Papers by Lawrence Shimmin
Associations of Endothelial System Genes With Blood Pressure Changes and Hypertension Incidence: The GenSalt Study
American journal of hypertension, Jan 25, 2014
We used single-marker and novel gene-based methods to examine the associations of endothelial sys... more We used single-marker and novel gene-based methods to examine the associations of endothelial system genes with blood pressure (BP) changes and hypertension in a longitudinal family study. The Genetic Epidemiology Network of Salt Sensitivity follow-up study was conducted among 1,768 Chinese participants from 633 families. Nine BP measurements were obtained at baseline and at 2 follow-up visits using a random-zero sphygmomanometer. Mixed-effect models were used to assess the additive associations of 206 single-nucleotide polymorphisms (SNPs) in 15 endothelial system genes with longitudinal BP changes and hypertension incidence. Gene-based analyses were conducted using the truncated product method. The Bonferroni method was used to adjust for multiple testing in all analyses. Among those free from hypertension at baseline, 512 (32.1%) developed hypertension during the average 7.2 years of follow-up. In single-marker analyses, each copy of the minor alleles of correlated SELE markers r...
Associations of Renin-Angiotensin-Aldosterone System Genes With Blood Pressure Changes and Hypertension Incidence
American journal of hypertension, Jan 28, 2015
The renin-angiotensin-aldosterone system (RAAS) plays an important role in blood pressure (BP) re... more The renin-angiotensin-aldosterone system (RAAS) plays an important role in blood pressure (BP) regulation. The current study uses single-marker and gene-based analyses to examine the association between RAAS genes and longitudinal BP phenotypes in a Han Chinese population. A total of 1,768 participants from the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) follow-up study were included in the current study. Twenty-seven BP measurements were taken using random-zero sphygmomanometers at baseline and 2 follow-up visits. Mixed-effect models were used to assess the additive associations of 106 single-nucleotide polymorphisms (SNPs) in 10 RAAS genes with longitudinal BP changes and hypertension incidence. Gene-based analyses were conducted using the truncated product method. Attempts were made to replicate significant findings among Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). False discovery rate procedures were used to adjust for multiple testing....
Genome-wide linkage and regional association study of blood pressure response to the cold pressor test in Han Chinese: the genetic epidemiology network of salt sensitivity study
Circulation. Cardiovascular genetics, 2014
Blood pressure (BP) response to cold pressor test (CPT) is associated with increased risk of card... more Blood pressure (BP) response to cold pressor test (CPT) is associated with increased risk of cardiovascular disease. We performed a genome-wide linkage scan and regional association analysis to identify genetic determinants of BP response to CPT. A total of 1961 Chinese participants completed the CPT. Multipoint quantitative trait linkage analysis was performed, followed by single-marker and gene-based analyses of variants in promising linkage regions (logarithm of odds ≥2). A suggestive linkage signal was identified for systolic BP response to CPT at 20p13 to 20p12.3, with a maximum multipoint logarithm of odds score of 2.37. On the basis of regional association analysis with 1351 single nucleotide polymorphisms in the linkage region, we found that marker rs2326373 at 20p13 was significantly associated with mean arterial pressure responses to CPT (P=8.8×10(-6)) after false discovery rate adjustment for multiple comparisons. A similar trend was also observed for systolic BP response...
PLoS ONE, 2014
Background: Serum and glucocorticoid regulated kinase (SGK) plays a critical role in the regulati... more Background: Serum and glucocorticoid regulated kinase (SGK) plays a critical role in the regulation of renal sodium transport. We examined the association between SGK genes and salt sensitivity of blood pressure (BP) using single-marker and gene-based association analysis.
PLoS ONE, 2014
Levels of omega-6 (n-6) and omega-3 (n-3), long chain polyunsaturated fatty acids (LcPUFAs) such ... more Levels of omega-6 (n-6) and omega-3 (n-3), long chain polyunsaturated fatty acids (LcPUFAs) such as arachidonic acid (AA; 20:4, n-6), eicosapentaenoic acid (EPA; 20:5, n-3) and docosahexaenoic acid (DHA; 22:6, n-3) impact a wide range of biological activities, including immune signaling, inflammation, and brain development and function. Two desaturase steps (D6, encoded by FADS2 and D5, encoded by FADS1) are rate limiting in the conversion of dietary essential 18 carbon PUFAs (18C-PUFAs) such as LA (18:2, n-6) to AA and a-linolenic acid (ALA, 18:3, n-3) to EPA and DHA. GWAS and candidate gene studies have consistently identified genetic variants within FADS1 and FADS2 as determinants of desaturase efficiencies and levels of LcPUFAs in circulating, cellular and breast milk lipids. Importantly, these same variants are documented determinants of important cardiovascular disease risk factors (total, LDL, and HDL cholesterol, triglycerides, CRP and proinflammatory eicosanoids). FADS1 and FADS2 lie head-to-head (59 to 59) in a cluster configuration on chromosome 11 (11q12.2). There is considerable linkage disequilibrium (LD) in this region, where multiple SNPs display association with LcPUFA levels. For instance, rs174537, located ,15 kb downstream of FADS1, is associated with both FADS1 desaturase activity and with circulating AA levels (p-value for AA levels = 5.95610 246 ) in humans. To determine if DNA methylation variation impacts FADS activities, we performed genome-wide allele-specific methylation (ASM) with rs174537 in 144 human liver samples. This approach identified highly significant ASM with CpG sites between FADS1 and FADS2 in a putative enhancer signature region, leading to the hypothesis that the phenotypic associations of rs174537 are likely due to methylation differences. In support of this hypothesis, methylation levels of the most significant probe were strongly associated with FADS1 and, to a lesser degree, FADS2 activities. Citation: Howard TD, Mathias RA, Seeds MC, Herrington DM, Hixson JE, et al. (2014) DNA Methylation in an Enhancer Region of the FADS Cluster Is Associated with FADS Activity in Human Liver. PLoS ONE 9(5): e97510.
Proceedings of the National Academy of Sciences, 1994
In humans and rodents the male-to-female ratio of mutation rate (alpha m) has been suggested to b... more In humans and rodents the male-to-female ratio of mutation rate (alpha m) has been suggested to be extremely large, so that the process of nucleotide substitution is almost completely male-driven. However, our sequence data from the last intron of the X chromosome-linked (Zfx) and Y chromosome-linked (Zfy) zinc finger protein genes suggest that alpha m is only approximately 2 in rodents with a 95% confidence interval from 1 to 3. Moreover, from published data on oogenesis and spermatogenesis we estimate the male-to-female ratio of the number of germ cell divisions per generation to be approximately 2 in rodents, confirming our estimate of alpha m and suggesting that errors in DNA replication are the primary source of mutation. As the estimated alpha m for rodents is only one-third of our previous estimate of approximately 6 for higher primates, there appear to be generation-time effects--i.e., alpha m decreases with decreasing generation time.
PLoS ONE, 2014
Chronic kidney disease (CKD) can be a consequence of diabetes, hypertension, immunologic disorder... more Chronic kidney disease (CKD) can be a consequence of diabetes, hypertension, immunologic disorders, and other exposures, as well as genetic factors that are still largely unknown. Glomerular filtration rate (GFR), which is widely used to measure kidney function, has a heritability ranging from 25% to 75%, but only 1.5% of this heritability is explained by genetic loci that have been identified to date. In this study we tested for associations between GFR and 234 SNPs in 26 genes from pathways of blood pressure regulation in 3,025 rural Chinese participants of the ''Genetic Epidemiology Network of Salt Sensitivity'' (GenSalt) study. We estimated GFR (eGFR) using baseline serum creatinine measurements obtained prior to dietary intervention. We identified significant associations between eGFR and 12 SNPs in 6 genes (ACE, ADD1, AGT, GRK4, HSD11B1, and SCNN1G). The cumulative effect of the protective alleles was an increase in mean eGFR of 4 mL/min per 1.73 m 2 , while the cumulative effect of the risk alleles was a decrease in mean eGFR of 3 mL/min per 1.73 m 2 . In addition, we identified a significant interaction between SNPs in CYP11B1 and ADRB2. We have identified common variants in genes from pathways that regulate blood pressure and influence kidney function as measured by eGFR, providing new insights into the genetic determinants of kidney function. Complex genetic effects on kidney function likely involve interactions among genes as we observed for CYP11B1 and ADRB2.
Variation in the Maternal Corticotrophin Releasing Hormone-Binding Protein (CRH-BP) Gene and Birth Weight in Blacks, Hispanics and Whites
PLoS ONE, 2012
Given the unique role of the corticotrophin-releasing hormone (CRH) system in human fetal develop... more Given the unique role of the corticotrophin-releasing hormone (CRH) system in human fetal development, the aim of our study was to estimate the association of birth weight with DNA sequence variation in three maternal genes involved in regulating CRH production, bioavailability and action: CRH, CRH-Binding Protein (CRH-BP), and CRH type 1 receptor (CRH-R1), respectively, in three racial groups (African-Americans, Hispanics, and non-Hispanic Whites). Our study was carried out on a population-based sample of 575 mother-child dyads. We resequenced the three genes in mouse-human hybrid somatic cell lines and selected SNPs for genotyping. A significant association was observed in each race between birth weight and maternal CRH-BP SNP genotypes. Estimates of linkage disequilibrium and haplotypes established three common haplotypes marked by the rs1053989 SNP in all three races. This SNP predicted significant birth weight variation after adjustment for gestational age, maternal BMI, parity, and smoking. African American and Hispanic mothers carrying the A allele had infants whose birth weight was on average 254 and 302 grams, respectively, less than infants having C/C mothers. Non-Hispanic White mothers homozygous for the A allele had infants who were on average 148 grams less than those infants having A/C and C/C mothers. The magnitudes of the estimates of the birth weight effects are comparable to the combined effects of multiple SNPs reported in a recent meta-analysis of 6 GWAS studies and is quantitatively larger than that associated with maternal cigarette smoking. This effect was persistent across subpopulations that vary with respect to ancestry and environment.
PLoS ONE, 2012
Background: Recent genome-wide association studies (GWAS) have identified common variants in the ... more Background: Recent genome-wide association studies (GWAS) have identified common variants in the UMOD region associated with kidney function and disease in the general population. To identify novel rare variants as well as common variants that may account for this GWAS signal, the exons and 4 kb upstream region of UMOD were sequenced.
Molecular Biology and Evolution, 2003
The two suborders of bats, Megachiroptera (megabats) and Microchiroptera (microbats), utilize dif... more The two suborders of bats, Megachiroptera (megabats) and Microchiroptera (microbats), utilize different sensory modalities for perceiving their environment.
Preterm birth is associated with mitochondrial DNA variation
Mitochondrion, 2013
Corticotropin releasing hormone (CRH) gene variation: Comprehensive resequencing for variant and molecular haplotype discovery in monosomic hybrid cell lines
DNA Sequence, 2007
Candidate gene association studies have met with mixed success due to many reasons including inco... more Candidate gene association studies have met with mixed success due to many reasons including incomplete surveys of genetic variation and differences in patterns of genetic variation among study populations. We present the results of comprehensive variant discovery for the corticotropin releasing hormone gene (CRH on chromosome 8) encoding a neuropeptide that is central to many physiologic pathways. Mouse-human hybrid cell lines were constructed that are monosomic for human chromosome 8 for resequencing of separated CRH alleles to identify variants and directly determine their chromosomal phase for three major ethnic groups including African Americans (AA), Mexican Americans (MA) and European Americans (EA). We also resequenced diploid individuals to evaluate single nucleotide polymorphism (SNP) discovery in the limited numbers of monosomic hybrid cell lines. Our results show that CRH variation is very different in AA, yielding larger numbers of variants and haplotypes compared to MA and EA. Analysis of LD structure found three haplotype blocks in AA and two blocks in EA. Comparisons between AA and EA groups yielded extremely high measures of genetic differentiation (Wright's F(ST)>0.6), likely reflecting disruptive selection in CRH evolution. Network analysis showed that AA have retained an ancestral CRH haplotype, while the most common EA haplotype is derived from a single recombination event.
Microbiology, 1984
Seven temperature-sensitive penicillin-tolerant mutants of Escherichia coli strain LD5 (thi lysA ... more Seven temperature-sensitive penicillin-tolerant mutants of Escherichia coli strain LD5 (thi lysA dapD) were isolated and characterized. Treatment with p-lactams caused lysis of the mutants at 30 "C. Although growth of the mutants at 42 "C was inhibited by 8-lactams, no lysis occurred. The mutants were also slightly tolerant to D-cycloserine at 42 "C but lysed readily when deprived of diaminopimelate or when treated with moenomycin. The minimum inhibitory concentrations of various antibiotics were the same for the mutants and their parent. The mutations conferring penicillin tolerance were phenotypically suppressed in the presence of a variety of compounds which may act as chaotropic or antichaotropic agents. No defects in penicillin-binding proteins and peptidoglycan hydrolases were detected. Temperature-resistant revertants of the mutants were no longer tolerant to penicillin-induced autolysis at 42 "C. The mutations in five isolates were localized to the 56 to 61 min region of the E. colilinkage map and to the 44 to 5 1 min region in the case of two other isolates. t Present address :
Journal of Molecular Evolution, 1989
Offprint requests to: P.P. Dennis the function of L10e-L12e complex in translation. From these se... more Offprint requests to: P.P. Dennis the function of L10e-L12e complex in translation. From these sequence comparisons a model depicting the evolutionary progression of the L10e and L12e genes and proteins from the primordial state to the contemporary archaebacterial, eucaryotic, and eubacterial states is presented.
Potential problems in estimating the male-to-female mutation rate ratio from DNA sequence data
Journal of Molecular Evolution, 1993
It is commonly believed that the rate of mutation is much higher in males than in females because... more It is commonly believed that the rate of mutation is much higher in males than in females because the number of germ-cell divisions per generation is much larger in males than in females. However, the precise magnitude of the male-to-female mutation rate ratio (alpha m) remains unknown. Recently there have been efforts to estimate alpha m by using DNA sequence data from different species. We have studied the potential problems in such an approach. We found that the rate of synonymous substitution varies about fivefold among X-linked genes, as large as the variation among autosomal genes. This large variation makes the assumption of selective neutrality of synonymous changes dubious, so one should be cautious in using the synonymous rates in X-linked and autosomal genes to estimate alpha m. A similar difficulty was also observed in using nonhomologous intron sequences to estimate alpha m. Contrary to the expectation that X-linked sequences should evolve more slowly than autosomal sequences, the Alu repeat in the last intron of the X-linked zinc finger gene has evolved faster than the four autosomal Alu repeats used in this study. It appears that the best way to estimate alpha m is to use homologous sequences. However, such sequences may be involved in gene conversion events. In fact, we found evidence that the Y-linked and X-linked zinc finger genes have been involved in multiple conversion events during primate evolution. Thus, the possibility of gene conversion should be considered when using homologous sequences to estimate alpha m.
Sequences and Evolution of Human and Squirrel Monkey Blue Opsin Genes
Journal of Molecular Evolution, 1997
The sequences of the entire blue opsin gene in the squirrel monkey (Saimiri boliviensis) and the ... more The sequences of the entire blue opsin gene in the squirrel monkey (Saimiri boliviensis) and the five introns of the human blue opsin gene were obtained. Intron 3 of these genes contains an Alu sequence and intron 4 contains a partial mer13 sequence. A comparison of the squirrel monkey opsin sequence with published mammalian opsin sequences shows that features believed to be functionally critical are all conserved. However, the blue opsin has evolved twice as fast as rhodopsin and is only as conservative as the beta globin, which has evolved at the average rate of mammalian proteins. Interestingly, the interhelical loops are, on average, actually more conservative than the transmembrane alpha helical regions. The introns of the blue opsin gene have evolved at the average rate of introns in primate genes.
Journal of Molecular Evolution, 1997
We sequenced three argininosuccinatesynthetase-processed pseudogenes (⌿AS-A1, ⌿AS-A3, ⌿AS-3) and ... more We sequenced three argininosuccinatesynthetase-processed pseudogenes (⌿AS-A1, ⌿AS-A3, ⌿AS-3) and their noncoding flanking sequences in human, orangutan, baboon, and colobus. Our data showed that these pseudogenes were incorporated into the genome of the Old World monkeys after the divergence of the Old World and New World monkey lineages. These pseudogene flanking regions show variable mutation rates and patterns. The variation in the G/C to A/T mutation rate (u) can account for the unequal GC contents at equilibrium: 34.9, 36.9, and 41.7% in the pseudogene ⌿AS-A1, ⌿AS-A3, and ⌿AS-3 flanking regions, respectively. The A/T to G/C mutation rate (v) seems stable and the u/v ratios equal 1.9, 1.7, and 1.4 in the flanking regions of ⌿AS-A1, ⌿AS-A3, and ⌿AS-3, respectively. These ''regional'' variations of the mutation rate affect the evolution of the pseudogenes, too. The ratio u/v being greater than 1.0 in each case, the overall mutation rate in the GC-rich pseudogenes is, as expected, higher than in their GC-poor flanking regions. Moreover, a ''sequence effect'' has been found. In the three cases examined u and v are higher (at least 20%) in the pseudogene than in its flanking region-i.e., the pseudogene appears as mutation ''hot'' spots embedded in ''cold'' regions. This observation could be partly linked to the fact that the pseudogene flanking regions are longstanding unconstrained DNA sequences, whereas the pseudogenes were relieved of selection on their coding functions only around 30-40 million years ago. We suspect that relatively more mutable sites maintained unchanged during the evolution of the argininosuccinate gene are able to change in the pseudogenes, such sites being eliminated or rare in the flanking regions which have been void of strong selective constraints over a much longer period. Our results shed light on (1) the multiplicity of factors that tune the spontaneous mutation rate and (2) the impact of the genomic position of a sequence on its evolution.
Journal of Hypertension, 2010
Objective-Although beneficial effects of potassium intake on blood pressure (BP) are well establi... more Objective-Although beneficial effects of potassium intake on blood pressure (BP) are well established, little is known about genetic factors that underlie interindividual variability in BP response to dietary potassium. In a previous study, we reported the first evidence for significant heritabilities for BP response in a dietary intervention study in rural Chinese. In this report, we extend our genetic studies to examine associations with polymorphisms in genes in vascular endothelial pathways.
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Papers by Lawrence Shimmin