Neurological symptoms and natural course of xeroderma pigmentosum

We have prospectively followed 16 Finnish xeroderma pigmentosum (XP) patients for up to 23 years. Seven patients were assigned by complementation analysis to the group XP-A, two patients to the XP-C group and one patient to the XP-G group. Six of the seven XP-A patients had the identical mutation (Arg228Ter) and the seventh patient had a different mutation (G283A). Further patients were assigned to complementation groups on the basis of their consanguinity to an XP patient with a known complementation group. The first sign of the disease in all the cases was severe sunburn with minimal sun exposure in early infancy. However, at the time the diagnosis was made in only two cases. The XP-A patients developed neurological and cognitive dysfunction in childhood. The neurological disease advanced in an orderly fashion through its successive stages, finally affecting the whole nervous system and leading to death before the age of 40 years. Dermatological and ocular damage of the XP-A patients tended to be limited. The two XP-C patients were neurologically and cognitively intact despite mild brain atrophy as seen by neuroimaging. The XP-G patients had sensorineural hearing loss, laryngeal dystonia and peripheral neuropathy. The XP-C patients had severe skin and ocular malignancies that first presented at pre-school age. They also showed immunosuppression in cell-mediated immunity. Neurological disease appears to be associated with the complementation group and the failure of fibroblasts to recover RNA synthesis following UV irradiation, but not necessarily to the severity of the dermatological symptoms, the hypersensitivity of fibroblasts to UVB killing or the susceptibility of keratinocytes to UVB-induced apoptosis

Iän tuomat iho-ongelmat

Tiivistelmä Ikääntyminen aiheuttaa rakenteellisia ja toiminnallisia muutoksia eri elimiin, myös ihoon. Monien ihosairauksien esiintyvyys kasvaa ikääntyessä (1). Nykyiselläänkin ihotaudit aiheuttavat kuolemaan johtamattomista sairauksista neljänneksi eniten tautitaakkaa sairauden vuoksi menetettyinä toimintakykyisinä elinvuosina mitaten (disability adjusted life years, DALY) (2). Väestön vanhetessa tämä taakka lisääntyy. Väestötason tutkimuksia ikäihmisten ihosairauksien yleisyydestä on niukasti. Noin 4 000 potilaan sairaalarekisteristä tehdyn tutkimuksen mukaan yleisimpiä olivat ekseemat, ihoinfektiot, kutina ja ihosyövät (3). Myös hyvänlaatuisten ihokasvainten, kuten seborrooisten keratoosien (rasvaluomien), kirsikkaluomien ja lentigojen, määrä lisääntyy iän karttuessa (4). Tässä katsauksessa käsittelemme tavanomaisia iän tuomia iho-ongelmia. Krooniset alaraajahaavat sekä lääkeaineihottumat on jätetty katsauksesta pois.Abstract Skin problems in the elderly Aging causes many structural changes in the skin and affects its functionality. Therefore, many skin diseases are more common in the older population. Measured on the DALY index (disability adjusted life years), skin diseases are the fourth most common disease group causing disability. The most common skin diseases in older adults are eczemas, skin infections, pruritus and malignant diseases. Skin aging can be divided into chronological aging and photoaging. Smoking, air pollutants and exposure to ultraviolet radiation are the most significant factors in skin aging. Dry skin is the most common cause of pruritus in the elderly but sometimes systemic diseases can be the cause and they must be excluded. Asteatotic eczema is a common skin disease found particularly in the elderly population. It is caused by structural changes in the skin and excessive washing with soap. It can be prevented by applying moisturizing cream daily. Sometimes corticosteroid creams or ultraviolet light treatment are needed. Seborrhoeic dermatitis is most common in older people and possibly caused by a weakened immune system. As many as half of the elderly population are estimated to have dermatitis in skinfolds. The term MASD (moistureassociated skin damage) is used when moisture and chemicals break the skin’s protective barrier. It is treated with washing and careful drying of the skinfolds. Sometimes local antimycotics are needed because of secondary infection. Skin infections caused by bacteria, viruses and fungi are common in the elderly because of their weakened immune system. Malignant and premalignant lesions are becoming more common due to aging of the population. The prevalence of actinic keratosis varies according to age, skin phototype and residence. Some actinic keratoses evolve to Bowen’s disease and eventually to squamous cell carcinoma. Diagnosis is confirmed by biopsy. Actinic keratoses with mild dysplasia can be treated topically. Otherwise treatment by a dermatologist is needed. Patients’ ability to function must be considered when treating older patients

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Abstract Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Genetic architecture of human plasma lipidome and its link to cardiovascular disease

Abstract Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD

Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata

Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.Peer reviewe

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele