Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome

Abstract

SummaryBackgroundA sexual dimorphism exists in the incidence and prevalence of coronary artery disease—men are more commonly affected than are age-matched women. We explored the role of the Y chromosome in coronary artery disease in the context of this sexual inequity.MethodsWe genotyped 11 markers of the male-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts: the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study (WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was tracked back into one of 13 ancient lineages defined as haplogroups. We then examined associations between common Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHS and prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects on monocyte and macrophage transcriptome in British men from the Cardiogenics Study.FindingsOf nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary artery disease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20–2·54, p=0·004), WOSCOPS (1·45, 1·08–1·95, p=0·012), and joint analysis of both populations (1·56, 1·24–1·97, p=0·0002). The association between haplogroup I and increased risk of coronary artery disease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis of macrophage transcriptome in the Cardiogenics Study revealed that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity, and that some of them have a strong relevance to atherosclerosis.InterpretationThe human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation.FundingBritish Heart Foundation; UK National Institute for Health Research; LEW Carty Charitable Fund; National Health and Medical Research Council of Australia; European Union 6th Framework Programme; Wellcome Trust.

Y chromosome haplogroup D2a1 is significantly associated with high levels of luteinizing hormone in Japanese men

“…Haplogroup D2a1 belongs to haplogroup D. It is suggested that as males belonging to haplogroup D2a1 possess significantly higher LH levels than other haplogroups males, haplogroup D males bear a higher prostate cancer risk than other haplogroup males in the Japanese population. Previously, it had been reported that the Y chromosome haplogroup I was associated with 50% of coronary artery disease compared with the other haplogroup, in 1444 British Heart Foundation Family Heart Study and 1534 West of Scotland Coronary Prevention Study (Charchar et al, 2012). However, haplogroup I did not exhibit an association with levels of five sex steroids (testosterone, androstenedione, 5-dehydroepiandrosterone sulfate, estradiol, and estrone) in the 1157 Young Men Cardiovascular Association Study recruited in Silesia, Poland (Bloomer et al, 2014).…”

“…In addition, there have been reports indicating that there exist associations between Y chromosome haplogroups and male infertility (Kuroki et al, 1999;Krausz et al, 2001;Lu et al, 2007;Yang et al, 2008;Puzuka et al, 2011;Ran et al, 2013;Sato et al, 2013), semen parameters (Sato et al, 2014), and prostate cancer (Ewis et al, 2006;Lindstr€ om et al, 2008;Wang et al, 2012) in some populations, including the Japanese. The Y chromosome haplogroup is also associated with several phenotypes other than male characteristics, including cardiovascular risk (Hiura et al, 2008;Bloomer et al, 2013;Kostrzewa et al, 2013), coronary artery disease (Charchar et al, 2012), lipids (Charchar et al, 2004;Russo et al, 2008), and blood pressure (Charchar et al, 2002).…”

A calibrated human Y-chromosomal phylogeny based on resequencing

“…These conclusions have been reached after genotyping small numbers of known markers, or limited resequencing. Despite the valuable insights that have been obtained, there have been other areas of Y-chromosomal study where uncertainty or debate have persisted for decades, such as the understanding of the causal mutations underlying Y-linked spermatogenic failure (Tyler-Smith and Krausz 2009), the role of Y-chromosomal variation in phenotypes such as coronary artery disease (Charchar et al 2012), or the origins of European male lineages. In the last case, opinions have included a Paleolithic origin for the major lineage (Semino et al 2000), a Neolithic origin for the equivalent lineage (Balaresque et al 2010), and the view that reliable age estimates for this lineage are currently impossible (Busby et al 2011).…”

Retrieving Y chromosomal haplogroup trees using GWAS data

“…4 The updated tree provides an important foundation for studies of evolutionary anthropology, 5 genealogical reconstruction, 6 molecular forensics, 7 and medical genetics. 8 Current commercial DNA chips (microarrays) for massive genomewide association studies (GWAS) 9 are designed to contain many Y-SNPs. In 2007, Underhill and Kivisild retrieved 295 Y-SNPs from customized Perlegen arrays in a previous study 10 and used them to reconstruct the Y chromosome tree for 33 males.…”