Calcium urolithiasis is often associated with increased intestinal absorption and urine excretion of calcium, and has been suggested to result from increased vitamin D production. The role of the enzyme 1 alpha-hydroxylase, the rate-limiting step in active vitamin D production, was evaluated in 36 families, including 28 sibships with at least a pair of affected sibs, using qualitative and quantitative trait linkage analyses. Sibs with a verified calcium urolithiasis passage (n = 117) had higher 24-h calciuria (P = 0.03), oxaluria (P = 0.02), fasting and postcalcium loading urine calcium/creatinine (Ca/cr) ratios (P = 0.008 and P = 0.002, respectively), and serum 1,25(OH)2 vitamin D levels (P = 0.02) compared with nonstone-forming sibs (n = 120). Markers from a 9-centiMorgan interval encompassing the VDD1 locus on chromosome 12q13-14 (putative 1 alpha-hydroxylase) were analyzed in 28 sibships (146 sib pairs) of single and recurrent stone formers and in 14 sibships (65 sib pairs) with recurrent-only (> or = 3 episodes) stone-forming sibs. Two-point and multipoint analyses did not reveal excess in alleles shared among affected sibs at the VDD1 locus. Linkage of stone formation to the VDD1 locus could be excluded, respectively, with a lambda d of 2.0 (single and recurrent stone formers) and 3.25 (recurrent stone formers). Quantitative trait analyses revealed no evidence for linkage to 24-h calciuria and oxaluria, serum 1,25(OH)2 vitamin D levels, and Ca/cr ratios. This study shows absence of linkage of the putative 1 alpha-hydroxylase locus to calcium stone formation or to quantitative traits associated with idiopathic hypercalciuria. In addition, there is coaggregation of calciuric and oxaluric phenotypes with stone formation.
The ABCG2 c.421C>A single-nucleotide polymorphism (SNP) was determined in 660 healthy Finnish volunteers, of whom 32 participated in a pharmacokinetic crossover study involving the administration of 20 mg atorvastatin and rosuvastatin. The frequency of the c.421A variant allele was 9.5% (95% confidence interval 8.1-11.3%). Subjects with the c.421AA genotype (n = 4) had a 72% larger mean area under the plasma atorvastatin concentration-time curve from time 0 to infinity (AUC(0-infinity)) than individuals with the c.421CC genotype had (n = 16; P = 0.049). In participants with the c.421AA genotype, the rosuvastatin AUC(0-infinity) was 100% greater than in those with c.421CA (n = 12) and 144% greater than in those with the c.421CC genotype. Also, those with the c.421AA genotype showed peak plasma rosuvastatin concentrations 108% higher than those in the c.421CA genotype group and 131% higher than those in the c.421CC genotype group (P
Previous studies have suggested that a locus predisposing to specific reading disability (dyslexia) resides on chromosome 6p23-p21.3. We investigated 79 families having at least two siblings affected with phonological coding dyslexia, the most common form of reading disability (617 people genotyped, 294 affected), and we tested for linkage with the genetic markers reported to be linked to dyslexia in those studies. No evidence for linkage was found by LOD score analysis or affected-sib-pair methods. However, using the affected-pedigree-member (APM) method, we detected significant evidence for linkage and/or association with some markers when we used published allele frequencies with weighting of rarer alleles. APM results were not significant when we used marker allele frequencies estimated from parents. Furthermore, results were not significant with the more robust SIMIBD method using either published or parental marker frequencies. Finally, family-based association analysis using the AFBAC program showed no evidence for association with any marker. We conclude that the APM method should be used only with extreme caution, because it appears to have generated false-positive results. In summary, using a large data set with high power to detect linkage, we were unable to find evidence for linkage or association between phonological coding dyslexia and chromosome 6p markers.
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Three methods were employed to assess whether human volunteers (Caucasian, Asian or Cree Indian) possessed the typical or atypical mitochondrial aldehyde dehydrogenase (ALDH2) isozyme. These methods were: (1) questioning individuals about facial flushing responses following alcohol consumption; (2) application of the ethanol skin patch test, and (3) direct analysis using isoelectric focusing and activity staining of ALDH activity in hair root samples. The results from the three methods were in good agreement and revealed that only the typical ALDH2 isozyme was expressed in Saskatchewan Cree Indians. In agreement with previous reports, the typical ALDH2 was expressed in the Caucasian group of subjects, while both the typical and atypical forms were expressed in the Asian subjects.
Homozygosity for a premature stop codon at amino acid position 577 in the alpha-actinin-3 (ACTN3) gene leads to a-actinin-3 deficiency. This genotype is observed in approximately 18% of Caucasians. The ACTN3 R577X polymorphism has been previously associated with indicators of physical performance in several, but not all, studies. We examined the prevalence of R577X (rs1815739) and two additional haplotype tagging single nucleotide polymorphisms (htSNPs) of the ACTN3 gene (rs1791690 and rs2275998) in the Genathlete study comprising 316 male elite endurance athletes (VO2max 79.0+3.5 ml · kg(-1) · min(-1); mean +/- s) from North America, Finland, and Germany and 304 sedentary controls (VO2max 40.1+7.0 ml · kg(-1) · min(-1) matched by country of origin. The distribution of genotype and allele frequencies between the two groups was tested by Pearson chi-square and/or Fischer exact test. The prevalence of the 577X homozygote genotype was similar in endurance athletes and controls (20% and 17.5%, respectively). The resulting odds ratio for endurance performance in 577X homozygotes compared with 577R-allele carriers was 1.24 (95%CI 0.82-1.87, P = 0.3). The genotype distribution of the two htSNPs and haplotype frequencies did not differ significantly between athletes and controls. In conclusion, our findings indicate that ACTN3 R577X and other SNPs in ACTN3 are not genetic determinants of endurance performance in Caucasian males.
CONTEXT: Hospital-based studies have found that increased susceptibility to certain infections is associated with low serum levels of mannose-binding lectin (MBL) due to MBL variant alleles. However, the contribution of MBL insufficiency to incidence of common childhood infections at a population level is unknown. OBJECTIVE: To investigate the effect of MBL insufficiency on risk for acute respiratory tract infection (ARI) in unselected children younger than 2 years. DESIGN AND SETTING: Population-based, prospective, cohort study conducted in Sisimiut, Greenland. PARTICIPANTS: Two hundred fifty-two children younger than 2 years who were followed up weekly between August 1996 and August 1998 for morbidity surveillance. MAIN OUTCOME MEASURE: Risk of ARI, based on medical history and clinical examination, compared by MBL genotype, determined from blood samples based on presence of structural and promoter alleles. RESULTS: A 2.08-fold (95% confidence interval [CI], 1.41-3.06) increased relative risk (RR) of ARI was found in MBL-insufficient children (n = 13) compared with MBL-sufficient children (n = 239; P
Comment In: JAMA. 2001 Mar 14;285(10):1348-911255392
Primary Sj?gren's syndrome (SS) shares many features with systemic lupus erythematosus (SLE). Here we investigated the association of the three major polymorphisms in IRF5 and STAT4 found to be associated with SLE, in patients from Sweden and Norway with primary SS. These polymorphisms are a 5-bp CGGGG indel in the promoter of IRF5, the single nucleotide polymorphism (SNP) rs10488631 downstream of IRF5 and the STAT4 SNP rs7582694, which tags the major risk haplotype of STAT4. We observed strong signals for association between all three polymorphisms and primary SS, with odds ratios (ORs) >1.4 and P-values
AIMS/HYPOTHESIS: Adiponectin is an adipocytokine with lowered blood levels in obesity and Type 2 diabetes mellitus. We sought to define the specific effects of different alleles of the gene encoding adiponectin. METHODS: We studied the associations of adiponectin gene sequence variations with body fat distribution and insulin indices in 503 White and 276 Black subjects of the HERITAGE Family Study cohort and subjects from a Finnish population. RESULTS: The His111 allele frequency of the Tyr111 His polymorphism in Finnish Type 2 diabetic subjects (n=254) was higher (5.1%) than in control subjects (n=270) (2.6%; P = 0.033). In the HERITAGE cohort, the His111 allele was associated with a lower insulin sensitivity index (P = 0.018) and a higher acute insulin response to glucose (P = 0.0098) in Whites. Other variants showed associations with adiposity and plasma lipid values only in Blacks. Among Blacks, the IVS2+G62T variant was associated with body fat (P = 0.002) and total cholesterol values (P = 0.005), and the Gly15Gly variant with cholesterol (P = 0.009) and triglyceride (P = 0.05) levels. The haplotype derived from these two polymorphisms was associated with total body fat, while the IVS2+G62T and Tyr111His-haplotype was associated with body fat and disposition index. CONCLUSIONS: The carriers of the His111 allele may have a higher risk of developing Type 2 diabetes mellitus. Racial differences were found between Blacks and Whites in body composition and lipids according to ACDC genotypes. Sequence variants in the adiponectin gene appear to be associated with diabetes and diabetes-related phenotypes.
Adiponectin is an adipocyte-expressed protein that regulates the glucose, lipid, and energy metabolism via adiponectin receptors 1 and 2. Obesity is a known risk factor for age-related macular degeneration (AMD). We, therefore, examined associations of single nucleotide polymorphisms in Adiponectin (ADIPOQ) and Adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2) genes with the prevalence of advanced AMD in Finnish population. Thirty-seven markers for ADIPOQ, ADIPOR1 and ADIPOR2 were genotyped in a sample collection of 91 men and 177 women having exudative AMD and 18 men and 26 women having severe atrophic AMD. Patients were diagnosed by fundus photographs and fluorescein angiography. The control group (no signs of AMD in fundus photographs) consisted of 55 men and 111 women. Inclusion criteria age was over 65 years old without diabetes diagnosis. Out of the tested SNPs, rs10753929 located in intron of ADIPOR1 gene was significantly associated (p=0.0471) with AMD status when using a permutation procedure that controlled for the number of tested genotypes and genetic models. Odds ratio (OR) for the association was 1.699 (95% CI 1.192-2.423). The SNP consists of C/T alleles and the risk allele T had a minor allele frequency (MAF) of 20.4%. Distribution of proportion of cases/controls between alleles revealed an additive genetic model. Our findings reveal that rs10753929 ADIPOR1 variant is a novel candidate for AMD genetic risk factor in Finnish population.
Department of Medicine, Division of General Internal Medicine, Institute for Human Genetics and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.
Among US Latinas and Mexican women, those with higher European ancestry have increased risk of breast cancer. We combined an admixture mapping and genome-wide association mapping approach to search for genomic regions that may explain this observation. Latina women with breast cancer (n= 1497) and Latina controls (n= 1272) were genotyped using Affymetrix and Illumina arrays. We inferred locus-specific genetic ancestry and compared the ancestry between cases and controls. We also performed single nucleotide polymorphism (SNP) association analyses in regions of interest. Correction for multiple-hypothesis testing was conducted using permutations (P(corrected)). We identified one region where genetic ancestry was significantly associated with breast cancer risk: 6q25 [odds ratio (OR) per Indigenous American chromosome 0.75, 95% confidence interval (CI): 0.65-0.85, P= 1.1 × 10(-5), P(corrected)= 0.02]. A second region on 11p15 showed a trend towards association (OR per Indigenous American chromosome 0.77, 95% CI: 0.68-0.87, P= 4.3 × 10(-5), P(corrected)= 0.08). In both regions, breast cancer risk decreased with higher Indigenous American ancestry in concordance with observations made on global ancestry. The peak of the 6q25 signal includes the estrogen receptor 1 (ESR1) gene and 5' region, a locus previously implicated in breast cancer. Genome-wide association analysis found that a multi-SNP model explained the admixture signal in both regions. Our results confirm that the association between genetic ancestry and breast cancer risk in US Latinas is partly due to genetic differences between populations of European and Indigenous Americans origin. Fine-mapping within the 6q25 and possibly the 11p15 loci will lead to the discovery of the biologically functional variant/s behind this association.
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