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PubMed2004

Sequence variants and haplotype analysis of serotonin transporter gene and association with bipolar affective disorder in Taiwan.

OBJECTIVES: Serotonin transporter (SLC6A4) is responsible for serotonin re-uptake into presynaptic terminals, thus fine-tuning brain serotonergic neurotransmission. Current studies have found associations of SLC6A4 polymorphisms with several psychiatric traits including bipolar affective disorder (BPD) in various populations; however, studies with contradictory results were also reported. This study examined the role of SLC6A4 in etiology of BPD in a Taiwanese population. METHODS: Ten markers including two variable number tandem repeat and eight single nucleotide polymorphisms (SNPs) on the SLC6A4 gene were used to study the genetic association with 90 unrelated BPD, type I patients and 103 controls. RESULTS: Two SNPs were not informative in a Taiwanese population and the other eight polymorphic markers were analyzed by Fisher's exact test and haplotype analysis. No association was detected for any single SLC6A4 marker and BPD. Additional statistic analyses including other factors also showed lack of association between the SLC6A4 gene polymorphisms and BPD. Significant linkage disequilibrium was obtained among eight SLC6A4 markers and eight common haplotypes were constructed that can be found in 95% of the total subjects. The four commonest haplotypes in both patients and controls were identical. However, the fifth commonest haplotype differed in patients and controls and was significantly associated with a protection from BPD. CONCLUSIONS: This study suggested that a particular SLC6A4 haplotype harboring functional sequence variant could play a significant role in BPD etiology in Taiwan. However, due to its modest sample size, the conclusion is not final and should be confirmed in the future studies.

Bipolar Disorder↗

PubMedDate not supplied

Growth hormone and insulin-like growth factor I axis and growth of children with different sickle cell anemia haplotypes.

BACKGROUND: The purpose of this study was to examine the relationships between growth in children with sickle cell anemia and the different beta-globin haplotypes, as well as components of the insulin-like growth factor (IGF)/insulin-like growth factor binding protein (IGFBP) axis. PATIENTS AND METHODS: Growth parameters and plasma concentrations of growth hormone (GH), IGF-I, and IGFBP-3 were studied in 41 children with sickle cell anemia whose haplotypes were defined. RESULTS: Plasma concentrations of IGF-I (total, free, and free/total fraction) and IGFBP-3 were significantly reduced in all patients with sickle cell anemia compared with the healthy children. Patients with the CAR/CAR haplotype had significantly lower mean growth velocity compared with those with Ben/Ben. When the GH/IGF axis elements were compared in relation with the different haplotypes, total IGF-I levels in CAR/CAR patients were significantly lower compared with levels in patients with Ben/Ben. A positive correlation was found between hematocrit and total IGF-I and between fetal hemoglobin percentages and the z-scores for total IGF-I and IGFBP-3. There was a positive correlation between age, weight, height, bone age, and the various elements of the GH/IGF-I axis when all groups were considered, although the correlation was lost when the auxologic data were expressed as standard deviation score for age. Growth velocity and the z-score for growth velocity were not correlated with any element of the axis. CONCLUSIONS: The positive relationship between hematocrit and fetal hemoglobin percentages with total IGF-I, free/total IGF-I, and IGFBP-3 in patients with sickle cell anemia could show that the delayed growth of these patients may be linked to intrinsic factors of the disease, which also determine the low circulating concentrations of the various elements of the GH/IGF-I axis. It is reasonable to assume that decrease of total IGF-I concentrations in patients with CAR/CAR haplotype is secondary to the severity of the disease.

Adolescent↗

PubMed2003

Globin haplotypes of human T-cell lymphotropic virus type I-infected individuals in Salvador, Bahia, Brazil, suggest a post-Columbian African origin of this virus.

The city of Salvador, Bahia, Brazil, has sociodemographic characteristics similar to some African cities. Up to now, it has had the highest prevalence of human T-cell lymphotropic virus type I (HTLV-I) infection (1.74%) in the country. To investigate which strains of HTLV-I are circulating in Salvador, we studied isolates from 82 patients infected with HTLV-I: 19 from the general population, 21 from pregnant women, 16 from intravenous drug users, and 26 from patients and their family attending a neurologic clinic. Phylogenetic analysis from part of the LTR fragments showed that most of these isolates belonged to the Transcontinental subgroup of the Cosmopolitan subtype (HTLV-Ia). Only one sample from a pregnant woman was closely related to the Japanese subgroup, suggesting recent introduction of a Japanese HTLV-I lineage into Salvador. betaA-Globin haplotypes were examined in 34 infected individuals and found to be atypical, confirming the racial heterogeneity of this population. A total of 20 chromosomes were characterized as Central African Republic (CAR) haplotype (29.4%), 31 (45.6%) were characterized as Benin (BEN) haplotype, and 17 (25%) were characterized as Senegal (SEN) haplotype. Five patients' genotypes (14.7%) were CAR/CAR; 10 (29,4%), BEN/BEN; 9 (26.5%), CAR/BEN; 2 (5.9%), BEN/SEN; and 7 (20.6%), SEN/SEN. One patient's genotype (2.9%) was CAR/SEN. The betaA-globin haplotype distribution in Salvador is unusual compared with other Brazilian states. Our data support the hypothesis of multiple post-Columbian introductions of African HTLV-Ia strains in Salvador, Bahia, Brazil.

Brazil↗

PubMed2005

Common genetic polymorphisms in the 5'-flanking region of the SULT1A1 gene: haplotypes and their association with platelet enzymatic activity.

SULT1A1 is a phase II detoxification enzyme involved in the biotransformation of a wide variety of endogenous and exogenous phenolic compounds. Human platelet SULT1A1 enzymatic activity shows marked inter-individual variability and a common coding polymorphism, SULT1A1*1/*2, has been described that accounts for a proportion of this variability. We examined the 5'-flanking region of the SULT1A1 gene to determine if genetic variability in this portion of the gene influenced enzymatic activity. Direct sequencing revealed five common genetic polymorphisms (-624G>C, -396G>A, -358A>C, -341C>G and -294T>C) that were present at different allele frequencies in Caucasian, African-American and Chinese groups. Platelet SULT1A1 enzymatic activity was significantly correlated with individual promoter region polymorphisms and the associations were different between African-Americans and Caucasians. Haplotypes were constructed and platelet enzymatic activity according to haplotype was examined. The haplotypes were also significantly correlated with activity; haplotypes GAACT and GGACT (accounting for 13% and 5% of inter-individual variability in platelet activity, respectively) were important in Caucasians while haplotypes GAACC, GAACT and GGACC (accounting for 8%, 5% and 4% of variability) were significantly associated with activity in African-Americans. The coding region polymorphism, SULT1A1*1/*2 was in linkage disequilibrium with the promoter region polymorphisms and showed no effect on activity when examined in the context of the 5'-flanking region polymorphisms. These studies indicate that variation in the promoter region of the SULT1A1 gene exerts a significant influence on enzymatic activity.

5' Flanking Region↗

PubMed2005

Endothelial nitric oxide synthase gene haplotypes associated with circulating concentrations of nitric oxide products in healthy men.

OBJECTIVES: Controversy exists regarding the effects of polymorphisms in the endothelial nitric oxide synthase (eNOS) gene on nitrites/nitrates (NOx) plasma concentrations. In this study we compared the distribution of haplotypes involving three relevant eNOS polymorphisms (T-786C in the promoter region; b/a in intron 4, and Glu298Asp in exon 7) in healthy subjects with low and high circulating NOx levels. METHODS: We studied 154 healthy subjects (fasting, white males, who were non-smokers, 18-60 years of age, and not taking any medication). Genomic DNA was isolated from blood samples and genotypes were determined by PCR and restriction fragment length digestion. Circulating NOx was determined by chemiluminescence. RESULTS: Haplotype frequencies were compared in two groups of subjects: those with the 30 lowest NOx levels (group L) and those with the 30 highest NOx levels (group H). NOx levels in group L and H were 24.2+/-4.5 microM and 80.9+/-8.9 microM, respectively. Genotype frequencies for the three polymorphisms were not different when the two groups were compared (all P>0.05, chi-squared test). However, the haplotype including the alleles C (promoter), 4b (intron 4), and Glu (exon 7) was significantly more common in group L (16%) than in group H (4%) (P=0.0047). The frequencies of the remaining haplotypes were not different among group L and H. CONCLUSIONS: While eNOS genotypes are not significantly associated with changes in the circulating NOx concentrations, the specific eNOS haplotype that includes the 'C', '4b', and 'Glu' alleles is associated with lower circulating NOx concentrations.

Adolescent↗

PubMed2006

Haplotype analysis of endothelial nitric oxide synthase (NOS3) genetic variants and tardive dyskinesia in patients with schizophrenia.

OBJECTIVES: Several studies have indicated the involvement of nitric oxide (NO) in the pathogenesis of tardive dyskinesia (TD), an incapacitating adverse movement disorder associated with long-term antipsychotic treatment. In human brain, the NO could be generated by endothelial nitric oxide synthase (NOS3). In this study, we studied whether the genetic variants in human NOS3 gene is associated with TD in patients with schizophrenia. METHODS: Two hundred and eighty-two chronic inpatients with schizophrenia treated with typical antipsychotics were recruited in this study. The patients were further grouped by the presence of TD or not according to the Research and Diagnostic Criteria for TD. The genetic variants in the NOS3 gene investigated in this study were -786T > C in the promotor region, 27-bp variable number of tandem repeats (27-bp VNTR) in intron 4, and Glu298Asp in exon 7. The frequencies of genotypes, alleles and haplotypes of the three markers were compared between the TD (n = 153) and non-TD (n = 129) groups. RESULTS: There were no significant associations between the genotypes and alleles of the three markers and TD. However, in the haplotype-based case-control analysis, the frequency of haplotype T-4b-Glu was significantly higher in non-TD than in TD group (TD vs. non-TD = 72.7% vs. 81.0%, permutation P value = 0.021, OR = 0.648, 95% CI = 0.432-0.973). CONCLUSIONS: We found that the haplotype T-4b-Glu represents a protective haplotype against TD after long-term antipsychotic treatment. This finding suggests that human NOS3 gene may be involved in the pathogenesis of TD.

Adult↗

PubMed2006

A haplotype of the methylenetetrahydrofolate reductase gene predicts poor tumor response in rectal cancer patients receiving preoperative chemoradiation.

OBJECTIVE: The objective of the present study was to evaluate whether germline methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as well as polymorphisms in the thymidylate synthase gene promoter, namely the variable number tandem repeat polymorphism (TS VNTR) and the intrarepeat G to C single nucleotide polymorphism (TS SNP), are predictive markers of tumor regression in rectal cancer patients following preoperative chemoradiotherapy. BASIC METHODS: Blood samples from 125 patients with primary adenocarcinoma of the mid-low rectum who received 5-fluorouracil-based chemotherapy and external beam radiotherapy (median dose 48.4 Gy), 125 patients (women n=45, men n=80; median age 60 years, range 31-79 years) were genotyped. Response to preoperative treatment was evaluated employing the Tumor Regression Grade criteria. On the basis of the pathologic response, patients were classified as responders (TRG 1-2, n=48) and non-responders (TRG 3-5, n=74). Three patients were excluded because of insufficient data. MAIN RESULTS: Among the polymorphic variants examined, the MTHFR 677T-1298A haplotype was, upon univariate analysis, the only variable found associated with tumor regression (P=0.004). Moreover, at multivariate analysis, the MTHFR 677T-1298A haplotype was an independent predictor of tumor regression. Patients not carrying the MTHFR 677T-1298A haplotype (odds ratio 0.29, 95% confidence interval 0.13-0.64, P=0.002) displayed a higher response rate than patients with the MTHFR 677T-1298A haplotype. CONCLUSIONS: Unlike TS VNTR and SNP polymorphisms, MTHFR 677T-1298A haplotype in genomic DNA has the potential to be a predictive marker of tumor response in rectal cancer patients submitted to preoperative chemoradiotherapy.

Adenocarcinoma↗

PubMed2006

CFTR 5T variant has a low penetrance in females that is partially attributable to its haplotype.

PURPOSE: The study's purpose was to understand the molecular basis for different clinical phenotypes of the 5T variant, a tract of 5 thymidines in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which disrupts processing of CFTR mRNA and reduces synthesis from the corresponding CFTR alleles. METHOD: We analyzed the polymorphic TG dinucleotide repeat adjacent to the 5T variant in intron 8 and the codon 470 in exon 10. Patients selected for this study were positive for both the 5T variant and the major cystic fibrosis mutation, Delta F508. Almost all Delta F508 mutation alleles occur in a 10TG-9T-470M haplotype. Therefore, it is possible to determine the haplotype of the 5T variant in trans. RESULTS: Of the 74 samples analyzed, 41 (55%) were 11TG-5T-470M, 31 (42%) were 12TG-5T-470V, and 2 (3%) were 13TG-5T-470M. Of the 49 cases for which we had clinical information, 17.6% of females (6/34) and 66.7% of males (10/15) showed symptoms resembling atypical cystic fibrosis. The haplotype with the highest penetrance in females (42% or 5/12) and more than 80% (5/6) in males is 12TG-5T-470V. We also evaluated 12 males affected with congenital bilateral absence of vas deferens and positive for the 5T variant; 10 of 12 had the 12TG-5T-470V haplotype. CONCLUSION: Overall, the 5T variant has a milder clinical consequence than previously estimated in females. The clinical presentations of the 5T variant are associated with the 5T-12TG-470M haplotype.

Alleles↗

PubMed2006

A complex additive model of inheritance for Hirschsprung disease is supported by both RET mutations and predisposing RET haplotypes.

PURPOSE: The RET proto-oncogene is considered to be the major susceptibility gene involved in Hirschsprung disease. Traditional RET germline mutations account for a small subset of Hirschsprung disease patients, but several studies have shown that there is a specific haplotype of RET associated with the sporadic forms of Hirschsprung disease. We have investigated for RET germline mutations and analyzed the RET haplotypic distribution in carriers versus noncarriers of RET germline mutations. METHODS: We have screened the coding region of RET in 106 Spanish Hirschsprung disease patients using dHPLC technology. Statistical comparisons of the distribution of RET haplotypes between sporadic patients with and without a RET germline mutation were performed. RESULTS: Nine novel germline mutations and one previously described were identified. A significant over-transmission of the "Hirschsprung disease haplotype" was detected when comparing transmitted versus nontransmitted alleles in the group of Hirschsprung disease triads without mutation. However, no distortion of the transmission of alleles was found in the group of mutated families. CONCLUSIONS: These results would be concordant with a complex additive model of inheritance. The whole findings seem to suggest that low-penetrance mutations would be necessary but not sufficient and the additional presence of the "Hirschsprung disease haplotype" could contribute to the manifestation of the disease.

DNA Mutational Analysis↗

PubMed2003

Coagulation factor V G allele and HR2 haplotype: factor V activity, activated protein C resistance and risk of venous thrombosis.

Factor V Leiden is a well-known risk factor for venous thrombosis. The dual role of factor V as a coagulatory and anticoagulatory cofactor permits the assumption that further mutations in the factor V gene are of importance in the study of the risk of thrombosis. Relevant studies to date have given rise to a controversy over this risk for the HR2 haplotype. For the G allele, defined in our work group as a G at the nucleotide positions 2391, 2663, 2684 and 2863, there have been to date no other investigations of thrombotic risk. In a case-control study on 347 patients with deep venous thrombosis (DVT) and 282 controls, we investigated the association of the HR2 haplotype and the G allele with DVT. We found no association between HR2 haplotype and DVT [odds ratio (OR) 0.87; 95% confidence interval (CI) 0.58-1.30; P = 0.537]. The frequency of the G allele was, on the contrary, higher in the control group than among the patients (OR 0.68, 95% CI: 0.53 to 0.89; P = 0.005). The factor V activity of the HR2 carriers was lower than that of the wild type and G allele carriers. The HR2 haplotype exhibited a moderate influence on activated protein C response. This study presented no evidence of thrombotic risk for the HR2 haplotype alone. The results here permit the assumption of a protective effect of the G allele. The source of a possible protective influence of the G allele on thrombotic risk is at present unclear.

Activated Protein C Resistance↗

PubMed2006

Single nucleotide polymorphisms and haplotypes of protein C and protein S genes in the Thai population.

Protein C (PC) and protein S (PS) play key roles in an anticoagulant pathway in order to control the haemostatic system. We identified single nucleotide polymorphisms (SNPs) and/or haplotypes in the promotor and exons of the whole PC and PS genes and in the 3'-untranslated region of the PS gene in 55 Thai individuals. The PC gene revealed 10 haplotypes. One synonymous SNP at 2196 was found in the normal Thai population with a minor allele frequency of 4.90%. One homozygous mutation in exon 7, R147W, co-segregated with the synonymous SNP 2196 (homozygote) of the PC gene, resulting in decreased PC activity and antigenic levels. The PS gene revealed three haplotypes with two frequent dimorphisms in exon 15 and the 3'-untranslated region. The most frequent haplotype in the PS gene was H3 (wild type). There was no correlation between the haplotypes of PC and PS genes with functional and antigenic levels of PC and PS.

Adult↗

PubMed2005

Haplotypes of variants in the UDP-glucuronosyltransferase1A9 and 1A1 genes.

OBJECTIVES: Nine different functional UGT1A enzymes are generated from a single UGT1A gene by alternative splicing, with each enzyme having a unique exon 1. SN-38, the active metabolite of the anticancer agent irinotecan, is metabolized by both UGT1A1 and UGT1A9. We aim to characterize the UGT1A9-UGT1A1 haplotypes in Asians and Caucasians and gain insights on their functional consequences. METHODS: Asian and Caucasian individuals were genotyped for UGT1A1 and UGT1A9 variants. RESULTS: A higher frequency of the UGT1A9 -118T10 allele was observed in Asians compared to Caucasians, while the -275T>A and -2152C>T variants were relatively uncommon in Caucasians and not found in Asians. The strongest linkage disequilibrium (LD) was observed between the UGT1A1 -53 and -3156 and between the UGT1A9 -275 and -2152 loci. Lower LD was observed between the -118 UGT1A9 variant and the UGT1A1 variants. Fourteen UGT1A9-UGT1A1 haplotypes were found in Asians, seven of them found to be shared by both populations. Common UGT1A9-UGT1A1 diplotypes were defined, and a difference was observed across the SN-38 glucuronidation rates in Caucasian livers stratified by diplotypes. CONCLUSION: This study for the first time described common UGT1A9-UGT1A1 haplotypes, highlighting important ethnic differences between Asians and Caucasians. If the functional effect of these haplotypes can be confirmed, this haplotypic information would be applicable to the correct design of prospective clinical studies of irinotecan, as well as of other drugs primarily metabolized by both UGT1A1 and UGT1A9.

Asian People↗

PubMed2005

Inference and analysis of haplotypes from combined genotyping studies deposited in dbSNP.

In the attempt to understand human variation and the genetic basis of complex disease, a tremendous number of single nucleotide polymorphisms (SNPs) have been discovered and deposited into NCBI's dbSNP public database. More than 2.7 million SNPs in the database have genotype information. This data provides an invaluable resource for understanding the structure of human variation and the design of genetic association studies. The genotypes deposited to dbSNP are unphased, and thus, the haplotype information is unknown. We applied the phasing method HAP to obtain the haplotype information, block partitions, and tag SNPs for all publicly available genotype data and deposited this information into the dbSNP database. We also deposited the orthologous chimpanzee reference sequence for each predicted haplotype block computed using the UCSC BLASTZ alignments of human and chimpanzee. Using dbSNP, researchers can now easily perform analyses using multiple genotype data sets from the same genomic regions. Dense and sparse genotype data sets from the same region were combined to show that the number of common haplotypes is significantly underestimated in whole genome data sets, while the predicted haplotypes over the common SNPs are consistent between studies. To validate the accuracy of the predictions, we bench-marked HAP's running time and phasing accuracy against PHASE. Although HAP is slightly less accurate than PHASE, HAP is over 1000 times faster than PHASE, making it suitable for application to the entire set of genotypes in dbSNP.

Animals↗

PubMed2005

Strong correlation between meiotic crossovers and haplotype structure in a 2.5-Mb region on the long arm of chromosome 21.

Although the haplotype structure of the human genome has been studied in great detail, very little is known about the mechanisms underlying its formation. To investigate the role of meiotic recombination on haplotype block formation, single nucleotide polymorphisms were selected at a high density from a 2.5-Mb region of human chromosome 21. Direct analysis of meiotic recombination by high-throughput multiplex genotyping of 662 single sperm identifies 41 recombinants. The crossovers were nonrandomly distributed within 16 small areas. All, except one, of these crossovers fall in areas where the haplotype structure exhibits breakdown, displaying a strong statistically positive association between crossovers and haplotype block breaks. The data also indicate a particular clustered distribution of recombination hotspots within the region. This finding supports the hypothesis that meiotic recombination makes a primary contribution to haplotype block formation in the human genome.

Chromosome Mapping↗

PubMed2003

Haplotype structure, LD blocks, and uneven recombination within the LRP5 gene.

Patterns of linkage disequilibrium (LD) in the human genome are beginning to be characterized, with a paucity of haplotype diversity in "LD blocks," interspersed by apparent "hot spots" of recombination. Previously, we cloned and physically characterized the low-density lipoprotein-receptor-related protein 5 (LRP5) gene. Here, we have extensively analysed both LRP5 and its flanking three genes, spanning 269 kb, for single nucleotide polymorphisms (SNPs), and we present a comprehensive SNP map comprising 95 polymorphisms. Analysis revealed high levels of recombination across LRP5, including a hot-spot region from intron 1 to intron 7 of LRP5, where there are 109 recombinants/Mb (4882 meioses), in contrast to flanking regions of 14.6 recombinants/Mb. This region of high recombination could be delineated into three to four hot spots, one within a 601-bp interval. For LRP5, three haplotype blocks were identified, flanked by the hot spots. Each LD block comprised over 80% common haplotypes, concurring with a previous study of 14 genes that showed that common haplotypes account for at least 80% of all haplotypes. The identification of hot spots in between these LD blocks provides additional evidence that LD blocks are separated by areas of higher recombination.

3' Flanking Region↗

PubMed2003

Haplotype information and linkage disequilibrium mapping for single nucleotide polymorphisms.

Single nucleotide polymorphisms in the human genome have become an increasingly popular topic in that their analyses promise to be a key step toward personalized medicine. We investigate two related questions, how much the haplotype information contributes to linkage disequilibrium (LD) mapping and whether an in silico haplotype construction preceding the LD analysis can help. For disease gene mapping, using both simulated and real data sets on cystic fibrosis and the Alzheimer disease, we reached the following conclusions: (1) for simple Mendelian diseases, in which case a tractable full statistical model can be developed, the loss of haplotype information for either control or disease data do not have a great impact on LD fine mapping, and haplotype inference should be carried out jointly with LD mapping; (2) for complex diseases, inferring haplotype phases for individuals prior to LD mapping helps achieve a better accuracy. An improved version of the linkage disequilibrium mapping program, BLADE v2, is available at http://www.fas.harvard.edu/junliu/TechRept/03folder/bladev2.tgz.

Algorithms↗

PubMed2003

Structural and transcriptional analysis of the self-incompatibility locus of almond: identification of a pollen-expressed F-box gene with haplotype-specific polymorphism.

Gametophytic self-incompatibility in Rosaceae, Solanaceae, and Scrophulariaceae is controlled by the S locus, which consists of an S-RNase gene and an unidentified "pollen S" gene. An approximately 70-kb segment of the S locus of the rosaceous species almond, the S haplotype-specific region containing the S-RNase gene, was sequenced completely. This region was found to contain two pollen-expressed F-box genes that are likely candidates for pollen S genes. One of them, named SFB (S haplotype-specific F-box protein), was expressed specifically in pollen and showed a high level of S haplotype-specific sequence polymorphism, comparable to that of the S-RNases. The other is unlikely to determine the S specificity of pollen because it showed little allelic sequence polymorphism and was expressed also in pistil. Three other S haplotypes were cloned, and the pollen-expressed genes were physically mapped. In all four cases, SFBs were linked physically to the S-RNase genes and were located at the S haplotype-specific region, where recombination is believed to be suppressed, suggesting that the two genes are inherited as a unit. These features are consistent with the hypothesis that SFB is the pollen S gene. This hypothesis predicts the involvement of the ubiquitin/26S proteasome proteolytic pathway in the RNase-based gametophytic self-incompatibility system.

Amino Acid Sequence↗

PubMed2026

Mitochondrial Haplotype Shapes the Trajectory of Ovarian Aging in Genetically Heterogeneous Rats.

Ovarian aging leads to permanent reproductive senescence and systemic hormonal changes that predispose women to age-associated comorbidities. Despite these observations, the intrinsic mechanisms driving age-related ovarian decline are poorly defined. Mitochondrial DNA (mtDNA) mutations and instability are strongly associated with aging; however, it remains unknown if naturally occurring mitochondrial genetic variation influences the trajectory of ovarian aging. To address this, we compared two genetically heterogeneous rat cohorts (OKC-HETB and OKC-HETW) that differ in mitochondrial haplotype on a randomized but equivalently distributed nuclear background. The OKC-HETW haplotype was associated with accelerated loss of primordial follicles and pathological remodeling marked by fibrosis, macrophage infiltration, and multinucleated giant cells. These tissue-level pathologies were paralleled by mitochondrial dysfunction, characterized by decreased respiratory complex activity, ATP production, and mtDNA copy number. Mechanistically, we identified a haplotype-specific defect in mitochondrial genome maintenance. Although TFAM expression was normal, and total TFAM protein was elevated, OKC-HETW ovaries showed reduced mitochondrial TFAM abundance, TFAM-mtDNA binding, and TOMM20, suggesting that impaired TOMM20-mediated import is associated with compromised mitochondrial genomic stability. Longitudinal transcriptomic and proteomic analyses further indicate that mitochondrial haplotype influences the rate of ovarian aging, with OKC-HETW ovaries showing accelerated activation of inflammatory and fibrotic pathways alongside suppressed proteostasis and mitochondrial function. These defects corresponded to impairments in ovulation and a trend toward worsening oocyte quality. Collectively, our findings identify mitochondrial haplotype as a heritable modifier of ovarian aging rate that acts in concert with the nuclear genome, and a putative target for preserving ovarian function and female healthspan.

Animals↗