An X-linked haplotype of Neandertal origin is present among all non-African populations.

Recent work on the Neandertal genome has raised the possibility of admixture between Neandertals and the expanding population of Homo sapiens who left Africa between 80 and 50 Kya (thousand years ago) to colonize the rest of the world. Here, we provide evidence of a notable presence (9% overall) of a Neandertal-derived X chromosome segment among all contemporary human populations outside Africa. Our analysis of 6,092 X-chromosomes from all inhabited continents supports earlier contentions that a mosaic of lineages of different time depths and different geographic provenance could have contributed to the genetic constitution of modern humans. It indicates a very early admixture between expanding African migrants and Neandertals prior to or very early on the route of the out-of-Africa expansion that led to the successful colonization of the planet.

Environmental influence on the worldwide prevalence of a 776C->G variant in the transcobalamin gene (TCN2).

BACKGROUND: A 776C-->G variant (dbSNP ID: rs1801198) in the transcobalamin gene (TCN2; MIM# 275350) decreases the cellular and plasma concentration of transcobalamin and thereby influences the cellular availability of vitamin B(12). OBJECTIVE: To evaluate the worldwide prevalence of this variant and its association with homocysteine plasma level. METHODS: The study was performed in 1433 apparently healthy subjects, including Afro-Americans and Afro-Africans and in 251 Afro-Africans participants with severe malaria. RESULTS: The frequencies of the 776G allele were the highest in China (0.607; 95% CI 0.554 to 0.659), low in West Africa (Bénin and Togo, 0.178; 0.154 to 0.206), and intermediate in France (0.445; 0.408 to 0.481), Italy (0.352; 0.299 to 0.409), Morocco (0.370; 0.300 to 0.447) and Mexico (0.374; 0.392 to 0.419). The 776G genotype was more frequent in Afro-Americans from New York (16.7; 8.4 to 30.7) and in Afro-African patients with severe malaria (6.0%; 95% CI 3.7 to 9.6) than in healthy Afro-African volunteers (p = 0.0004 and p = 0.033, respectively), while no difference was observed for MTHFR 677TT and 677T alleles. A disequilibrium of TCN2 genotype distribution was recorded in patients with severe malaria, with a twofold higher GG genotype than expected (p = 0.010). An association between the TCN2 polymorphism and homocysteine was observed only in Mexico and France, the two countries with the highest rate of low plasma concentration of vitamin B(12) (<100 pmol/l). CONCLUSION: Given the dramatic heterogeneity of the 776G allele frequency worldwide, this polymorphism may be prone to a selective pressure or confers an evolutionary advantage in confronting environmental factors, one of which is malaria.

BRIP1 coding variants are associated with a high risk of hepatocellular carcinoma occurrence in patients with HCV- or HBV-related liver disease.

The molecular mechanisms of hepatocellular carcinoma (HCC) carcinogenesis are still not fully understood. DNA repair defects may influence HCC risk. The aim of the study was to look for potential genetic variants of DNA repair genes associated with HCC risk among patients with alcohol- or viral-induced liver disease. We performed four case-control studies on 2,006 European- (Derivation#1 and #2 studies) and African-ancestry (Validation#1 and #2 studies) patients originating from several cohorts in order to assess the association between genetic variants on DNA repair genes and HCC risk using a custom array encompassing 94 genes. In the Derivation#1 study, the BRIP1 locus reached array-wide significance (Chi-squared SV-Perm, P=5.00×10-4) among the 253 haplotype blocks tested for their association with HCC risk, in patients with viral cirrhosis but not among those with alcoholic cirrhosis. The BRIP1 haplotype block included three exonic variants (rs4986763, rs4986764, rs4986765). The BRIP1 'AAA' haplotype was significantly associated with an increased HCC risk [odds ratio (OR), 2.01 (1.19-3.39); false discovery rate (FDR)-P=1.31×10-2]. In the Derivation#2 study, results were confirmed for the BRIP1 'GGG' haplotype [OR, 0.53 (0.36-0.79); FDR-P=3.90×10-3]. In both Validation#1 and #2 studies, BRIP1 'AAA' haplotype was significantly associated with an increased risk of HCC [OR, 1.71 (1.09-2.68); FDR-P=7.30×10-2; and OR, 6.45 (4.17-9.99); FDR-P=2.33×10-19, respectively]. Association between the BRIP1 locus and HCC risk suggests that impaired DNA mismatch repair might play a role in liver carcinogenesis, among patients with HCV- or HBV-related liver disease.

Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: a comparative study in Mexican, West African, and European populations.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism is heterogeneously distributed worldwide, with the highest and lowest frequencies of the T allele in Mexico and Africa, respectively, and a south-to-north gradient in Europe. Distribution of MTHFR 1298A-->C is less well known. It has been hypothesized that 677T frequency could result in part from gene-nutrient interactions. OBJECTIVE: The objective was to compare the association of 677T and 1298C alleles with plasma concentrations of homocysteine, folate, and vitamin B-12 in geographical areas with contrasting 677T allele frequencies. DESIGN: Healthy young adults (n = 1277) were recruited in Mexico City, the West African countries of Bénin and Togo, France, and Sicily (Italy). Homocysteine, folate, and vitamin B-12 were measured in plasma, and MTHFR polymorphisms were measured in genomic DNA. RESULTS: Mexico City and Sicily reported the highest and Bénin and Togo reported the lowest plasma concentrations of folate. Mexico City had the highest 677T allele prevalence and the lowest influence of 677TT genotype on homocysteine, whereas the opposite was observed in Africa. The prevalence of the 1298C allele was lowest in the Mexicans and Africans and highest in the French. The percentage of the 677T genotype was significantly associated with the folate concentrations in 677CC carriers in a univariate analysis (R = 0.976; 95% CI: 0.797, 0.996; P < 0.0002) and in a multiple regression model that included homocysteine, vitamin B-12, and age (P = 0.0002). CONCLUSION: Our data agree with the hypothesis of a gene-nutrient interaction between MTHFR 677C-->T polymorphism and folate status that may confer a selective advantage of TT-homozygous genotype when dietary intake of folate is adequate, at least in the areas studied.

High prevalence of hyperhomocysteinemia related to folate deficiency and the 677C-->T mutation of the gene encoding methylenetetrahydrofolate reductase in coastal West Africa.

BACKGROUND: Moderate hyperhomocysteinemia is a risk for neural tube defect and neurodegenerative and vascular diseases and has nutritional, metabolic, and genetic determinants. Its prevalence in sub-Saharan Africa remains unknown. OBJECTIVE: Our goal was to evaluate the prevalence of hyperhomocysteinemia and the influence of nutritional, metabolic, and genetic determinants in savanna and coastal regions of Togo and Benin. DESIGN: Volunteers were recruited from coastal (C groups; n = 208) and savanna (S group; n = 68) regions. Vitamin B-12, folate, total homocysteine (tHcy), cystatin C (a marker of glomerular filtration), and inflammatory and nutritional protein markers were measured in plasma, and the methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298A--> C polymorphisms and the methionine synthase 2756A-->G polymorphism were examined in genomic DNA. RESULTS: Moderate hyperhomocysteinemia (tHcy > 15 micromol/L) was recorded in 62.3% and 29.4% of the subjects from the coast and savanna, respectively (P < 0.0001). A histogram distribution of tHcy in the coastal groups showed a distinct group, C2 (15% of the total group), with tHcy > 28 micro mol/L. Folate < 6.75 nmol/L (lower quartile) and MTHFRCT/TT genotype were the 2 main risk factors for moderate hyperhomocysteinemia in the whole population [odds ratios: 5.3 (95% CI: 2.5, 11.2; P < 0.0001) and 4.9 (1.6, 14.8; P = 0.0048), respectively] and in the C2 group [odds ratios: 15.9 (4.5, 56.8; P < 0.0001) and 9.0 (2.3, -35.2; P = 0.0017), respectively]. Cystatin C was another potent risk factor in the C2 group. CONCLUSION: A high prevalence of hyperhomocysteinemia in coastal West Africa, related to folate concentrations and the MTHFR 677 T allele, suggests the need to evaluate the influence of hyperhomocysteinemia on disease in this area.

Serum concentrations of sex hormone binding globulin are elevated in kwashiorkor and anorexia nervosa but not in marasmus.

BACKGROUND: Customary blood protein markers for malnutrition are of limited value in the diagnosis of protein-energy malnutrition or anorexia nervosa in children and in the follow-up to refeeding in such children. OBJECTIVES: For these diseases, we compared the diagnostic value of sex hormone binding globulin (SHBG) with that of albumin, transferrin, transthyretin, and retinal binding protein and determined the relations between concentrations of insulin, insulin-like growth factor I, and SHBG. DESIGN: SHBG was assayed in children with protein-energy malnutrition (29 children with kwashiorkor and 28 with marasmus), in 29 anorectic girls (before and after refeeding), and in age- and sex-matched control subjects. RESULTS: Mean (+/-SE) serum SHBG concentrations were higher in the children with kwashiorkor (0.18 +/- 0.07 micromol/L) than in the children with marasmus (0.11 +/- 0.05 micromol/L, P < 0.0001) or the control subjects (0.11 +/- 0.03 micromol/L, P < 0.0005). In the children with anorexia nervosa before weight gain, serum SHBG concentrations were significantly higher (0.10 +/- 0.04 micromol/L) than in the age-matched control subjects (0.06 +/- 0.03 micromol/L, P < 0.001) and decreased significantly after 30 d of refeeding (0.04 +/- 0.01 micromol/L, P < 0.0001). This decrease was negatively correlated with insulin-like growth factor I but not with insulin. Mean serum SHBG concentrations were influenced neither by inflammation, as indicated when C-reactive protein was used as a marker (0.27 +/- 0.27, 0.34 +/- 0.42, and <0.04 micromol/L in the children with marasmus, kwashiorkor, and anorexia nervosa, respectively), nor by glomerular filtration, as indicated when cystatin-C was used as a marker (68.46 +/- 23.08, 66.90 +/- 43.08, and 49.23 +/- 7.69 micromol/L, respectively). CONCLUSIONS: The high SHBG concentration observed in anorexia nervosa and kwashiorkor seems to be of multifactorial origin. For these 2 diseases, SHBG is a reliable marker of nutritional status, is unrelated to either C-reactive protein or cystatin-C, and may be helpful in distinguishing kwashiorkor from marasmus and as a follow-up marker after refeeding.

Helicobacter pylori serologic status has no influence on the association between fucosyltransferase 2 polymorphism (FUT2 461 G->A) and vitamin B-12 in Europe and West Africa.

BACKGROUND: Genomewide association studies have shown a relation between plasma vitamin B-12 concentration and the 461G→A polymorphism of fucosyltransferase 2 (FUT2), a gene associated with susceptibility to Helicobacter pylori infection. OBJECTIVE: We evaluated in 2 populations the association of FUT2 461 G→A polymorphism with vitamin B-12 and related metabolic markers and investigated whether the influence of FUT2 on H. pylori serology is part of the mechanisms that underlie these associations. DESIGN: The study included 1282 ambulatory subjects from Europe and West Africa. Blood concentrations of vitamin B-12, folate, homocysteine, and methylmalonic acid were measured. Genotyping was performed by real-time polymerase chain reaction. H. pylori serology testing was performed by using ELISA. RESULTS: In univariate analysis, FUT2 461 A/A genotype was associated with higher plasma vitamin B-12 concentration in the total population (P = 0.0007) as well as in Europe (P = 0.0009) and in West Africa (P = 0.0015). Positivity for H. pylori serology was higher in West Africa (P < 0.0001) and was not associated with low plasma vitamin B-12. The prevalence of H. pylori-positive patients did not differ among FUT2 461 G→A genotypes (P = 0.2068). In multivariate analysis, FUT2 461 G→A genotype (P = 0.0008), but not positive H. pylori serology, was an independent predictor of plasma vitamin B-12 concentration. CONCLUSION: This study confirms the influence of FUT2 461 G→A polymorphism on plasma vitamin B-12 concentration and showed no influence of H. pylori serologic status on this association in ambulatory subjects from Europe and West Africa.

Methylenetetrahydrofolate reductase 677 T allele protects against persistent HBV infection in West Africa.

BACKGROUND/AIMS: Homocysteine metabolism is linked to DNA methylation, a mechanism potentially involved in the course of hepatitis B virus (HBV) infection. We evaluated the association of determinants of homocysteine metabolism with the outcome of HBV infection. METHODS: Four hundred and fifty-five healthy adults from Togo and Benin were tested for HBV serologic markers, HLA DR alleles, folate, vitamin B12, methylenetetrahydrofolate reductase (MTHFR) 677 C-->T, 1298 A-->C and methionine synthase 2756 A-->G polymorphisms. RESULTS: Seventy-eight percent of the study population was anti-HBc positive. Among them, 202 (56.9%) were anti-HBs positive and 58 (16.3%) were HBsAg positive. After stepwise logistic regression, the MTHFR 677 T allele was independently associated with persistence of detectable anti-HBs antibodies (OR: 2.47; 95% CI: 1.29-4.71; p=0.006). The mean HBV DNA level was significantly lower in HBsAg positive subjects carrying the 677 T allele than in those with the 677 CC genotype (1000+/-1406 vs. 2,400,000+/-214,000 copies/ml, p=0.005). Beninese origin and HLA-DRB1*09 allele were the other determinants independently associated with favorable outcome of HBV infection. CONCLUSIONS: The methylenetetrahydrofolate reductase 677 T allele seems to protect against chronic HBV infection in young African adults.

Low frequency of mutated methylenetetrahydrofolate reductase 677C-->T and 1298A-->C genetics single nucleotide polymorphisms (SNPs) in Sub-Saharan populations.

5,10-Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are two of the key enzymes in the folate/vitamin B12-dependent remethylation of homocysteine to methionine. The frequencies of MTHFR single nucleotide polymorphisms (SNPs), 677C-->T, 1298A-->C, 1317T-->C and of MTR, 2756A-->G, have been widely studied in Caucasians, but they have never been reported simultaneously in a large population from Sub-Saharan Africa. Presently, we report the prevalence of these SNPs and their relationship to homocysteine in 240 subjects recruited in West Africa. The frequencies of the mutant genotypes 677TT (0.8%) and 1298CC (2%) were lower than that usually observed in Caucasians, while the frequency of the mutant 1317CC was higher (16%). We formed a systematic association of the mutated MTHFR 677C-->T SNP with a 1298A/1317T common haplotype. The MTHFR mutant genotype 677TT was associated with an intermediate hyperhomocysteinemia (92.4 +/- 6.0 micromol/l) higher than that described in Caucasians. The 2756A-->G SNP in the MTR was similarly distributed in Africans compared to Caucasians. In conclusion, the MTHFR 677TTor 1298CC genotypes are much rarer in Africans than in Caucasians. The 677TT low frequency may be related to the high effect of this mutation on homocysteine metabolism in the environmental conditions of this African region.