The effects of biological sex and cardiovascular disease on COVID-19 mortality.

Cardiovascular disease (CVD) is a common comorbidity observed in patients with coronavirus disease 2019 (COVID-19), which is associated with increased severity and mortality. However, the effects of biological sex on CVD-associated mortality in patients with COVID-19 are poorly established, particularly among Hispanic/Latin Americans. We examined the association of preexisting CVD with COVID-19 mortality in hospitalized Latin American men and women. This multicenter study included Mexican patients hospitalized with a positive diagnosis of COVID-19. The main outcome was in-hospital mortality. Multivariable regression analyses were used to calculate the adjusted odds ratio with 95% confidence interval for mortality in women and men. Of 81,400 patients with a positive diagnosis for SARS-CoV-2 infection, 28,929 (35.54%) hospitalized patients were evaluated. Of these, 35.41% (10,243) were women. In-hospital death was higher in men than in women. In relation to CVD between the sexes, women had a higher incidence of CVD than men (4.69 vs. 3.93%, P = 0.0023). The adjusted logistic regression analyses showed that CVD was significantly associated with COVID-19 mortality in women but not men. We then stratified by sex according to age <52 and ≥52 yr old. Similar significant association was also found in prespecified analysis in women ≥52 yr old but not in men of similar age. We conclude that CVD's effect on mortality among patients hospitalized with COVID-19 is dependent on biological sex and age in this Latin American cohort. These results suggest that therapeutic strategies for Latin American women with CVD and COVID-19 should include particular attention to their cardiovascular health.NEW & NOTEWORTHY CVD's effect on COVID-19 mortality is dependent on biological sex and age. CVD in women but not men with COVID-19 is associated with significantly unfavorable outcomes.

Genetic variation at the coronary artery disease risk locus GUCY1A3 modifies cardiovascular disease prevention effects of aspirin.

AIMS: Efficacy of aspirin in primary prevention of cardiovascular disease (CVD) may be influenced by a common allele in guanylate cyclase GUCY1A3, which has been shown to modify platelet function and increase CVD risk. METHODS AND RESULTS: We investigated whether homozygotes of the GUCY1A3 rs7692387 risk (G) allele benefited from aspirin in two long-term, randomized placebo-controlled trials of aspirin in primary CVD prevention: the Women's Genome Health Study (WGHS, N = 23 294) and a myocardial infarction (MI, N = 550) and stroke (N = 382) case-control set from the Physician's Health Study (PHS, N = 22 071). Bleeding risk was evaluated in the WGHS. In the placebo group of the WGHS, the GUCY1A3 risk (G) allele was confirmed to increase CVD risk [hazard ratio 1.38; 95% confidence interval (CI) 1.08-1.78; P = 0.01]. Random-effects meta-analysis of the WGHS and PHS revealed that aspirin reduced CVD events among risk allele homozygotes [G/G: odds ratio (OR) 0.79; 95% CI 0.65-0.97; P = 0.03] but increased CVD events among non-risk allele carriers (e.g. G/A: OR 1.39; 95% CI 1.03-1.87; P = 0.03) thus implying an interaction between genotype stratum and aspirin intake (Pinteraction = 0.01). Bleeding associated with aspirin increased in all genotype groups, with higher risks in heterozygotes. CONCLUSION: In two randomized placebo-controlled trials in the setting of primary prevention, aspirin reduced the incidence of CVD events in individuals homozygous for the GUCY1A3 risk (G) allele, whereas heterozygote individuals had more events when taking aspirin.

Gene Variation of Endoplasmic Reticulum Aminopeptidases 1 and 2, and Risk of Blood Pressure Progression and Incident Hypertension among 17,255 Initially Healthy Women.

Recent studies have demonstrated the importance of endoplasmic reticulum aminopeptidase (ERAP) in blood pressure (BP) homeostasis. To date, no large prospective, genetic-epidemiological data are available on genetic variation within ERAP and hypertension risk. The association of 45 genetic variants of ERAP1 and ERAP2 was investigated in 17,255 Caucasian female participants from the Women's Genome Health Study. All subjects were free of hypertension at baseline. During an 18-year follow-up period, 10,216 incident hypertensive cases were identified. Multivariable linear, logistic, and Cox regression analyses were performed to assess the relationship of genotypes with baseline BP levels, BP progression at 48 months, and incident hypertension assuming an additive genetic model. Linear regression analyses showed associations of four tSNPs (ERAP1: rs27524; ERAP2: rs3733904, rs4869315, and rs2549782; all p < 0.05) with baseline systolic BP levels. Three tSNPs (ERAP1: rs27851, rs27429, and rs34736, all p < 0.05) were associated with baseline diastolic BP levels. Multivariable logistic regression analysis showed that ERAP1 rs27772 was associated with BP progression at 48 months (p = 0.0366). Multivariable Cox regression analysis showed an association of three tSNPs (ERAP1: rs469783 and rs10050860; ERAP2: rs2927615; all p < 0.05) with risk of incident hypertension. Analyses of dbGaP for genotype-phenotype association and GTEx Portal for gene expression quantitative trait loci revealed five tSNPs with differential association of BP and nine tSNPs with lower ERAP1 and ERAP2 mRNA expression levels, respectively. The present study suggests that ERAP1 and ERAP2 gene variation may be useful for risk assessment of BP progression and the development of hypertension.

A Prospective Study Investigating Prediagnostic Leukocyte Telomere Length and Risk of Developing Rheumatoid Arthritis in Women.

OBJECTIVE: To prospectively examine the association between leukocyte telomere length (LTL) and subsequent rheumatoid arthritis (RA) development in women. METHODS: Using a case-control design nested within the prospective Nurses' Health Study (NHS), NHS II (NHSII), and Women's Health Study (WHS), each validated case of RA with a prediagnostic blood sample was matched to 3 controls by cohort, age, menopausal status, postmenopausal hormone therapy, and blood collection covariates. We measured telomere length in genomic DNA extracted from stored buffy coat samples using quantitative PCR. We used unconditional logistic regression to determine OR and 95% CI, and random-effects metaanalysis to combine study results. RESULTS: In total, we analyzed 296 incident RA cases and 827 matched controls. Mean age of diagnosis among women who developed RA was 60.5 in NHS/NHSII and 61.3 in WHS. Metaanalysis demonstrated that longer prediagnostic LTL was associated with increased RA risk when women in the longest versus shortest LTL tertile were compared (OR 1.51, 95% CI 1.03-2.23, Pheterogeneity = 0.27). However, statistically significant between-study heterogeneity was observed for the intermediate tertile category (Pheterogeneity = 0.008). We did not observe heterogeneity by menopausal status, inflammatory cytokine levels, age at diagnosis, age at blood collection, body mass index, seropositivity, or HLA-DRß1 shared epitope status. CONCLUSION: Our results do not support an involvement for short LTL preceding RA development.

Gene variations of ROCKs and risk of ischaemic stroke: the Women's Genome Health Study.

Recent animal and human studies have demonstrated the importance of the ROCK (RhoA/Rho-associated kinase) pathway in IsST (ischaemic stroke). Whether the genetic variation within ROCK-associated genes modulates the risk of IsST remains elusive. The association between 66 tSNPs [tagging SNPs (single nucleotide polymorphisms)] of three ROCK-associated genes [ROCK1, ROCK2 and ARHGEF10 (Rho guanine-nucleotide-exchange factor 10)] and the incidence of IsST was investigated in 23294 Caucasian female participants of the prospective WGHS (Women's Genome Health Study). All were free of known cancer and cardiovascular disease at baseline. During a 15-year follow-up period, 323 participants developed their first ever IsST. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and risk of IsST assuming an additive genetic model. Haplotype-block analysis was also performed. A total of ten tSNPs were associated with the risk of IsST (three in ARHGEF10 and seven in ROCK1; P<0.050). Further investigation using the haplotype-block analysis revealed a similar significant association of pre-specified haplotypes of ROCK1 with the risk of IsST (P=0.005). If corroborated in other large prospective studies, the findings of the present study suggest that genetic variation within the ROCK-associated pathway gene loci examined, and in particular ROCK1 gene variation, may influence the risk of IsST.

Strain-specific variations in cation content and transport in mouse erythrocytes.

Studies of ion transport pathophysiology in hematological disorders and tests of possible new therapeutic agents for these disorders have been carried out in various mouse models because of close functional similarities between mouse and human red cells. We have explored strain-specific differences in erythrocyte membrane physiology in 10 inbred mouse strains by determining erythrocyte contents of Na(+), K(+), and Mg(2+), and erythrocyte transport of ions via the ouabain-sensitive Na-K pump, the amiloride-sensitive Na-H exchanger (NHE1), the volume and chloride-dependent K-Cl cotransporter (KCC), and the charybdotoxin-sensitive Gardos channel (KCNN4). Our data reveal substantial strain-specific and sex-specific differences in both ion content and trans-membrane ion transport in mouse erythrocytes. These differences demonstrate the feasibility of identifying specific quantitative trait loci for erythroid ion transport and content in genetically standardized inbred mouse strains.

Genetic variation of fifteen folate metabolic pathway associated gene loci and the risk of incident head and neck carcinoma: the Women's Genome Health Study.

OBJECTIVE: Recent studies have demonstrated the importance of folate metabolic pathway (FMP) in the pathogenesis of head and neck carcinoma (HNC). Whether the genetic variation within the FMP associated genes modulates HNC remains elusive. To date, prospective, epidemiological data on the relationship of FMP gene variation with the risk of HNC are sparse. METHODS: The association between 203 tag-SNPs (tSNPs) of 15 FMP associated genes (CBS, BHMT, DHFR, FOLR1, FOLR2, FOLR3, MTHFR, MTR, MTRR, MTHFD1, RFC1, SHMT1, SLC19A1, TCN2, and TYMS) and incident HNC was investigated in 23,294 Caucasian female participants of the prospective Women's Genome Health Study. All were free of known cancer at baseline. During a 15-year follow-up period, 55 participants developed a first ever HNC. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and HNC risk assuming an additive genetic model. Haplotype-block analysis was also performed. RESULTS: A total of 11 tSNPs within DHFR, MTHFR, RFC1, and TYMS were associated with HNC risk (all p-uncorrected <0.050). Further investigation using the haplotype-block analysis revealed an association of several prespecified haplotypes of RFC1 with HNC risk (all p-uncorrected <0.050). CONCLUSION: If corroborated in other large prospective studies, the present findings suggest that genetic variation within the folate metabolic pathway gene loci examined, in particular, the replication factor C-1 (RFC1) gene variation may influence HNC risk.

Genetic variants of 11 telomere-pathway gene loci and the risk of incident type 2 diabetes mellitus: the Women's Genome Health Study.

OBJECTIVE: Leukocyte telomere length shortening has recently been associated with type 2 diabetes mellitus (T2D). Whether this observation was modulated by genetic variation within the telomere-pathway genes remains elusive. To date, no prospective epidemiological data on the relationship of telomere-pathway gene variation with T2D are available. METHODS: The association between 150 tagging-SNPs (tSNPs) of 11 telomere-pathway genes (TERC, UCP1, TERT, POT1, TNKS, TERF1, TNKS2, TEP1, ACD, TERF2 and TERF2IP) and incident T2D was investigated in 22,715 Caucasian female participants of the prospective Women's Genome Health Study. All were free of known cardiovascular disease, cancer and diabetes at baseline. During a 13-year follow-up period, 1445 participants developed an incident T2D. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and T2D risk assuming an additive genetic model. Haplotype block analysis was also performed. RESULTS: A total of eleven tSNPs within TERF1, TNKS, TEP1, ACD, and TERF2 were associated with T2D risk (all p-uncorrected <0.050). Further investigation using the haplotype-block analysis again revealed an association of several prespecified haplotypes of TERF1, and TEP1 with T2D risk (all p-uncorrected <0.040). CONCLUSION: If corroborated in other prospective studies, the present findings suggest that genetic variation within the telomere-pathway gene loci examined may be useful predictor for T2D risk assessment.

Genome-wide association study reveals three susceptibility loci for common migraine in the general population.

Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.

Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.

BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

Islet amyloid polypeptide gene variation (IAPP) and the risk of incident type 2 diabetes mellitus: the Women's Genome Health Study.

BACKGROUND: Islet amyloid polypeptide (IAPP) gene variation has recently been implicated in type 2 diabetes mellitus (T2D). However, to date, no prospective epidemiological data are available. METHODS: The association between 10 IAPP tag-single nucleotide polymorphisms (tSNPs) and incident T2D was investigated in 22,715 Caucasian participants of the prospective Women's Genome Health Study. All were free of known cardiovascular disease, cancer, and diabetes at baseline. During a 13-year follow-up period, 1445 participants developed an incident T2D. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and T2D risk. Haplotype-based analysis was also performed. RESULTS: No evidence for an association of any of the tSNPs tested or haplotypes thereof with T2D risk. CONCLUSIONS: If corroborated in other large, prospective studies, the present findings further suggest that the IAPP gene locus may not be useful predictor for T2D risk assessment.

Genetic variants in eleven telomere-associated genes and the risk of incident cardio/cerebrovascular disease: The Women's Genome Health Study.

BACKGROUND: Candidate genes associated with telomere length maintenance, an important molecular marker for biological aging, represent potential risk predictors for cardiovascular disease (CVD). To date, no prospective data are available. METHODS: The associations between 154 tag-single nucleotide polymorphisms (tSNPs) of 11 telomere-associated candidate genes (TERT, POT1, TNKS, TERF1, TNKS2, UCP2, TEP1, ACD, TERF2, TERF2IP, and TERC) were investigated in 23,294 Caucasian participants of the Women's Genome Health Study. All were free of known CVD and cancer at baseline. The primary outcome measure was a composite CVD end point (incident ischemic stroke, myocardial infarction (MI), or death due to ischemic CVD); other measures were incident MI and ischemic stroke. During follow-up, 1178 total incident CVD, 315 incident MI cases, and 323 incident ischemic stroke events were identified. Multivariable Cox regression analysis and a haplotype-based approach were performed to investigate the relationship between genotypes/haplotypes and CVD risk, assuming an additive model. RESULTS: In a marker-by-marker analysis, 7 (TEP1, TNKS, and ACD), 11 (TEP1, ACD, and TERT), and 24 (TEP1, TNKS, TERT, TERF2IP, TNKS2, and UCP2) SNPs were associated-at the level of p < 0.05-with the total CVD, MI, and ischemic stroke risk, respectively. Further analysis using a haplotype-based approach showed similar findings. Although none remained significant after the correction of multiple testing, the false discovery rate analysis revealed 28% of the nominally significant SNPs with true associations in relation to ischemic stroke risk. CONCLUSIONS: The present large prospective study encourages further investigation of the biological role of telomere-associated pathway genes in the pathogenesis and early assessment of vascular events.

Mitochondrial uncoupling protein gene cluster variation (UCP2-UCP3) and the risk of incident type 2 diabetes mellitus: the Women's Genome Health Study.

OBJECTIVE: Uncoupling protein 2, mitochondrial, (UCP2) gene variation has recently been implicated in type 2 diabetes mellitus (T2DM). To date, no prospective epidemiological data are available. METHODS: The association between 14 UCP (UCP2-UCP3) gene cluster tagging-SNPs and incident T2DM was investigated in 22,715 Caucasian participants of the prospective Women's Genome Health Study. All were free of known cardiovascular disease and diabetes at baseline. During a 13-year follow-up period, 1445 participants developed an incident T2DM. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and T2DM risk assuming an additive model. Stratified analysis by smoking status, and haplotype analysis were also performed. RESULTS: No evidence for an association of any of the tagging-SNPs tested with T2DM risk. Further investigation using stratified analysis, and haplotype-based approach showed similar null findings. CONCLUSION: The present investigation suggests that the UCP gene cluster variation may not be useful predictor for T2DM risk assessment.

Gene variation of the transient receptor potential cation channel, subfamily M, members 6 (TRPM6) and 7 (TRPM7), and type 2 diabetes mellitus: a case-control study.

Transient receptor potential cation channel, subfamily M, members 6 (TRPM6) and 7 (TRPM7), have been implicated in inflammatory disorders including diabetes, a major source of morbidity and mortality in developing and Western society. We hypothesized that gene variation of TRPM6 and TRPM7 may play a role in type 2 diabetes mellitus (T2DM) Using a case-control population sample of the Boston metropolitan area (all whites, 455 controls and 467 cases), we assessed the relationship of 29 TRPM6 and 11 TRPM7 tag-single nucleotide polymorphisms (SNPs) with (1) several diabetes-related intermediate phenotypes (fasting insulin levels, fasting glucose levels, hemoglobin A1c, and homeostatic model assessment) and (2) the presence of T2DM. All SNPs examined were in Hardy-Weinberg equilibrium. Overall, genotype distributions were similar between cases and controls. Linear regression analysis, adjusted for potential risk factors/confounders, showed no evidence of an association of any SNPs tested with the aforementioned diabetes-related intermediate phenotypes after correcting for multiple testing. Marker-by-marker multivariable logistic regression analysis showed no evidence of an association of any SNPs tested with the presence of T2DM after correcting for multiple testing. Continued investigation using an entropy-blocker-defined haplotype-based approach showed similar null findings. If corroboration occurs in future large prospective investigations, then the present investigation further suggests that TRPM6 and TRPM7 gene variation may not be useful predictors for T2DM risk assessment.

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Gene variation of the transient receptor potential cation channel, subfamily M, member 2 (TRPM2) and type 2 diabetes mellitus: A case-control study.

BACKGROUND: Disordered cellular calcium regulation has been implicated in the pathophysiology of diabetes through mechanisms that remain unresolved. The non-selective calcium channel, transient receptor potential cation channel, subfamily M, member 2 (TRPM2), has been recently reported to play a role in insulin secretion by pancreatic beta-cells. We hypothesized that gene variation of TRPM2 may play a role in the pathophysiology of type 2 diabetes mellitus (T2DM). METHODS: Using a case-control study from a community-based population sample of the Boston metropolitan area (all whites: 455 controls and 467 cases), we assessed the relationship of 9 TRPM2 tag-SNPs with (i) diabetes-related intermediate phenotypes and (ii) the presence of T2DM. RESULT: All SNPs examined were in Hardy-Weinberg equilibrium. Overall allele, genotype, and haplotype distributions were similar between cases and controls. Three TRPM2 variants (rs2838553, rs2838554 and rs4818917) were associated with homeostasis model assessment of beta-cell function (HOMA-%B), but not with HOMA-insulin resistance (HOMA-IR), fasting glucose levels nor hemoglobin A1c levels. Marker-by-marker logistic regression analysis, adjusted for potential risk factors, showed no evidence for an association of any of the tag-SNPs tested with T2DM. Further investigation using an entropy blocker-defined haplotype-based approach showed similar null findings. CONCLUSIONS: The present investigation found no evidence for an association of the variants tested with T2DM, although HOMA-%B was negatively associated with three TRPM2 variants (rs2838553, rs2838554 and rs4818917). More importantly, our present findings require replication/confirmation in future large-scale, prospective investigations.

Relative leukocyte telomere length and risk of incident ischemic stroke in men: a prospective, nested case-control approach.

Recent data have implicated telomere-length shortening as potential risk predictor for vascular diseases, including stroke. However, to date, prospective epidemiological data are scarce in relation to ischemic stroke risk. Using leukocyte DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the relationship of leukocyte telomere repeat copy number to single gene copy number (TSR), using a quantitative polymerase chain reaction protocol, amongst 259 white males who subsequently developed an ischemic stroke and amongst an equal number of age- and smoking-matched white males who remained free of reported vascular disease during follow up (controls). The observed TSRs were inversely correlated with age in the controls (p < 0.0001). However, the observed TSRs were similar between cases and controls (p = 0.92). In a multivariable adjusted analysis, no evidence was found for an association of the TSRs with ischemic stroke risk (odds ratio [OR] = 1.100, 95% confidence interval [CI], 0.506-2.392, p = 0.811). The present investigation has shown no evidence for an association of relative leukocyte telomere length with risk of incident ischemic stroke. More importantly, our present findings require replication/confirmation in future large, prospective studies.

Mean leukocyte telomere length shortening and type 2 diabetes mellitus: a case-control study.

Recent data have implicated leukocyte telomere length shortening as a potential risk predictor for type 2 diabetes mellitus (T2DM) and its associated phenotypes. However, to date, epidemiologic data are scarce. Using a case-control study from a community-based population sample of the Boston metropolitan area (all whites: 424 controls and 432 cases), we examined the relationship of mean leukocyte telomere repeat copy number to single gene copy number (TSR) and T2DM. Associations of log(e)-transformed TSR with age, race, sex, body mass index (BMI), current smoking status, fasting insulin levels, fasting glucose levels, and hemoglobin A1c (HbA1c) were examined by multivariable linear regression analysis. A logistic regression analysis was performed to evaluate the association of log(e)-transformed TSR with T2DM with or without adjustment for potential confounders. The log(e)-transformed TSR was significantly shorter in the white cases than the white controls (P=0.003). In a multivariable linear regression analysis, an inverse association of log(e)-transformed TSR with BMI was observed (P=0.04). Furthermore, in a multivariable logistic regression analysis, decreased log(e)-transformed TSR was significantly associated with T2DM (adjusted odds ratio=1.748; 95% confidence interval [CI]=1.015-3.012; P=0.044). In summary, the current investigation has shown an association of mean leukocyte telomere length shortening with T2DM in white subjects. If corroborated in other studies, our findings suggest the potential importance of telomere biology in T2DM.

Genetic variation in sex-steroid receptors and synthesizing enzymes and colorectal cancer risk in women.

OBJECTIVES: Several lines of evidence have suggested that female hormones may lower the risk for developing colorectal cancer. However, the mechanisms by which sex hormones affect colorectal cancer development remain unknown. We sought to determine whether the association may be under genetic control by evaluating genetic variation in estrogen receptors (ESR1 and ESR2), progesterone receptor (PGR), aromatase cytochrome 450 enzyme (CYP19A1), and 17 beta-hydroxysteroid dehydrogenase type 2 gene (HSD17B2). METHODS: We included 158 incident cases of colorectal cancer and 563 randomly chosen control subjects from 28,345 women in the Women's Health Study aged 45 or older who provided blood samples and had no history of cancer or cardiovascular disease at baseline in 1993. All cases and controls were Caucasians of European descent. A total of 63 tagging and putative functional SNPs in the 5 genes were included for analysis. Unconditional logistic regression was used to estimate odds ratio (ORs) and 95% confidence intervals (CIs). RESULTS: There was no association between variation in ESR1, ESR2, PGR, CYP19A1 and HSD17B2 and colorectal cancer risk after correction for multiple comparisons (p values after correction > or =0.25). There was also no association with any of the haplotypes examined (p > or = 0.15) and no evidence of joint effects of variants in the 5 genes (p > or = 0.51). CONCLUSION: Our data offer insufficient support for an association between variation in ESR1, ESR2, PGR, CYP19A1, and HSD17B2 and risk for developing colorectal cancer.

Mean leukocyte telomere length and risk of incident colorectal carcinoma in women: a prospective, nested case-control study.

BACKGROUND: To date, no prospective epidemiological data are available, particularly in women, on mean leukocyte telomere length as a risk predictor. METHODS: Using leukocyte DNA samples collected at baseline in a prospective cohort of over 28,000 initially healthy women, we examined the relationship between mean leukocyte telomere repeat copy number to single gene copy number (TSR) in 134 incident cases of colorectal carcinoma (CRC), and 357 matched controls; all were Caucasian. RESULTS: The observed log(e)-transformed TSRs were similar between cases and controls (p=0.79). Using an adjusted analysis, we found no evidence for an association of the log(e)-TSRs with CRC risk [adjusted odds ratio (OR)=0.943, 95% confidence interval (CI)=0.647-1.376, p=0.762]. Stratified analysis by median follow-up time, or postmenopausal status also showed similar null findings. CONCLUSIONS: In concordance with our previous findings in Caucasian men, the present study in Caucasian women found no evidence for an association of mean leukocyte telomere length with risk of incident CRC, further suggesting that leukocyte telomere length may not be a useful indicator for risk assessment.