interaction tests were performed. RESULTS: We observed differences in allele distribution patterns between agriculturalists and hunter-gatherers for some markers. For instance, between-groups component of genetic variance (FCT ) for APOE rs429358 showed strong differences in allelic distributions between hunter-gatherers and agriculturalists (p = 0.00196). Gene-gene interaction analysis indicated that the APOE E4/CD36 TT and APOE E4/IGF2BP2 A carrier combinations occur at a higher frequency in hunter-gatherers, but this combination is not replicated in archaic (Neanderthal and Denisovan) and ancient (Anzick, Saqqaq, Ust-Ishim, Mal'ta) hunter-gatherer individuals. DISCUSSION: A complex scenario explains the observed frequencies of the tested markers in hunter-gatherers. Different factors, such as pleotropic alleles, rainforest selective pressures, and population dynamics, may be collectively shaping the observed genetic patterns. We conclude that although TGH seems a plausible hypothesis to explain part of the data, other factors may be important in our tested populations.

Selection scan reveals three new loci related to high altitude adaptation in Native Andeans.

The Andean Altiplano has been occupied continuously since the late Pleistocene, ~12,000 years ago, which places the Andean natives as one of the most ancient populations living at high altitudes. In the present study, we analyzed genomic data from Native Americans living a long-time at Andean high altitude and at Amazonia and Mesoamerica lowland areas. We have identified three new candidate genes - SP100, DUOX2 and CLC - with evidence of positive selection for altitude adaptation in Andeans. These genes are involved in the TP53 pathway and are related to physiological routes important for high-altitude hypoxia response, such as those linked to increased angiogenesis, skeletal muscle adaptations, and immune functions at the fetus-maternal interface. Our results, combined with other studies, showed that Andeans have adapted to the Altiplano in different ways and using distinct molecular strategies as compared to those of other natives living at high altitudes.

Novel genetic associations and gene-gene interactions of chemokine receptor and chemokine genetic polymorphisms in HIV/AIDS.

OBJECTIVE: To investigate the influence of candidate polymorphisms on chemokine receptor/ligand genes on HIV infection and AIDS progression (HIV/AIDS). DESIGN: Fifteen polymorphisms of the CCR3, CCR4, CCR5, CCR6, CCR8, CXCR3, CXCR6, CCL20, CCL22 and CXCL10 genes were analysed in 206 HIV-positive patients classified as rapid progressors (n = 40), or nonrapid progressors (n = 166), and in 294 HIV-seronegative patients. METHODS: The polymorphisms were genotyped using minisequencing. Genetic models were tested using binomial logistic regression; nonparametric multifactor dimensionality reduction (MDR) was used to detect gene-gene interactions. RESULTS: The CCR3 rs3091250 [TT, adjusted odds ratio (AOR): 2.147, 95% confidence interval (CI) 1.076-4.287, P = 0.030], CCR8 rs2853699 (GC/CC, AOR: 1.577, 95% CI 1.049-2.371, P = 0.029), CXCL10 rs56061981 (CT/TT, AOR: 1.819, 95% CI 1.074-3.081, P = 0.026) and CCL22 rs4359426 (CA/AA, AOR: 1.887, 95% CI 1.021-3.487, P = 0.043) polymorphisms were associated with susceptibility to HIV infection. The CCL20 rs13034664 (CC, OR: 0.214, 95% CI 0.063-0.730, P = 0.014) and CCL22 rs4359426 (CA/AA, OR: 2.685, 95% CI 1.128-6.392, P = 0.026) variants were associated with rapid progression to AIDS. In MDR analyses revealed that the CXCL10 rs56061981 and CCL22 rs4359426 combination was the best model, with 57% accuracy (P = 0.008) for predicting susceptibility to HIV infection. CONCLUSION: Our results provide new insights into the influence of candidate chemokine receptor/ligand polymorphisms and significant evidence for gene-gene interactions on HIV/AIDS susceptibility.