Fine-mapping in African-American women confirms the importance of the 10p12 locus to sarcoidosis.

Sarcoidosis is a chronic granulomatous disease with a wide spectrum of symptoms. Genome-wide association studies in European populations have reported significant associations between sarcoidosis and single-nucleotide polymorphisms (SNPs) located in the intergenic region between the C10ORF67 and OTUD1 genes on chromosome 10p12, and the ANXA11 gene (chromosome 10q22). We carried out fine-mapping at 10p12 and 10q22 to assess associations of genetic variants in these regions with sarcoidosis risk in African-American women, based on 486 sarcoidosis cases and 943 age- and geography-matched controls in a nested case-control study within the Black Women's Health Study. There were no significant associations with variants of the ANXA11 gene (P=0.17). Haplotypic analyses of the C10ORF67-OTUD1 intergenic region revealed a strong inverse association of the variants rs1398024 and rs11013452 with sarcoidosis (odds ratio=0.52; P=0.01). Both SNPs are located inside an ∼300 kb low recombination region of chromosome 10p12, suggesting that both SNPs are tagging the same causal variant. Our top SNP (rs11013452) is located inside a smaller linkage disequilibrium block in HapMap YRI, further narrowing the position of the causal SNP to a region of ~8 kb on chromosome 10p12. The present findings confirm the potential importance of the 10p12 locus in the etiology of sarcoidosis.

Association between hepatic lipase -514 C/T promoter polymorphism and myocardial infarction is modified by history of hypercholesterolemia and waist circumference.

BACKGROUND AND AIMS: To examine whether the association between the -514 C/T polymorphism of the hepatic lipase gene and myocardial infarction (MI) is modified by history of hypercholesterolemia and increased waist circumference. METHODS AND RESULTS: A total of 1940 pairs of nonfatal MI cases and population-based controls were genotyped. Multiple conditional logistic regression was used for data analyses. The -514T variant was not associated with MI in the whole population. However, among people with history of hypercholesterolemia the T allele increased MI risk for heterozygous and homozygous carriers, respectively [OR=1.25 (95%CI=0.92-1.70) and OR=1.59 (95%CI=1.09-2.32). In contrast, the T allele decreased MI risk among people with no history of hypercholesterolemia [OR=0.85 (95%CI=0.70-1.03) and OR=0.76 (95%CI=0.60-0.97)], p for interaction=0.004. Among subjects with normal waist circumference there was no association between the -514T allele and MI for heterozygous and homozygous carriers, respectively [OR=1.04 (95%CI=0.86-1.25) and OR=0.96 (95%CI=0.77-1.21)], while among subjects with waist circumference above the limits of the metabolic syndrome definition there was a protective association [OR=0.63 (95%CI=0.45-0.90) and OR=0.81 (95%CI=0.53-1.25) p for interaction=0.04]. CONCLUSION: The -514T allele is associated with MI in opposite directions depending on the background of the studied population. This could explain what seem like inconsistent results across studies.

TNF microsatellites polymorphism is associated with rheumatoid arthritis. Confirming evidence in northwestern Colombians.

OBJECTIVE: To examine the contribution of tumor necrosis factor alpha (TNF) microsatellite (a to e) polymorphism to the genetic risk of developing rheumatoid arthritis (RA) in a northwestern Colombian population. METHODS: This was an association study in which 108 RA patients and 222 matched individuals were enrolled. HLA-DRB1 and DQB1 polymorphisms were evaluated to examine for linkage disequilibrium between these loci and TNF micro- satellites. Genotyping was performed using denaturing polyacrylamide gels and polymerase chain reaction-sequence techniques. RESULTS: By unconditional logistic regression analysis, the TNFa6 allele (OR=2.37, 95%CI 1.07-5.24) and the TNFb4 allele (OR=3.01, 95%CI 1.07-9.00) were observed to be associated with disease. These associations were independent of HLA-DR and HLA-DQ since linkage disequilibrium between HLA class II and TNF microsatellites was not observed. In addition, patients with the TNFa8 allele had a five times greater risk of developing extra-articular manifestations as compared to patients without this allele (OR=5.07, 95%CI 1.14-22.52), regardless of age and the duration of disease. Haplotype analysis disclosed a protective effect for TNFa7/b7/c1/d4/e3/-308G/-238G. CONCLUSION: These results confirm that the TNF locus exerts a primary influence on both susceptibility to and the severity of RA.

Macrophage migration inhibitory factor gene influences the risk of developing tuberculosis in northwestern Colombian population.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that regulates innate and adaptative immunity responses against pathogens. The MIF gene, at 22q11.2, is polymorphic. Functional promoter variants in the MIF gene influence susceptibility to inflammatory diseases in Caucasians and Africans. An association study was carried out to examine the influence of MIF-173 single nucleotide polymorphism and the MIF-794 microsatellite on the susceptibility to develop human tuberculosis (TB) in a well-defined Latin-American population. To this purpose, 230 northwestern Colombian patients with pulmonary TB, negative for human immunodeficiency virus infection, and 235 matched healthy individuals stratified by the tuberculin skin test were examined. Multivariate analysis showed that MIF-173C allele was associated with disease (odds ratio = 1.64, 95% confidence interval 1.07-2.52) in a dominant pattern. No allele in the MIF-794 CATT microsatellite was associated with risk of TB. These results indicate that MIF gene influences the risk of developing TB in the studied population.

Analysis of IL1B, TAP1, TAP2 and IKBL polymorphisms on susceptibility to tuberculosis.

Genetic determinants of human susceptibility to tuberculosis (TB) have not been completely elucidated. Interleukin-1 beta (IL-1beta) and the inhibitor of kB-like (IkBL) are important molecules that participate in the inflammatory response required for the immunological control of a broad spectrum of infectious agents. The transporter associated with antigen processing (TAP) is involved in the antigen processing via major histocompatibility complex class I molecules and in turn might regulate the T-cell response against Mycobacterium tuberculosis. To better characterize the host genetic factors determining the susceptibility to TB, we evaluated the influence of functional polymorphisms in IL1B, TAP and IKBL genes on the risk of developing pulmonary TB in a Northwestern Colombian population, an endemic area of M. tuberculosis infection. A total of 122 TB patients and 166 healthy controls (N = 166) negative for human immunodeficiency virus infection were examined for IL1B-511 and +3,953, TAP1 and TAP2 and IKBL+738 polymorphisms. Univariate analysis disclosed significant differences between patients and controls for IL1B+3,953 polymorphism. After unconditional logistic regression analysis, a strong protection conferred by IL1B+3,953 T-allele-carrying genotypes was observed. A trend between TAP2*0201 allele and disease was observed. Association between IL1B-511, TAP1 or IKBL polymorphisms and TB disease was not found. These results indicate that a functional polymorphism in the IL1B gene influences the susceptibility to TB and suggest a role for IL-1beta in the pathogenesis of mycobacterial infection.

Is the Ala12 variant of the PPARG gene an "unthrifty allele"?

BACKGROUND: The thrifty genotype hypothesis proposes that genetic susceptibility to type 2 diabetes results from the positive selection of "thrifty" alleles in the past. A corollary of this hypothesis is that genetic variants protecting against the development of diabetes are "unthrifty" and thus subject to negative selection during human evolution. METHODS: It was assessed whether age estimates of the diabetes protective PPARG Ala12 allele indicate effects of natural selection. Based on published data from four populations, the date of origin of the diabetes protective PPARG Ala12 variant was estimated using both allele frequency and linkage disequilibrium (LD) with the C1431T single nucleotide polymorphism in exon 6 of the PPARG gene. RESULTS: The best LD based estimate of the age of the Ala12 allele gave an average of approximately 32,000 years with a maximum upper bound of approximately 58,000 years. Assuming a population with a growth rate of r = 0.01 per generation, the frequency based estimate of the age of the Ala12 variant gave an average of approximately 27,000 years with a maximum upper bound of approximately 42,000 years. DISCUSSION: The similarity of both time estimates is consistent with selective equivalence of the diabetes protective PPARG Ala12 allele and the diabetes susceptible PPARG Pro12 allele.