A single nucleotide polymorphism within the acetyl-coenzyme A carboxylase beta gene is associated with proteinuria in patients with type 2 diabetes.

It has been suggested that genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy. A large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes identified the gene encoding acetyl-coenzyme A carboxylase beta (ACACB) as a candidate for a susceptibility to diabetic nephropathy; the landmark SNP was found in the intron 18 of ACACB (rs2268388: intron 18 +4139 C > T, p = 1.4x10(-6), odds ratio = 1.61, 95% confidence interval [CI]: 1.33-1.96). The association of this SNP with diabetic nephropathy was examined in 9 independent studies (4 from Japan including the original study, one Singaporean, one Korean, and two European) with type 2 diabetes. One case-control study involving European patients with type 1 diabetes was included. The frequency of the T allele for SNP rs2268388 was consistently higher among patients with type 2 diabetes and proteinuria. A meta-analysis revealed that rs2268388 was significantly associated with proteinuria in Japanese patients with type 2 diabetes (p = 5.35 x 10(-8), odds ratio = 1.61, 95% Cl: 1.35-1.91). Rs2268388 was also associated with type 2 diabetes-associated end-stage renal disease (ESRD) in European Americans (p = 6 x 10(-4), odds ratio = 1.61, 95% Cl: 1.22-2.13). Significant association was not detected between this SNP and nephropathy in those with type 1 diabetes. A subsequent in vitro functional analysis revealed that a 29-bp DNA fragment, including rs2268388, had significant enhancer activity in cultured human renal proximal tubular epithelial cells. Fragments corresponding to the disease susceptibility allele (T) had higher enhancer activity than those of the major allele. These results suggest that ACACB is a strong candidate for conferring susceptibility for proteinuria in patients with type 2 diabetes.

International Lung Cancer Consortium: coordinated association study of 10 potential lung cancer susceptibility variants.

BACKGROUND: Analysis of candidate genes in individual studies has had only limited success in identifying particular gene variants that are conclusively associated with lung cancer risk. In the International Lung Cancer Consortium (ILCCO), we conducted a coordinated genotyping study of 10 common variants selected because of their prior evidence of an association with lung cancer. These variants belonged to candidate genes from different cancer-related pathways including inflammation (IL1B), folate metabolism (MTHFR), regulatory function (AKAP9 and CAMKK1), cell adhesion (SEZL6) and apoptosis (FAS, FASL, TP53, TP53BP1 and BAT3). METHODS: Genotype data from 15 ILCCO case-control studies were available for a total of 8431 lung cancer cases and 11 072 controls of European descent and Asian ethnic groups. Unconditional logistic regression was used to model the association between each variant and lung cancer risk. RESULTS: Only the association between a non-synonymous variant of TP53BP1 (rs560191) and lung cancer risk was significant (OR = 0.91, P = 0.002). This association was more striking for squamous cell carcinoma (OR = 0.86, P = 6 x 10(-4)). No heterogeneity by center, ethnicity, smoking status, age group or sex was observed. In order to confirm this association, we included results for this variant from a set of independent studies (9966 cases/11,722 controls) and we reported similar results. When combining all these studies together, we reported an overall OR = 0.93 (0.89-0.97) (P = 0.001). This association was significant only for squamous cell carcinoma [OR = 0.89 (0.85-0.95), P = 1 x 10(-4)]. CONCLUSION: This study suggests that rs560191 is associated to lung cancer risk and further highlights the value of consortia in replicating or refuting published genetic associations.

cMET and refractive error progression in children.

OBJECTIVE: To assess whether genetic variation in cMET is associated with refractive error or change in refractive error over time. DESIGN: Cohort study. PARTICIPANTS AND CONTROLS: Discovery set (Set 1: N = 579 children; 403 cases, 176 controls). Confirmatory set (Set 2: N = 547 children; 338 cases, 209 controls). METHODS: Children in the discovery set were genotyped for a panel of genetic markers within cMET. Markers that were found to be significantly associated with the presence of refractive error or more rapid change in refractive error were then genotyped in the confirmatory set. MAIN OUTCOME MEASURES: Presence or absence of myopia and the rate of change in refractive error over a 3-year follow-up period. RESULTS: Carriage of the variant cMET +110703 A allele was found to associate with increased susceptibility to myopia. The variant was also found to associate with a faster rate of change in refractive error in both the discovery set and the confirmatory cohort regardless of the initial refractory ability (School 1; chi(2) for trend P = 0.014) (Schools 2 and 3; chi(2) for trend = 5.42, P = 0.020) (combined N = 1126, overall chi(2) for trend = 10.90, P = 9.6 x 10(-4)). Carriage of the variant allele was also found to be significantly overrepresented in children within the fastest changing quartile (Q4: mean change of -3.01 D over 3 years) compared with the slowest (Q1: mean change of -0.28 D over 3 years) (P(Set1) = 0.004, P(Set2) = 0.02, Combined N = 559, P = 3.0 x 10(-4)). CONCLUSIONS: Our data implicate the involvement of cMET in the pathogenesis of myopia in general, as well as more rapid progression in refractive error regardless of the initial refractory ability. These results underline the importance of eye growth genes in the development of common myopia.

Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes.

OBJECTIVE: Despite extensive evidence for genetic susceptibility to diabetic nephropathy, the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to diabetic nephropathy, a genome-wide association scan was implemented on the Genetics of Kidneys in Diabetes collection. RESEARCH DESIGN AND METHODS: We genotyped approximately 360,000 single nucleotide polymorphisms (SNPs) in 820 case subjects (284 with proteinuria and 536 with end-stage renal disease) and 885 control subjects with type 1 diabetes. Confirmation of implicated SNPs was sought in 1,304 participants of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term, prospective investigation of the development of diabetes-associated complications. RESULTS: A total of 13 SNPs located in four genomic loci were associated with diabetic nephropathy with P < 1 x 10(-5). The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR] = 1.45, P = 5.0 x 10(-7)). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR = 1.36, P = 3.1 x 10(-6)). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR] = 1.33, P = 0.02, and HR = 1.32, P = 0.01, respectively). We demonstratedexpression of both FRMD3 and CARS in human kidney. CONCLUSIONS: We identified genetic associations for susceptibility to diabetic nephropathy at two novel candidate loci near the FRMD3 and CARS genes. Their identification implicates previously unsuspected pathways in the pathogenesis of this important late complication of type 1 diabetes.

International Lung Cancer Consortium: pooled analysis of sequence variants in DNA repair and cell cycle pathways.

BACKGROUND: The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies. METHODS: Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects. RESULTS: Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79-0.99 and homozygote OR, 0.84; 95% CI, 0.71-1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% CI, 0.89-1.10 and homozygote OR, 1.19; 95% CI, 1.02-1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% CI, 1.00-1.29 and homozygote OR, 1.20; 95% CI, 1.02-1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01-1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk. DISCUSSION: In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies.

An IL-6 haplotype on human chromosome 7p21 confers risk for impaired renal function in type 2 diabetic patients.

The human chromosome 7p21 locus harbors a major gene that influences variation of glomerular filtration rate and development of end-stage renal disease. The pro-inflammatory IL-6 cytokine is a candidate gene since chronic inflammation has been implicated in diabetic nephropathy and this gene is located under the peak of linkage. To test this, single nucleotide polymorphism (SNP) and haplotype analyses were performed using a case-control study of 295 patients consisting of 138 with proteinuria, 157 with chronic renal failure and these were compared to 174 control patients with normal albumin excretion. Five tagging SNPs were selected for analysis based on linkage disequilibrium patterns and proximity to the functionally important -634G>C SNP in the IL-6 promoter. Initial analysis suggested that a -174G>C polymorphism may be associated with risk of chronic renal failure but this was not significant after Bonferroni correction. While haplotype analyses showed no association with proteinuria; a significant association with chronic renal failure was found. There was significantly more of the GGGAGC haplotype among patients with chronic renal failure compared to controls and this association remained significant even after correction for multiple testing. Our study has found a specific IL-6 haplotype conferring risk for impaired renal function in patients with type 2 diabetes.

CYP1A1 polymorphisms and risk of lung cancer in non-smoking Chinese women: influence of environmental tobacco smoke exposure and GSTM1/T1 genetic variation.

OBJECTIVE: We examined whether polymorphisms of CYP1A1, which plays a role in the metabolic activation of polycyclic aromatic hydrocarbons (PAHs), confer an increased risk of lung cancer in lifetime non-smoking Chinese women. METHODS: A total of 126 incident lung cancer cases, of which 87.7 were pathologically confirmed, and 162 age-matched hospital controls were included. CYP1A1 MspI and Ile(462)Val polymorphisms were genotyped and tested for association with this disease. RESULTS: An elevated risk of lung cancer was observed among individuals with the MspI CC (OR=1.7, 95 CI=0.9-3.3) and Ile(462)Val ValVal genotypes (OR=2.8, 95 CI=1.1-7.6). After stratifying by environmental tobacco smoke (ETS) exposure, the risk of lung cancer associated with both polymorphisms was higher among individuals with lower exposure to ETS, compared with those who reported at least weekly exposure. Individuals with the MspI CC genotype showed a two-fold higher risk of lung cancer if they were also null for either GSTM1 or T1 (OR=2.3, 95CI=1.0-5.0 and OR=2.7, 95 CI=1.1-6.9, respectively, compared to other genotype combinations combined). CONCLUSIONS: CYP1A1 is a susceptibility gene for lung cancer among non-smoking Asian women and this association can be influenced by ETS exposure and genetic variation at GST genes.

Avaliação do diagnóstico densitométrico de osteoporose/osteopenia conforme o sítio ósseo / Evaluation of densitometric diagnosis of osteoporosis/osteopenia according to the bone region

O objetivo deste estudo foi avaliar a freqüência de osteoporose de acordo com os sítios ósseos avaliados, utilizando um estudo transversal de base clínica. Foram avaliados 610 exames densitométricos em relação a freqüência de osteoporose/osteopenia e concordância do diagnóstico de acordo com o local avaliado. Apesar de alta correlação da DMO entre os sítios ósseos, a freqüência de osteoporose variou de acordo com o sítio avaliado. Osteoporose esteve presente em 14 e 18 por cento dos pacientes, quando considerado o colo do fêmur e fêmur total, e 42 e 30 por cento quando considerados o triângulo do Ward e coluna (p< 0,05). Um quarto das mulheres consideradas em risco aumentado de fratura pelo exame da coluna lombar foi classificado como normal pelo estudo do colo do fêmur; 16 por cento com risco aumentado pelo estudo do colo do fêmur foi classificado como normal no estudo da coluna. Este estudo demonstra que existe discordância nos resultados densitométricos de acordo com a área estudada, afetando a ocorrência de osteoporose. Para julgamento clínico de risco de fratura, a avaliação combinada de dois sítios ósseos é o procedimento mais adequado.