To determine the nature of the genetic component controlling liability to alcoholism, complex seg... more To determine the nature of the genetic component controlling liability to alcoholism, complex segregation analysis was performed on 35 multigenerational families each ascertained through a pair of male alcoholics. The results suggest that liability to alcoholism is, in part, controlled by a major effect with or without additional multifactorial effects. Mendelian transmission of this major effect was rejected, as was the hypothesis that the major effect is due to a single major locus. Absence of this major effect, leaving only multifactorial effects, was also rejected. Some sources for the non-Mendelian character of the major effect are suggested, such as a combination of two or more Mendelian loci, the presence of phenocopies, sex-dependent differences in the underlying liability model, or heterogeneity in the alcoholism phenotype. Evidence for and against each is discussed.
4494 The proportion of breast cancer in the general population attributable to germline mutations... more 4494 The proportion of breast cancer in the general population attributable to germline mutations in highly penetrant genes (e.g., BRCA1/2) is small because of the low frequency of these mutations. Common, but weakly penetrant, functional genetic polymorphisms are likely to account for most of the genetic risk for breast cancer in the general population. Current polygenic risk models assume, perhaps erroneously, that the effects of the component genes act independently. Potential gene-gene interactions among ten genes, with known or predicted functional consequences in development of breast carcinoma, were examined in a case-control study of more than 1000 Caucasian women with breast cancer and more than 2000 controls. Association of breast cancer risk with variation in single genes and two- and three- gene combinations was analyzed for two age groups: 53 years and under, and over 53 years. The OR for a genotype was calculated and compared to a null distribution of ORs generated for this genotype by randomizing (10,000 times in these analyses) the case-control status of the individuals in the sample to give an empirical estimate for the p-value for the observed OR. Re-sampling was performed to give an empirical estimate of the 95% confidence interval and a likely more stable estimate of the OR for the genotype, particularly for the less common genotypes. In these analyses the population of individuals was resampled 10,000 times with each repetition composed of 80% of the controls and 80% of the cases selected at random from the whole sample. Over 100 genotypes met stringent criteria for significance (α=1/10,000) with ORs ranging from 0.20 to 5.2. The majority of the significant ORs were two- and three-gene combinations. Comparing observed ORs to ORs predicted by an independent gene model showed that about 25% of the significant multigenic combinations differed markedly from the predicted value. Thus, combinations of genes interact to affect risk for breast cancer in a manner that is not predictable by combining the effects of the individual component genes. While independent genes are a valid starting point in a polygenic model, identifying and incorporating modification of risks associated with gene-gene interactions will improve accuracy of the model and should be taken into consideration when building polygenic models for breast cancer risk. In addition, further exploration of the biologic basis for these multigenic interactions might reveal etiologic or therapeutic insights into breast cancer and other cancers.
Objective Is polycystic ovary syndrome (PCOS) associated with activating autoantibodies (AAb) to ... more Objective Is polycystic ovary syndrome (PCOS) associated with activating autoantibodies (AAb) to the second extracellular loop (ECL2) of gonadotropin-releasing hormone receptor (GnRHR)? Design and Methods We retrospectively screened sera from 40 patients with PCOS and 14 normal controls (NCs) with regular menses using enzyme-linked immunosorbent assay (ELISA) for the presence of GnRHR-ECL2-AAb. We obtained similar data from 40 non-PCOS ovulatory but infertile patients as a control group (OIC) of interest. We analyzed GnRHR-ECL2-AAb activity in purified immunoglobulin (Ig)G using a cell-based GnRHR bioassay. Results The mean ELISA value in the PCOS group was markedly higher than the NC (P = .000036) and the OIC (P = .0028) groups. IgG from a sample of 5 PCOS subjects, in contrast to a sample of 5 OIC subjects, demonstrated a dose-dependent increase in GnRHR-stimulating activity qualitatively similar to the acute action of the natural ligand GnRH and the synthetic agonist leuprolide. ...
Objective A subset of parents of children with disorders/differences of sex development (DSD) inc... more Objective A subset of parents of children with disorders/differences of sex development (DSD) including ambiguous genitalia experience clinically elevated levels of anxious and depressive symptoms. Research indicates that uncertainty about their child’s DSD is associated with parent psychosocial distress; however, previous studies have been cross-sectional or correlational in nature. The current study is the first to examine the longitudinal trajectory of the relationship between caregiver-perceived uncertainty about their child’s DSD and caregiver anxious and depressive symptoms across the first 12 months following genital surgery in young children, or if surgery was not performed, the first 12 months following study entry. Methods One hundred and thirteen caregivers (Mage = 32.12; 57.5% mothers; 72.6% Caucasian) of children (N = 70; Mage = 9.81 months; 65.7% female) with DSD were recruited from 12 DSD specialty clinics in the United States. Caregivers completed psychosocial measur...
Background: Activating autoantibodies (AAb) are directed to the gonadotropin releasing hormone re... more Background: Activating autoantibodies (AAb) are directed to the gonadotropin releasing hormone receptor second extracellular loop (GnRHR-ECL2) and are pathogenic when induced in rats. We previously reported GnRHR-ECL2-AAb were elevated in sera from patients with PCOS (Rotterdam criteria) compared to ovulatory infertile controls (OIC). Methods:Human studies: ELISA detection of GnRHR Abs used a synthetic h-GnRHR-ECL2 28 mer peptide (LifeTein) as the target antigen. We assayed AAb activity in GnRHR transfected cells using a GeneBLAzer FRET assay (Invitrogen). ELISA AAb epitope locations on the ECL2 were identified on a minipin plate (pins 1-11 containing sequential 2 aa offsetting octapeptides, Mimotope, Inc) using sera from 30 PCOS subjects, 33 OIC and 18 normal controls (NC). Results:Human sera: An ELISA assay for GnRHR-ECL2-AAbs in the PCOS group was markedly higher than the NC group (P<0.0001) and the OIC subjects (P<0.003). The minipin data demonstrated one or more positive ...
The Journal of Clinical Endocrinology & Metabolism, 2019
ContextThe incidence of preeclampsia (PE) is increased in women with diabetes (∼20% vs ∼5% in the... more ContextThe incidence of preeclampsia (PE) is increased in women with diabetes (∼20% vs ∼5% in the general population), and first trimester lipoprotein profiles are predictive. Haptoglobin (Hp), a protein with functional genetic polymorphisms, has antioxidant, anti-inflammatory, and angiogenic effects. Among people with diabetes, the Hp 2-2 phenotype is associated with cardiorenal disease.ObjectiveTo investigate whether Hp phenotype is associated with PE in type 1 diabetes mellitus (T1DM) and/or modulates lipoprotein-associated risks.Design and SettingMulticenter prospective study of T1DM pregnancy.PatientsPregnant women with T1DM (normal albuminuria, normotensive at enrolment, n = 47) studied at three visits, all preceding PE onset: 12.3 ± 1.9, 21.8 ± 1.5, and 31.5 ± 1.6 weeks’ gestation (mean ± SD).Main Outcome MeasuresHp phenotype and lipoprotein profiles in women with (n = 23) vs without (n = 24) subsequent PE.ResultsHp phenotype did not predict PE, but lipoprotein associations w...
OBJECTIVE Increased oxidative stress and immune dysfunction are implicated in preeclampsia (PE) a... more OBJECTIVE Increased oxidative stress and immune dysfunction are implicated in preeclampsia (PE) and may contribute to the two- to fourfold increase in PE prevalence among women with type 1 diabetes. Prospective measures of fat-soluble vitamins in diabetic pregnancy are therefore of interest. RESEARCH DESIGN AND METHODS Maternal serum carotenoids (α- and β-carotene, lycopene, and lutein) and vitamins A, D, and E (α- and γ-tocopherols) were measured at first (12.2 ± 1.9 weeks [mean ± SD], visit 1), second (21.6 ± 1.5 weeks, visit 2), and third (31.5 ± 1.7 weeks, visit 3) trimesters of pregnancy in 23 women with type 1 diabetes who subsequently developed PE (DM PE+) and 24 women with type 1 diabetes, matched for age, diabetes duration, HbA1c, and parity, who did not develop PE (DM PE−). Data were analyzed without and with adjustment for baseline differences in BMI, HDL cholesterol, and prandial status. RESULTS In unadjusted analysis, in DM PE+ versus DM PE−, α-carotene and β-carotene w...
BJOG: An International Journal of Obstetrics & Gynaecology, 2012
Please cite this paper as: Yu Y, Hanssen K, Kalyanaraman V, Chirindel A, Jenkins A, Nankervis A, ... more Please cite this paper as: Yu Y, Hanssen K, Kalyanaraman V, Chirindel A, Jenkins A, Nankervis A, Torjesen P, Scholz H, Henriksen T, Lorentzen B, Garg S, Menard M, Hammad S, Scardo J, Stanley J, Wu M, Basu A, Aston C, Lyons T. Reduced soluble receptor for advanced glycation end‐products (sRAGE) scavenger capacity precedes pre‐eclampsia in Type 1 diabetes. BJOG 2012;119:1512–1520.Objective Increased advanced glycation end‐products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre‐eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four‐fold increase in PE.Design Prospective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset.Setting Antenatal clinics.Popu...
Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, 1994
A large number of rare mutations in the low-density lipoprotein (LDL) receptor gene cause the aut... more A large number of rare mutations in the low-density lipoprotein (LDL) receptor gene cause the autosomal dominant disorder familial hypercholesterolemia. In addition, a number of common DNA polymorphisms have been identified in the LDL receptor gene, but their significance in affecting plasma cholesterol levels in the general population has not been studied widely. We investigated the role of two common DNA polymorphisms, Ava II (exon 13) and Nco I (exon 18), at the LDL receptor locus in affecting plasma lipid profiles in normolipidemic Hispanics (n = 385) and non-Hispanic whites (NHWs; n = 543) from the San Luis Valley, Colorado. While the distribution of the Nco I polymorphism was comparable between Hispanics and NHWs, the allele frequencies at the Ava II restriction site differed significantly between the two ethnic groups (P < .001). The Ava II and Nco I polymorphisms were in linkage disequilibrium (P < .05) in both Hispanics and NHWs. Both polymorphisms revealed a gender-s...
Background Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk fact... more Background Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. Methods We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. Results One rare LoF variant (rs138326449) with a 37% reduc...
To determine the nature of the genetic component controlling liability to alcoholism, complex seg... more To determine the nature of the genetic component controlling liability to alcoholism, complex segregation analysis was performed on 35 multigenerational families each ascertained through a pair of male alcoholics. The results suggest that liability to alcoholism is, in part, controlled by a major effect with or without additional multifactorial effects. Mendelian transmission of this major effect was rejected, as was the hypothesis that the major effect is due to a single major locus. Absence of this major effect, leaving only multifactorial effects, was also rejected. Some sources for the non-Mendelian character of the major effect are suggested, such as a combination of two or more Mendelian loci, the presence of phenocopies, sex-dependent differences in the underlying liability model, or heterogeneity in the alcoholism phenotype. Evidence for and against each is discussed.
4494 The proportion of breast cancer in the general population attributable to germline mutations... more 4494 The proportion of breast cancer in the general population attributable to germline mutations in highly penetrant genes (e.g., BRCA1/2) is small because of the low frequency of these mutations. Common, but weakly penetrant, functional genetic polymorphisms are likely to account for most of the genetic risk for breast cancer in the general population. Current polygenic risk models assume, perhaps erroneously, that the effects of the component genes act independently. Potential gene-gene interactions among ten genes, with known or predicted functional consequences in development of breast carcinoma, were examined in a case-control study of more than 1000 Caucasian women with breast cancer and more than 2000 controls. Association of breast cancer risk with variation in single genes and two- and three- gene combinations was analyzed for two age groups: 53 years and under, and over 53 years. The OR for a genotype was calculated and compared to a null distribution of ORs generated for this genotype by randomizing (10,000 times in these analyses) the case-control status of the individuals in the sample to give an empirical estimate for the p-value for the observed OR. Re-sampling was performed to give an empirical estimate of the 95% confidence interval and a likely more stable estimate of the OR for the genotype, particularly for the less common genotypes. In these analyses the population of individuals was resampled 10,000 times with each repetition composed of 80% of the controls and 80% of the cases selected at random from the whole sample. Over 100 genotypes met stringent criteria for significance (α=1/10,000) with ORs ranging from 0.20 to 5.2. The majority of the significant ORs were two- and three-gene combinations. Comparing observed ORs to ORs predicted by an independent gene model showed that about 25% of the significant multigenic combinations differed markedly from the predicted value. Thus, combinations of genes interact to affect risk for breast cancer in a manner that is not predictable by combining the effects of the individual component genes. While independent genes are a valid starting point in a polygenic model, identifying and incorporating modification of risks associated with gene-gene interactions will improve accuracy of the model and should be taken into consideration when building polygenic models for breast cancer risk. In addition, further exploration of the biologic basis for these multigenic interactions might reveal etiologic or therapeutic insights into breast cancer and other cancers.
Objective Is polycystic ovary syndrome (PCOS) associated with activating autoantibodies (AAb) to ... more Objective Is polycystic ovary syndrome (PCOS) associated with activating autoantibodies (AAb) to the second extracellular loop (ECL2) of gonadotropin-releasing hormone receptor (GnRHR)? Design and Methods We retrospectively screened sera from 40 patients with PCOS and 14 normal controls (NCs) with regular menses using enzyme-linked immunosorbent assay (ELISA) for the presence of GnRHR-ECL2-AAb. We obtained similar data from 40 non-PCOS ovulatory but infertile patients as a control group (OIC) of interest. We analyzed GnRHR-ECL2-AAb activity in purified immunoglobulin (Ig)G using a cell-based GnRHR bioassay. Results The mean ELISA value in the PCOS group was markedly higher than the NC (P = .000036) and the OIC (P = .0028) groups. IgG from a sample of 5 PCOS subjects, in contrast to a sample of 5 OIC subjects, demonstrated a dose-dependent increase in GnRHR-stimulating activity qualitatively similar to the acute action of the natural ligand GnRH and the synthetic agonist leuprolide. ...
Objective A subset of parents of children with disorders/differences of sex development (DSD) inc... more Objective A subset of parents of children with disorders/differences of sex development (DSD) including ambiguous genitalia experience clinically elevated levels of anxious and depressive symptoms. Research indicates that uncertainty about their child’s DSD is associated with parent psychosocial distress; however, previous studies have been cross-sectional or correlational in nature. The current study is the first to examine the longitudinal trajectory of the relationship between caregiver-perceived uncertainty about their child’s DSD and caregiver anxious and depressive symptoms across the first 12 months following genital surgery in young children, or if surgery was not performed, the first 12 months following study entry. Methods One hundred and thirteen caregivers (Mage = 32.12; 57.5% mothers; 72.6% Caucasian) of children (N = 70; Mage = 9.81 months; 65.7% female) with DSD were recruited from 12 DSD specialty clinics in the United States. Caregivers completed psychosocial measur...
Background: Activating autoantibodies (AAb) are directed to the gonadotropin releasing hormone re... more Background: Activating autoantibodies (AAb) are directed to the gonadotropin releasing hormone receptor second extracellular loop (GnRHR-ECL2) and are pathogenic when induced in rats. We previously reported GnRHR-ECL2-AAb were elevated in sera from patients with PCOS (Rotterdam criteria) compared to ovulatory infertile controls (OIC). Methods:Human studies: ELISA detection of GnRHR Abs used a synthetic h-GnRHR-ECL2 28 mer peptide (LifeTein) as the target antigen. We assayed AAb activity in GnRHR transfected cells using a GeneBLAzer FRET assay (Invitrogen). ELISA AAb epitope locations on the ECL2 were identified on a minipin plate (pins 1-11 containing sequential 2 aa offsetting octapeptides, Mimotope, Inc) using sera from 30 PCOS subjects, 33 OIC and 18 normal controls (NC). Results:Human sera: An ELISA assay for GnRHR-ECL2-AAbs in the PCOS group was markedly higher than the NC group (P<0.0001) and the OIC subjects (P<0.003). The minipin data demonstrated one or more positive ...
The Journal of Clinical Endocrinology & Metabolism, 2019
ContextThe incidence of preeclampsia (PE) is increased in women with diabetes (∼20% vs ∼5% in the... more ContextThe incidence of preeclampsia (PE) is increased in women with diabetes (∼20% vs ∼5% in the general population), and first trimester lipoprotein profiles are predictive. Haptoglobin (Hp), a protein with functional genetic polymorphisms, has antioxidant, anti-inflammatory, and angiogenic effects. Among people with diabetes, the Hp 2-2 phenotype is associated with cardiorenal disease.ObjectiveTo investigate whether Hp phenotype is associated with PE in type 1 diabetes mellitus (T1DM) and/or modulates lipoprotein-associated risks.Design and SettingMulticenter prospective study of T1DM pregnancy.PatientsPregnant women with T1DM (normal albuminuria, normotensive at enrolment, n = 47) studied at three visits, all preceding PE onset: 12.3 ± 1.9, 21.8 ± 1.5, and 31.5 ± 1.6 weeks’ gestation (mean ± SD).Main Outcome MeasuresHp phenotype and lipoprotein profiles in women with (n = 23) vs without (n = 24) subsequent PE.ResultsHp phenotype did not predict PE, but lipoprotein associations w...
OBJECTIVE Increased oxidative stress and immune dysfunction are implicated in preeclampsia (PE) a... more OBJECTIVE Increased oxidative stress and immune dysfunction are implicated in preeclampsia (PE) and may contribute to the two- to fourfold increase in PE prevalence among women with type 1 diabetes. Prospective measures of fat-soluble vitamins in diabetic pregnancy are therefore of interest. RESEARCH DESIGN AND METHODS Maternal serum carotenoids (α- and β-carotene, lycopene, and lutein) and vitamins A, D, and E (α- and γ-tocopherols) were measured at first (12.2 ± 1.9 weeks [mean ± SD], visit 1), second (21.6 ± 1.5 weeks, visit 2), and third (31.5 ± 1.7 weeks, visit 3) trimesters of pregnancy in 23 women with type 1 diabetes who subsequently developed PE (DM PE+) and 24 women with type 1 diabetes, matched for age, diabetes duration, HbA1c, and parity, who did not develop PE (DM PE−). Data were analyzed without and with adjustment for baseline differences in BMI, HDL cholesterol, and prandial status. RESULTS In unadjusted analysis, in DM PE+ versus DM PE−, α-carotene and β-carotene w...
BJOG: An International Journal of Obstetrics & Gynaecology, 2012
Please cite this paper as: Yu Y, Hanssen K, Kalyanaraman V, Chirindel A, Jenkins A, Nankervis A, ... more Please cite this paper as: Yu Y, Hanssen K, Kalyanaraman V, Chirindel A, Jenkins A, Nankervis A, Torjesen P, Scholz H, Henriksen T, Lorentzen B, Garg S, Menard M, Hammad S, Scardo J, Stanley J, Wu M, Basu A, Aston C, Lyons T. Reduced soluble receptor for advanced glycation end‐products (sRAGE) scavenger capacity precedes pre‐eclampsia in Type 1 diabetes. BJOG 2012;119:1512–1520.Objective Increased advanced glycation end‐products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre‐eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four‐fold increase in PE.Design Prospective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset.Setting Antenatal clinics.Popu...
Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, 1994
A large number of rare mutations in the low-density lipoprotein (LDL) receptor gene cause the aut... more A large number of rare mutations in the low-density lipoprotein (LDL) receptor gene cause the autosomal dominant disorder familial hypercholesterolemia. In addition, a number of common DNA polymorphisms have been identified in the LDL receptor gene, but their significance in affecting plasma cholesterol levels in the general population has not been studied widely. We investigated the role of two common DNA polymorphisms, Ava II (exon 13) and Nco I (exon 18), at the LDL receptor locus in affecting plasma lipid profiles in normolipidemic Hispanics (n = 385) and non-Hispanic whites (NHWs; n = 543) from the San Luis Valley, Colorado. While the distribution of the Nco I polymorphism was comparable between Hispanics and NHWs, the allele frequencies at the Ava II restriction site differed significantly between the two ethnic groups (P < .001). The Ava II and Nco I polymorphisms were in linkage disequilibrium (P < .05) in both Hispanics and NHWs. Both polymorphisms revealed a gender-s...
Background Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk fact... more Background Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. Methods We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. Results One rare LoF variant (rs138326449) with a 37% reduc...
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